Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([C:5]1[N:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[S:8][C:9]=1[CH3:10])O)C.Cl.[NH2:16][CH2:17][CH2:18][SH:19].Br>>[CH3:14][N:12]([CH2:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:3][S:19][CH2:18][CH2:17][NH2:16])[N:6]=1)[CH3:13]
Reactant: CCC(O)c1nc(CN(C)C)sc1C
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1sc(CN(C)C)nc1CSCCN

Procedure:
Following the procedure of Example 3, a reaction mixture consisting of 6.4 g. of ethyl 2-dimethylaminomethyl-5-methyl-4-thiazolemethanol, 4.2 g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromic acid was maintained at a temperature of about 100° C. under a nitrogen atmosphere for about 4 hours. The reaction mixture was cooled and the volatile constituents removed in vacuo. The resulting dark residue was twice trituated with ethanol and the ethanol removed by evaporation to remove residual HBr. The residue was then treated with 50 ml. of 5 N aqueous sodium hydroxide. The alkaline layer was continuously extracted with ether over an 18 hour period. The ether extract was dried and the ether removed therefrom in vacuo to provide 2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamine prepared in the above reaction; yield=1.38 g. The compound was a brown oil having the following physical characteristics:
Reaction SMILES: [C:1]([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C2CC2)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:10]([CH:5]4[CH2:1][CH2:4]4)[N:13]=[N:12][N:11]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: ClCc1nnnn1C1CC1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3nnnn3C3CC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as white solid. MS (m/e): 397.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].C(#N)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C>[CH3:37][O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)=[CH:6][CH:7]=1)=[O:35]
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)COc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
3-Phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether (3.0 g), 0.36 g of sodium hydride and 20 ml of acetonitrile were heated under reflux for about 20 minutes, followed by the dropwise addition of 2 ml of methyl bromoacetate at room temperature. The resulting mixture was stirred at 60° C. for 20 minutes. After concentration of the reaction mixture, about 50 ml of ethyl acetate were added to the concentrate, followed by washing with water, drying and concentration. The resulting concentrate was fractionated and purified by chromatography on a silica gel column, whereby 3.0 g of 3-phenoxybenzyl 2-{4-(methoxycarbonylmethyloxy)phenyl}-2-methylpropyl ether were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O[C:15]1[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[C:17]=2[N:18]=[N:19][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:15]2[C:16]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[C:17]=3[N:18]=[N:19][N:20]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 4 was prepared following general synthetic scheme 7 wherein (4-chloro-3-(trifluoromethyl)phenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [382 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m, 2H), 8.54 (d, 1H), 8.48 (d, 1H), 8.05 (s, 1H), 8.02-7.98 (m, 1H), 7.95 (s, 1H), 7.73-7.68 (m, 2H), 4.96 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:54][CH:55]([F:66])[O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][NH2:62])=[CH:59][C:58]=1[F:65]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:62][CH2:61][C:60]2[CH:63]=[CH:64][C:57]([O:56][CH:55]([F:54])[F:66])=[C:58]([F:65])[CH:59]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)F)c(F)c2)C1
Yield: 109.2 %

Procedure:
To a solution of the compound (1.83 g) obtained in Example 783, Step 2 in N,N-dimethylformamide (10 ml) were successively added, with stirring under ice-cooling, 1-hydroxybenzotriazole hydrate (677 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (847 mg) and a solution of 4-difluoromethoxy-3-fluorobenzylamine (806 mg) in N,N-dimethylformamide (3 ml). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.76 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:23])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5,5-dimethylcyclohexane-1,3-dione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-5,5-DIMETHYLCYCLOHEXANE-1,3-DIONE, m.p. 103°-105.5° C. (corr.).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])[CH3:10])[CH3:7].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=1)[O:34][Si](C)(C)C(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.C1COCC1>[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH2:28][CH2:30][C:31]1[CH:32]=[C:33]([OH:34])[CH:42]=[CH:43][CH:44]=1)[CH3:10])[CH3:7]
Reactant: CCOC(C)n1c(C)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)n1c(CCc2cccc(O)c2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
n-Butyllithium (3.89 g, 61mmol) in hexane (24.31 mL) was added dropwise to a stirred solution of 1-(1-ethoxyethyl)-2-methyl-4,5-diphenyl-1H-imidazole (l5.50 g, 51 mmol) in dry THF (300 mL) maintained at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 45 minutes and [3-(bromomethyl)-phenoxy]dimethyl(1,1-dimethylethyl)silane (l6.77 g, 50 mmol) added dropwise. After 10 minutes, the mixture was poured onto water, extracted with CH2Cl2, the extracts combined and dried over sodium sulfate. Evaporation of the solvent left an oil which was dissolved in THF (75 mL) and a solution of tetra-n-butylammonium fluoride (l7.22 g, 66mol) in THF (65 mL) added. The solution was stirred at room temperature for 30 minutes, the solvent evaporated and the residue diluted with water. After addition of 2N HCl solution (about 20 mL) to pH=5, the mixture was extracted with CH2Cl 2 The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual material chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexanes (1.0 gave 3-[2-[1-(1-ethoxyethyl)-4,5-diphenyl-1H-imidazol-2-yl]ethyl]-phenol (8.l8 g, 39%), mp 165.5°-167° C. after recrystallization from a mixture of CH2Cl2 and hexanes.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11]>C(OCC)C.C(N(CC)CC)C>[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][S:11][C:2]1[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=1
Reactant: O=C1CCC2OC12
Reactant: CCCCCC(C)(O)CS
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCC(C)(O)CSC1=CCCC1=O
Yield: 69.3 %

