Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:35]([N:37]([CH2:40][CH2:41]Cl)[CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:35]([N:37]([CH2:40][CH2:41][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:10])[CH2:38][CH3:39])[CH3:36]
Reactant: CCN(CC)CCCl
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 49.6 %

Procedure:
A mixture of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (320 mg, 0.65 mmol), 2-[(N,N-diethyl)amino]ethyl chloride hydrochloride (579 mg, 3.26 mmol) and potassium carbonate (451 mg, 3.27 mmol) in ethyl acetate (5 mL) and water (5 mL) was at room termperature overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to afford N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester (190 mg, 49%) as an amorphous white solid. ES-HRMS m/e calcd for C29H34Cl2N4O5 (M+H) 589.1978, found 589.1980.
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N-]>C(Cl)Cl>[CH2:1]([CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][CH:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC(Cc2ccccc2)C(=O)CC1
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1=CC(Cc2ccccc2)C(=O)C(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the above ketone (19) (8.18 g) in methylene chloride (18 mL) at -78° C. was added a cold solution of triethyloxonium tetrafluoroborate (28 mL, 1N in CH2Cl2). Immediately afterwards t-butyl diazoacetate (4.1 mL) was added and the reaction stirred for 15 min at -78° C. then allowed to slowly warm up in an ice bath. After the cessation of gas evolution (~15 min), the reaction was quenched by the addition of aqueous saturated NaHCO3 (150 mL) and stirred an additional 15 min. The organic phase was removed and the aqueous phase re-extracted with fresh CH2Cl2. The CH2Cl2 phases were then combined, dried over MgSO4 and evaporated. The product (20) was obtained by silica gel chromatography (5.0×100 cm) eluting with 2.5% ethyl acetate in n-hexane (2.11 g, 17.4%). Another later eluting fraction was obtained which corresponded to the other regioisomer (21) (3.71 g, 30.6%).
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Product: CC1CCCC(C)N1CCCNC(=O)C1CCC2CCC(=O)N21
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3 carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in cis-3-[2,6-dimethylpiperidinyl]propylamine (34 g, 0.2 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[3-[2,6-dimethyl-1-piperidinyl]propyl]hexahydro-5 oxo1H-pyrrolizine-3-carboxamide.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OCC)=[NH:19])[CH3:9].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:33][NH:32][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:9]
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC(=N)CCCCCCC(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCC(N)=NNC(=O)c1ccccc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Add triethylamine (5.6 mL, 40 mmol) to a solution of 7-ethoxycarbonimidoylheptanoic acid ethyl ester (11.0 g, 41 mmol) and benzoic acid hydrazide (5.5 g, 40 mmol) in ethanol (110 mL) at room temperature under nitrogen and stir the mixture for 12 hours. Remove the solvent under reduced pressure, dissolve the residue in ethyl acetate (200 mL), wash with saturated NaHCO3 (200 mL) and brine (200 mL) solutions, and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 8-amino-8-(benzoylhydrazono)octanoic acid ethyl ester (8.3 g, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:26])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH2:24][CH3:25])[CH3:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].O.[C:38]([OH:42])(=[O:41])[CH:39]=O>>[C:31]([C:30]1[CH:29]=[C:28]([NH:27][CH:39]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:26])=[C:16]([CH2:24][CH3:25])[CH:17]=2)[C:38]([OH:42])=[O:41])[CH:36]=[CH:35][CH:34]=1)(=[O:32])[NH2:33]
Reactant: CCc1cc(B(O)O)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Reactant: O=CC(=O)O
Reactant: NC(=O)c1cccc(N)c1
Solvent: O
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Yield: 37 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 36E (183 mg, 0.52 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 36F (95 mg, 37%) as a yellow film. MS (ESI) m/z 500.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:16]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Yield: 87.2 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.0 g, 0.01 mol) in dry toluene (15 ml) was treated with 2-benzylaniline (1.83 g, 0.01 mol) and a catalytic amount of p-toluenesulfonic acid monohydrate (50 mg), and the mixture was heated at 60° C. for 1.5 h. The reaction was diluted with diethyl ether, and washed with water followed by brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown foam (3.37 g) which was used in the next stage without purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[O:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[O:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2oc3c(c2c(=O)[nH]1)CCCC3
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c2c3c(oc2n1)CCCC3
Yield: 82 %

