Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.Cl.CO>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2nc(Cl)nc3c2SCC3)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1nc2c(c(NC3CCCNC3)n1)SCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
1.77 g (4.8 mmol) of tert-butyl 3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate (V) is placed in 21.5 mL of a 4% hydrochloric acid solution in dioxane, and methanol is added. The solution is stirred for 0.5 hours at ambient temperature, whereupon a precipitate is formed. This is suction filtered, washed with diethyl ether, and dried. 1.33 g of product (VI) (91%) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][N:18](C)C=O>O>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: Brc1ccc(C2CCCc3cncn32)cc1
Solvent: O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A mixture of 85 mg of 5-(p-bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and 74 mg of cuprous cyanide in 1 ml of N,N-dimethylformamide is heated under nitrogen at 120° for 11 h. The reaction mixture is cooled, diluted with 10 ml of water and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated. The resulting oil is chromatographed on silica gel with ethyl acetate to yield the title compound, m.p. 117°-118°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-formyl-4-hydroxybenzoate (3.55 g, 19.7 mmol) in DMF (20 ml) was added benzyl bromide (3.70 g, 21.67 mmol) and K2CO3 (4.1 g, 29.6 mmol). The reaction was stirred at ambient temperature overnight and the solvent evaporated to dryness (at reduced pressure). The residue was partitioned between ethyl ether and water and the aqueous layer extracted a second time with ethyl ether. The organic extracts were combined, washed with brine, dried (MgSO4 ) and evaporated to give methyl 3-formyl-4-benzyloxybenzoate as an off-white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20]
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2cccc(Cl)c2)CC1
Yield: 10.1 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 3-chloro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (7.7 mg, 10%) as light yellow oil. MS m/e=589.1 (75%); 591.1 (25%) [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14](=[O:21])[N:15]([CH2:18][O:19][CH3:20])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[OH-:37].[Na+].CO.Cl>C1COCC1>[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[C:8](/[CH:11]=[C:12](\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]([NH:15][CH2:18][O:19][CH3:20])=[O:21])/[C:16]([OH:17])=[O:37])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(COC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C(/C(=O)O)N(CCCC)C(=O)NCOC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[3-butyl-1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate monohydrochlorde. (0.100 g, 0.193 mmol) in THF was added 1N NaOH (0.22 mL, 0.22 mmol) and then methanol (2 mL). The yellow solution was stirred for 1.5 hours and then 1N HCl (0.22 mL, 0.22 mmol) was added. The reaction mixture was evaporated in vacuo to a white solid. This solid was dissolved in ethyl acetate and water. The organic layer was dried briefly over MgSO4 and then concentrated to 1/6 original volume. An equal volume of hexane was added and the solid collected.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11]C(C)(C)[O:9][C:8]2=[O:16])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[OH-].[Na+].Cl>>[S:1]1[C:5]([CH2:6][CH:7]([C:12]([OH:13])=[O:11])[C:8]([OH:16])=[O:9])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.0 g, 6.88 mmol, Intermediate 39: step a) and 3 M aqueous NaOH (14 mL) was heated in a 102° C. oil bath for 28 hours. The reaction mixture was poured over ice and acidified to pH 1 with concentrated aqueous HCl. The suspension was stirred at room temperature for 2 hours then filtered rinsing further with water and dried to provide the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14]CC3C=CC=CC=3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[H][H]>[Pd].CO>[NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(NCc4ccccc4)CC3)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC(N)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.9 %

Procedure:
To methyl 4-(3-amino-6-(4-(benzylamino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (350 mg, 0.806 mmol) in a round bottom flask that was flushed with argon was added Pd—C 10% degaussa, wet (171 mg, 0.161 mmol). Then under argon with syringe, was added MeOH (5 mL) and last a hydrogen balloon. The flask was evacuated and refilled with hydrogen six times. The reaction was stirred at room temperature for 14 h. The reaction was purged with argon, then Pd—C 10% degaussa, wet (171 mg, 0.161 mmol) was carefully added. Then a hydrogen balloon was added, and the flask was evacuated and refilled with hydrogen six times. The reaction was stirred for additional 10 h to give a total of 24 h, followed by LCMS. The reaction was flushed with argon and 35 mL of DCM was added. The crude mixture was filtered through a Celite plug, and concentrated to constant mass to give 230 mg of desired product (which is 2:1 trans to cis ratio), used as is (83%). LCMS (m/z): 345.2 (MH+), 0.48 min and 0.51 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>C1COCC1.[Zn+2].[Br-].[Br-]>[CH2:2]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)OC)cc1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
A mixture of dry Mg (900 mg, 37 mmol) and ZnBr2 (5.63 g, 25 mmol) in THF (25 mL) was treated with 5-bromopent-1-ene (4.45 mL, 37.6 mmol) and the subsequent suspension was heated at 56° C. for 18 h. The mixture was cooled to room temperature and methyl 4-bromobenzoate (7.1 g, 33 mmol) and tetrakis-(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) were added, and the mixture was stirred at room temperature for 24 h. The mixture was quenched with 3N HCl (aqueous) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane) to give the crude title compound which was used without further purification.
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]([NH:25][C:26](=O)[C:27]5[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[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]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4cccnc4)ccc32)n1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@H](Nc1cncc(-n2cnc3cc(NCc4cccnc4)ccc32)n1)c1ccccc1
Yield: 23.7 %