Procedure:
2,3-Epoxycyclopentanone (1.47 g) and 2.0 g of 2-hydroxy-2-methylheptyl mercaptan were dissolved in 30 ml of diethyl ether, and 30 drops of triethylamine were added. They were reacted at room temperature for 2 hours. The solvent was distilled off from the reaction mixture to afford 4.01 g of a crude product. The crude product was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 2.07 g of 2-(2-hydroxy-2-methylheptylthio)cyclopent-2-en-1-one in a yield of 69%. The product had the following characteristics.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23]/[C:24](/[C:29]#[N:30])=[C:25](\[NH2:28])/[C:26]#[N:27]>C(O)C>[OH:15][C:13]1[N:28]=[C:25]([C:26]#[N:27])[C:24]([C:29]#[N:30])=[N:23][C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CCO
Product: N#Cc1nc(O)c(-c2cc(O)c(O)c([N+](=O)[O-])c2)nc1C#N

Procedure:
A solution of 4.0 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 1.5 g of diaminomaleonitrile in 35 ml of ethanol is heated to boiling under reflux for 24 hours. The alcohol is then distilled , the residue is dissolved in ether, washed with water, dried over sodium sulfate, filtered and evaporated. There is obtained 6-hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazinedicarbonitrile of m.p. >300° (from ether/methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COC2CCCCC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(COC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a solution of tert-butyl 5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoate (1.86 g, 5.43 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (20 mL). The reaction solution was stirred at ambient temperature for 3 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with brine (3×25 mL), dried over anhydrous sodium sulfate, filtered the solid. The filtrate was concentrated in vacuo to dryness to afford the title compound (0.50 g, 32% crude yield) which was subjected to next step without any further purification: MS (ES+) m/z 287.0, 285.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH3:11])[NH:19][C:20]([CH3:26])=[C:21]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)c1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1cccc(Cl)c1

Procedure:
12.82 g (50 mmol) of 1-(3-chlorophenyl)-2-phenyl-3-oxo-1-butene in 80 ml of ethanol are heated to reflux with 11.5 g (100 mmol) of methyl β-aminocrotonate and 6 ml (100 mmol) of acetic acid overnight. 11.5 g of methyl β-aminocrotonate and 6 ml of acetic acid are added once more, and the mixture is heated under reflux for 24 hours. On cooling, crystals are produced, and these are filtered off with suction and washed with ethanol. For complete purification, they are passed through a silica gel column using toluene/ethyl acetate 20:1. 5.3 g of a colorless substance, of melting point 191° C., are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>O>[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:41][CH:40]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N(C)C)cc4)cc23)CC1
Yield: 6.1 %