Procedure:
To a 50 mL flask was added 3 (2.04 g, 10 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added mL of CHCl3 and 3 g of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 1.67 g (82%) of 4 as a yellow solid: TLC Rf 0.41 (Hexane/EtOAc 15:1); mp 42.4-43.8° C.; 1H NMR (DMSO-d6) δ 1.79 (q, 2H, J=8 Hz), 1.87 (q, 2H, J=8 Hz), 2.63 (s, 3H), 2.75 (d, 4H, J=8 Hz).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[S:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8]1>O>[Br:1][C:8]1[S:7][C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=1
Reactant: O=C1c2ccccc2CCc2sccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2CCc2sc(Br)cc21
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Bromine (8.5 mL, 165 mmol) was added dropwise to a chloroform (300 mL) solution of 9,10-dihydro-1-thiabenzo[f]azulen-4-one (23.2 g, 108 mmol), and the mixture was stirred for 4 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, the organic layer was then washed with a saturated aqueous sodium bicarbonate solution and with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate), to give 22.0 g (69%) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](C(O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N:17]([CH2:20]C)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])=CC=1>CN(C=O)C>[N:17]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)=[C:20]=[O:29]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)O)c2ccccc2n1
Solvent: CN(C)C=O
Product: Cc1cc(N=C=O)c2ccccc2n1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a solution of 2-methyl-quinoline-4-carboxylic acid (276 mg, 1.2 mmol) in DMF (4 mL) at 0° C. is added triethylamine (1.22 mg, 1.2 mmol) and slowly (30 min) DPPA (332 mg, 1.2 mmol). The reaction mixture is stirred for 2 h at 0° C. and 12 h at 20° C. The reaction is quenched with ice (10 g) and extracted with Et2O (6×30 mL). The combined organic extracts are washed successively with saturated NaHCO3 (2×15 mL) and water (2×10 mL), and are evaporated without heating in vacuo. The residue is dissolved in dry toluene and heated at reflux for 2 h. The resulting solution is carried forward without further isolation of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[S:13](C)=O>O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[SH:13]
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,3-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol) in 300 mL of DMSO was added powdered Na2S 9H2O (Aldrich, 24.0 g, 100 mmol). The mixture was stirred at ambient temperature for 24 h, then was diluted with 2 L of water. The mixture was clarified by filtration and the filtrate was acidified to pH 4 with con. HCl. The mixture was extracted 3× with Et2O (400 mL). The organic layers were combined and washed twice with a brine solution (400 mL), dried over Na2SO4. Removal of the solvent under reduced pressure gave 18.4 g product. 1H NMR (400 MHz, DMSO) δ 8.11 (dd, J=8.3, 1.3 Hz, 1H), 7.93 (dd, J=8.0, 1.3 Hz, 1H), 7.40 (td, J=8.2, 1.3 Hz, 1H) 5.06 (s, 1H). MS (EI): m/z 188 (M−H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:29](O)=[O:30]>>[C:1]([O:4][C:5]1[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([OH:11])=[C:9]([CH:10]=1)[CH:29]=[O:30])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)Oc1cc(C=O)c(O)cc1C(C)(C)C
Yield: 52 %

Procedure:
To 6.25 g of 4-acetoxy-3-t-butylphenol dissolved in 15 ml of trifluoroacetic acid was added 4.63 g of hexamethylenetetramine and the mixture was heated under reflux for 1 hour. The reaction mixture was allowed to attain room temperature, then poured into water and extracted with ethyl acetate. The organic layers were successively washed with a 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 3.68 g of 5-acetoxy-4-t-butyl-2-hydroxybenzaldehyde as a pale yellow oil (52%).
Reaction SMILES: CN(CCN(C)C)C.[NH:9]1[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]1=[O:11].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:14][C:13]1[CH:15]=[CH:16][N:9]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:11])[N:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CO
Product: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 321.7 %