Procedure:
In a procedure analogous to example 46, reaction of N-[1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-yl]nicotinamide (33 mg, 0.10 mmol) with LiAlH4 (5.7 mg 0.15 mmol) furnished the product (10 mg, 24%) after chromatography.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br[CH2:11][CH2:12][CH2:13][CH3:14].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:11]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2sccc2C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2ccsc2-3)no1
Reaction time: 1 h
Yield: 24.6 %

Procedure:
1.85 ml (10.9 mmol) of N-ethyldiisopropylamine and 0.7 ml (6.3 mmol) of 1-bromobutane were added to a solution of 1.0 g (3.16 mmol) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one in 30 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 290 mg (25%) of 7-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one as a colourless foam, Rf=0.37 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([OH:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.N1C=CC=CC=1>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([O:24][C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:12]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 16.6 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.84 g, 4.4 mmol), 1-adamantanol (0.60 g, 3.9 mmol), pyridine (10 mL), and water (100 mL) yielding 0.20 g (16%) of (92):
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1/[CH:14]=[CH:15]/[C:16]([OH:18])=O)(=[O:3])[CH3:2].[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:30][C@H:29]([CH3:31])[NH:28][CH2:27][C@H:26]2[CH3:32])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:6](/[CH:14]=[CH:15]/[C:16]([N:28]2[CH2:27][C@H:26]([CH3:32])[N:25]([CH2:24][C:23]3[CH:33]=[CH:34][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:30][C@H:29]2[CH3:31])=[O:18])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)c(NC(C)=O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(NC(C)=O)cc1Cl
Yield: 55.3 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-5-methoxyphenyl)-acrylic acid (100 mg; 0.37 mmol), (2R,5S)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (Mavunkel, Babu J. et al., WO 00/71535) (83 mg; 0.37 mmol) and EDCl.HCl (85 mg, 0.44 mmol) were dissolved in DMF (3 ml) and stirred over night. The reaction mixture was evaporated, taken up in 2N Na2CO3 and extracted with EtOAc three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 3/7 to 4/6) to yield the title compound as colorless crystals (97 mg; 55%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]4[CH:46]=[C:45]([CH3:47])[C:44]5[C:40](=[CH:41][N:42](COCC[Si](C)(C)C)[N:43]=5)[CH:39]=4)[C:23](=[O:36])[N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[O:20])[CH2:15][CH2:14]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]4[CH:39]=[C:40]5[C:44](=[C:45]([CH3:47])[CH:46]=4)[NH:43][N:42]=[CH:41]5)[C:23](=[O:36])[N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[O:20])[CH2:15][CH2:14]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4ccc(F)cc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4ccc(F)cc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-3-(7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(7-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (93 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (5:95:1 to 10:90:1 methanol/dichloromethane/triethylamine). The residue was dissolved in 10% methanol/dichloromethane and passed through a plug of basic alumina to give 41 mg (53%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ −0.38-0.15 (m, 0.7H), 0.60-0.95 (m, 1H), 1.18-2.18 (m, 17H), 2.29 (m, 0.7H), 2.35-2.50 (m, 3H), 2.58-3.01 (m, 3.4H), 3.01-3.25 (m, 2.4H), 3.65-4.60 (m, 7H), 5.47 (m, 0.4H), 5.55 (dd, J=9.5, 6.1, 0.7H), 6.51 (m, 0.8H), 6.62 (m, 0.8H), 6.90-7.20 (m, 2.2H), 7.45 (bs, 1.1H), 7.98 (bs, 1H). Mass spec.: 648.64 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)=[CH:23][CH:22]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[CH:35][C:27]=2[C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[NH:31][C:30]1=[O:36]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 63.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (31 mg, 63.9%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>O1CCCC1.CCCCCC>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[CH:9]=[CH:8]1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)C=Cc2cc(C(=O)O)ccc2O1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-benzo[b]pyran (see J. Med. Chem., 33, 3028 [1990]) (5.0 g) in dry tetrahydrofuran (100 ml) at -70° C. under nitrogen was added, dropwise, a 1.6M solution of n-butyllithium in hexane (17 ml). The reaction mixture was stirred at -70° C. for 15 minutes then treated with an excess of finely ground solid CO2. The reaction was further stirred for one hour, the solvent evaporated in vacuo and the residue taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer was concentrated in vacuo to a solid which was triturated with hexane to provide a white solid, 1.6 g.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([N+:12]([O-])=O)[S:10][CH:11]=1)(=[O:4])=[O:3]>[Pd].O1CCCC1>[NH2:12][C:9]1[S:10][CH:11]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]=1[S:15]([NH2:18])(=[O:16])=[O:17]
Reactant: CS(=O)(=O)NCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1csc(N)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Palladium on carbon (12 g, 10%, activated, Aldrich) was added to a solution of 4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (prepared as described in Example 1g; 15 g, 47.6 mmol) dissolved in tetrahydrofuran (150 mL). The flask was degassed and backfilled with hydrogen gas. The mixture stirred under an atmosphere of hydrogen gas (balloon) for 20 h at 25° C. and then was filtered through Celite. The filtrate was concentrated in vacuo to afford 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide as a thick golden oil. The oil was dissolved in N,N-dimethylformamide (150 mL) and 3,3-diethoxy-acrylic acid ethyl ester (10.62 g, 56.4 mmol) was added. A slow stream of nitrogen gas was applied to the atmosphere above the reaction mixture and the solution stirred at 70° C. for 5 h. Triethylamine (19 g, 188 mmol) was added directly to the reaction mixture and the solution continued to stir for 1 h. Upon cooling, the solution was concentrated in vacuo to reduce the total volume to 25 mL. The mixture was diluted with ethyl acetate (150 mL) and washed with 1.0 M aqueous hydrochloric acid solution (1×50 mL) followed by saturated aqueous brine solution (1×50 mL). The aqueous phase was back extracted with ethyl acetate (1×25 mL). The organic phases were combined, passed through a plug of silica gel (Merck silica gel 60, 40-63 μm) and concentrated in vacuo to afford a thick oil. The oil was dissolved in ethyl acetate (30 mL) and was stored at 25° C. for 16 h. The resulting solid was collected by vacuum filtration (10.75 g). The filtrate was concentrated in vacuo to afford a thick oil. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40-100% ethyl acetate in hexanes) to afford a solid (3.23 g) which was combined with the solid from above followed to afford [7-(methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid ethyl ester (13.98 g, 3.7 mmol, 77%) as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccc(Cl)cc1N
Product: O=S(=O)(Nc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1