Procedure:
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.097 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (40 mg, 0.289 mmol) in water (1.2 mL). To this mixture was added [4-(dimethylamino)phenyl]boronic acid (65 mg, 0.386 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol). The vial was capped and the reaction was reacted in a CEM microwave for 10 min at 160° C. The reaction was concentrated under a stream of nitrogen at 80° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified through a 1 g silica SPE cartridge eluting with dimethyl sulfoxide (4 mL). The dimethyl sulfoxide was concentrated in a Genevac at 65° C. for 3 h, and the residue was reconstituted in dimethyl sulfoxide (1 mL) and filtered through an acrodisc. The solution of crude product was then purified on the Agilent MDAP (UV 214 selection). The purified product was passed through a polymer-bound carbonate SPE cartridge to afford 2.7 mg of the title compound (6.2%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1CCCCC1.C(O)C>[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid benzylamide (63.5 mg, 0.2625 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]([O:15][CH3:16])=[O:14].CCN(CC)CC>C(Cl)Cl>[CH3:16][O:15][C:13](=[O:14])[NH2:10].[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Agent: NCCc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-chloro-2-fluoro-phenyl)-ethylamine (1.30 g, 7.9 mmol) in CH2Cl2 (25 mL) was added dropwise methyl chloroformate (1.04 g, 11 mmol) and Et3N at 5° C. with vigorous stirring. The solution was then stirred at room temperature for 1 h. The reaction was poured into ice-water (50 mL) and extracted with CH2Cl2 (2×25 mL). The organic phase was washed with H2O (2×25 mL), dried over Na2SO4, filtered and evaporated to afford the final product without purification (1.78 g, 98%). MS: 232.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:40]6[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]6)=[CH:25][CH:26]=5)[CH:17]=4)[N:12]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-(3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde (2.1 g) was suspended in anhydrous dichloromethane (15 mL), treated with tert-butyl piperazine-1-carboxylate (1.6 g), and stirred for one hour. To the resulting mixture was added sodium triacetoxy borohydride 1.36 g in three portions. The reaction was stirred for 3 hours, diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over MgSO4, and purified by MPLC silica gel chromatography (30-60% EtOAc in hexane) to yield 2.62 g of the title compound (M+H 662).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:42]=1.[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68]O>C1(C)C=CC=CC=1>[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68][O:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:42]=1
Reactant: Cn1c(CCCO)nc2ccccc21
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCCCc2nc3ccccc3n2C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
Toluene (20 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (345 mg), and triphenylphosphine (459 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg), and further, 3-(1-methyl-1H-benzimidazol-2-yl)propan-1-ol (285 mg) were added, and the mixture was stirred at room temperature for 64 hr. The crystals precipitated from the reaction mixture were collected by filtration, washed successively with toluene, methanol, and diisopropyl ether, and dried to give the title compound (217 mg).
Reaction SMILES: Br[CH:2]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=O.[C:17]([NH2:20])(=[S:19])[CH3:18]>ClC(Cl)C>[CH3:18][C:17]1[S:19][C:2]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][N:20]=1
Reactant: CCOC(=O)C(CC(Br)C=O)C(=O)OCC
Reactant: CC(N)=S
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(Cc1cnc(C)s1)C(=O)OCC
Temperature: 25 °C
Yield: 112.8 %

Procedure:
A mixture of 108 g of α-bromo-γ,γ-dicarbethoxy-butyraldehyde 300 ml of anhydrous dichloroethane and 27 g of thioacetamide was refluxed for 6 hours during which 200 ml of dichloroethane were slowly distilled and the same quantity of dichloroethane was added again to the mixture. The mixture was cooled to room temperature and 500 ml of ice water were added thereto. Concentrated ammonium hydroxide solution was added to the mixture to adjust the pH to 10-12 and the mixture was decanted. The aqueous phase was extracted with methylene chloride and the organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to obtain 110 g of diethyl 2-(2-methyl-5-thiazolyl-methyl)-propanedioate. A sample of the product was rectified to obtain the product with a boiling point of 102°C at 0.02 mm Hg.
Reaction SMILES: [CH3:1][Li].[CH2:3]([N:7]1[C:11]2[CH2:12][O:13][CH2:14][C:15](=[O:16])[C:10]=2[S:9]/[C:8]/1=[N:17]\[C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([N:7]1[C:11]2[CH2:12][O:13][CH2:14][C:15]([OH:16])([CH3:1])[C:10]=2[S:9]/[C:8]/1=[N:17]\[C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(=O)COC2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(C)(O)COC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of methyllithium (0.8 mL, 1.3 mmol, 1.6M in tetrahydrofuran, Aldrich) in tetrahydrofuran (10 mL) was added slowly a solution of Example 10 (0.25 g, 0.63 mmol) in tetrahydrofuran (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes and was allowed to reach room temperature. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in methylene chloride) to afford 92 mg (35%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3H), 1.24-1.37 (m, 2H), 1.39 (s, 3H), 1.56-1.76 (m, 2H), 3.64-3.70 (m, J=3.4 Hz, 2H), 3.79 (s, 3H), 3.92-4.13 (m, 2H), 4.55-4.80 (m, 2H), 5.57 (s, 1H), 7.12 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H), 7.73 (s, 1H)); MS (ESI+) m/z 411 (M+H)+.