Procedure:
TMEDA (8 mL, 54 mmol) was added to a stirred suspension of cytosine (3 g, 27 mmol), 4-fluorophenylboronic acid (7.55 g, 5 mmol) and copper(II)acetate monohydrate (5.44 g, 27 mmol) in a mixture of MeOH (960 mL) and H2O (240 mL). The mixture was stirred at RT for 16 hours. The solvents were evaporated in vacuo and the crude product purified by open column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with MeOH and DCM and the solid formed filtered and dried in vacuo to yield 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (3.3 g, 60% yield) as a white solid.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].CO[CH:7]1[CH2:15][C:14]2[C:9](=CC=[CH:12][CH:13]=2)[C:8]1=[O:16].[C:17]([O-:20])(=O)[CH3:18].Cl.[CH:22]1C=CC=CC=1>>[OH:20][C:17]1[CH:18]=[C:9]2[C:14]([CH2:15][CH:7]([CH3:22])[C:8]2=[O:16])=[CH:13][CH:12]=1
Reactant: COC1Cc2ccccc2C1=O
Reactant: c1ccccc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Product: CC1Cc2ccc(O)cc2C1=O

Procedure:
To a stirred solution of anhydrous aluminum bromide (69.82 g, 0.261 mole) in anhydrous benzene (250 mL) kept under nitrogen is added dropwise over 30 minutes a solution of the methoxy indanone (18 g, 0.102 mole) of Step C, in benzene (60 mL). The mixture is gently refluxed for 3 hours (TLC, dichloromethaneethyl acetate 8:2, UV), cooled in an ice bath and treated dropwise with 6N-HCl (ca. 200 mL) to decompose the aluminum complex. The aqueous phase is extracted with ether (3 times), the extracts are concentrated at reduced pressure and extracted with 2.5N-NaOH (2×75 mL and 1×50 mL). The basic extracts are neutralized (ice bath) with concentrated HCl and the oil that separates is extracted with ether (3 times). The combined extracts are washed with brine, dried (MgSO4) and evaporated to yield an oil that readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH2Cl2, CH2Cl2 -ethyl acetate 85:15 ) to provide the pure title compound (13.60 g, nearly colorless solid, 82%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11](/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1>CS(C)=O.[H-].[Na+]>[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11]([CH:38]2[CH2:2][CH:39]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Trimethylsulfoxonium iodide (45.1 mg, 0.205 mmol) in anhydrous methyl sulfoxide (4 mL) and 60% sodium hydride in mineral oil (16.4 mg, 0.411 mmol) was stirred for 5 minutes at room temperature and treated with a mixture of ethyl (2E)-3-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]acrylate (108 mg, 0.205 mmol) in methyl sulfoxide (2 mL) was added. After 4 hours the mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (7 mL). The aqueous layer was extracted with dichloromethane (3×10 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified via HPLC preparative to give the title compound as a white solid (33.6 mg 0.062 mmol): LCMS (Conditions a): MH+=541 Rt =4.20 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1 H), 7.99 (1 H), 7.69 (2 H), 7.58 (2 H), 7.35 (2 H), 7.18 (1 H), 7.15 (1 H), 7.06 (1 H), 5.49 (1 H), 4.18 (2 H), 4.04 (3 H), 3.91 (3 H), 2.45 (1 H), 1.86 (1 H), 1.56 (1 H), 1.47 (1 H), 1.26 (3 H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]([NH2:11])=[NH:10].[C:12]([C:19](OCC)=[O:20])#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[OH:20][C:19]1[N:11]=[CH:9][N:10]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1
Reactant: N=CN
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(O)ncn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Triethylamine (17.3 mL) was added dropwise to a solution of formamidine hydrochloride (10.0 g) and diethyl acetylenedicarboxylate (19.9 mL) in acetonitrile (300 mL) at room temperature. The reaction mixture was stirred at 50° C. for 1 hr and heated under reflux overnight. The solvent of the reaction mixture was evaporated under reduced pressure to give a crude product of the title compound as a brown solid. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([O-:22])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].[CH3:25]O>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:25])=[O:21])=[N:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)[O-])nc2)CC1
Agent: [Pd]
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 3 h
Yield: 100 %