Procedure:
N,N′-(4-chloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (310 mg) was prepared as in Example 31 using 4-chlorobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C@@H:10]([CH:13]=[CH2:14])[CH2:11][OH:12].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][O:12][CH2:11][C@@H:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH:13]=[CH2:14]
Reactant: C=C[C@@H](CO)N1Cc2ccccc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@@H](COC)N1Cc2ccccc2C1

Procedure:
To a solution of (S)-2-(Isoindolin-2-yl) but-3-en-1-ol (FIG. 2, No. 3)(2.0 g, 9.2 mmol) in 40 mL DMF was successively added NaH (442 mg, 18.4 mmol) at 0° C., stirred for ten minutes followed by addition of MeI (1.73 mL, 27.6 mmol) and then the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by addition of ice cold water, extracted with diethyl ether, washed with brine and dried over anhydrous MgSO4. The organic layer was then concentrated in vacuo and purified by silica gel column chromatography using ethyl acetate/hexane (1:9) as eluent to furnish 1.83 g (86%) yield of (S)-2-(1-Methoxybut-3-en-2-yl) isoindoline (FIG. 2, No. 4) as a crystalline white solid. [Rf=0.56, ethyl acetate/hexane (3:7)]; [α]D25 −75.1 (c 1.0, CH2Cl2); IR (CH2Cl2) v: 1773, 1708, 1468, and 1384 cm−1; 1H NMR (400 MHz, CDCl3) δ:3.3 (s, 3H), 3.6 (m, 1H), 4.06 (m, 1H), 5.0 (m, 1H), 5.22-5.31 (m, 2H), 6.12 (ddd, J=7.32 Hz, 1H), 7.68 (dd, J=2.76, 5.48 Hz, 2H), 7.80 (dd, J=2.76, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 52.8, 58.7, 71.3, 119.0, 123.2, 131.9, 132.1, 133.9, 168.0; HRMS (ESI-TOF) m/z calcd for C13H13NO3Na [M+Na+] 254.080. Found 254.079.