Procedure:
5-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate from Step 1 (250 mg, 0.79 mmol) was taken up in MeOH/EtOAC (3:1, v/v) and 10% Pd/C (50 mg) was added. The resulting mixture was hydrogenation with a hydrogen balloon at rt for over night. Hydrogenation continued for another 3 h at 55° C. LC-MS indicated that the reaction was complete. The reaction mixture was filtered over a celite plug and washed with MeOH. The filtrate was evaporated under reduced pressure and dried in vacuum oven to give methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)picolinate (250 mg, 100%). LC-MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:16])=O.[C:19](=[O:22])([O-])O.[Na+]>CN(C)C=O>[Cl:16][C:4]1[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]([CH3:1])[C:3]=1[CH:19]=[O:22]
Reactant: Cc1cc(O)n(-c2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution containing 1.0 g of 5-methyl-2-phenyl-2H-pyrazol-3-ol (commercially available e.g. Aldrich M7,080-0) and 2.1 ml of phosphorus oxychloride in 10 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 4 h. The mixture was poured into 70 ml of saturated sodium hydrogen carbonate and extracted three times with 60 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane/methanol for the elution to give 177 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde as yellow needles.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].C(N(CC)CC)C.[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25].O>C1COCC1>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C:24](=[O:25])[C:23]([Br:22])([CH3:28])[CH3:27])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C1c2ccccc2C(=O)N1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Br)C(=O)OCCN1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 75.8 %

Procedure:
N-(2-hydroxyethyl)phthalimide (19.12 g, 0.1 mol) was dissolved in anhydrous THF (250 mL) with triethylamine (28.1 mL, 0.2 mol) under nitrogen in a 500 mL round bottom flask equipped with a magnetic stirrer and dropping funnel. The flask was cooled to 0° C. with an ice/salt bath before the dropwise addition of 2-bromo-2-methylpropionyl bromide (13.9 mL, 0.11 mol). The mixture was stirred for 45 minutes and allowed to reach room temperature before the mixture was poured into an excess of cold water and the product extracted with diethyl ether (3×100 mL). The organic layer was subsequently washed with a saturated aqueous solution of sodium carbonate (3×100 mL), acidified water (pH 4.6, 3×100 mL) and again with saturated aqueous solution of sodium carbonate (3×100 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. The product was isolated via reduction under reduced pressure to obtain a white solid (25.79 g, 75.8% yield). 1H NMR (CDCl3) δ (ppm) 1.81 (s, 6H, C(CH3)2Br), 3.95 (t, 2H, J=5.3 Hz, CH2—N), 4.35 (t, 2H, J=5.4 Hz, CH2—O), 7.67 (m, 2H, Haro), 7.78 (m, 2H, Haro). 13C NMR (CDCl3) δ (ppm) 31.00 (2C, C(CH3)2Br), 37.12 (1C, CH2—N), 55.92 (1C, C(CH3)2Br), 63.42 (1C, CH2—O), 123.78 (2C, Caro), 132.35 (1C, CIVaro), 133.54 (2C, Caro), 168.40 (2C, Ccycl═O), 171.87 (1C, C═O). IR (solid, ATR cell) ν (cm−1) 2975, 1774 (Ccycl═O), 1705 (C═O), 1417, 1392, 1321, 1276, 1158, 1105, 1063, 985, 763, 716, 632. Melting point 63-65° C.