Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:33][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CO)CC4)cc3)n(C)c(=O)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CBr)CC4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
In dichloromethane (25 ml) was dissolved 2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (1.081 g) followed by addition of carbon tetrabromide (1.050 g). Then, triphenylphosphine (982 mg) was added over 10 minutes and the mixture was stirred at room temperature for 2 hours. The salt was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate =1:1) and rinsed with ether to provide the title compound as colorless solid (496 mg).
Reaction SMILES: [C:1]([CH2:9][CH:10]1[CH2:14][CH2:13][O:12][C:11]1=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C2CC(C(O)=O)CCC=2)C=CC=CC=1>CS(C)=O.O1CCCC1>[C:2]1([C:1]2[CH2:9][CH:10]([C:11]([OH:12])=[O:15])[CH2:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CCOC1=O)c1ccccc1
Agent: Br
Agent: O=C(O)C1CCC=C(c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)C1CC=C(c2ccccc2)C1
Temperature: 170 °C
Yield: 67.3 %

Procedure:
3-(Benzoylmethyl)-4,5-dihydro-2(3H)-furanone (5.00 g, Step A) and triphenylphosphine hydrobromide (8.41 g) are mixed and heated to 170° C. in an oil bath under nitrogen for 1 hour. The mixture is cooled and powdered. The powder is dissolved in dimethylsulfoxide (50 mL) and diluted with tetrahydrofuran (30 mL). The solution is stirred under nitrogen and cooled in an ice-bath. Dimsyl sodium (25 mL of 2M, see Example D, Step C) is added dropwise over 20 minutes keeping the internal temperature below 14° C. The mixture is stirred at 25° C. for 2 hours and the solvents evaporated. The residue is treated with water (80 mL) containing saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3×50 mL). The extracts are washed with dilute aqueous sodium bicarbonate. The aqueous layers are washed with dichloromethane (30 mL) and acidified with concentrated hydrochloric acid. The aqueous layers are extracted with dichloromethane (3×50 mL), the extracts dried over magnesium sulfate, filtered, and evaporated to a brown oil. The oil is washed through silica gel (30 g) with 2:1 chloroform:ethyl acetate to give 3.1 g of 3-phenyl-3-cyclopentenecarboxylic acid as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](=[O:27])=[O:26]>O1CCCC1>[C:1]1([CH2:7][C:8]2[CH:17]=[C:16]([C:25]([OH:27])=[O:26])[C:15]3[C:10]([C:9]=2[O:18][CH3:19])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g, 0.015 mole) in dry tetrahydrofuran (50 mL) was cooled to -78° and treated dropwise with n-butyllithium (1.55M in hexane; 10.9 mL, 0.017 mole). The mixture was stirred at -78° for 45 minutes, and a stream of gaseous carbon dioxide was directed onto the surface of the stirred solution. The cooling bath was removed from the reaction vessel and the addition of carbon dioxide was continued for 5 minutes. The mixture was then poured into 1.0N hydrochloric acid, and the crude product isolated by extraction with methylene chloride. This was recrystallized (methylcyclohexane) to provide the title compound (4.0 g, 90%) as a pale yellow solid, mp 146°-148°.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[Se:9][C:5]=2[C:4](=[O:14])[NH:3][N:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:15][N:3]1[C:4](=[O:14])[C:5]2[Se:9][C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[C:6]=2[N:1]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nnc2c3c([se]c12)CCCC3
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2c3c([se]c2c1=O)CCCC3
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-3H-benzo[1,2-b]1,2,3-triazino[4,5-d]selenophen-4-one (450 mg, 1.76 mmol) in acetone (50 mL) was added sequentially potassium carbonate (480 mg, 3.52 mmol), iodomethane (0.13 mL, 2.11 mmol) and a catalytic amount of PEG-400 was added and stirred at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as a pale yellow color solid (340 mg, 72%), which was recrystallized from chloroform-hexane (170 mg), mp 110-112° C. IR (neat) νmax 3438, 1668, 1220, 1018 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.05 (3H, s, —NCH3), 2.94-2.96 (4H, m, H-6,9), 1.91-1.97 (4H, m, H-7,8); 13C NMR (100 MHz, CDCl3): δ 156.1, 155.1, 152.5, 133.9, 128.5, 37.4, 28.4, 24.8, 23.6, 21.4; LC-MS (positive ion mode): m/z 268, 270 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)[N:9]=[C:4]2[C:3]=1[C:31]([OH:33])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67]([NH2:71])([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C>[C:67]([NH:71][C:31]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)[N:9]=2)[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:2]=1[CH3:1])=[O:33])([CH3:70])([CH3:69])[CH3:68]
Reactant: CC(C)(C)N
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)O)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (95 mg) in 1.5 mL of DMF was added PyBOP (128 mg) followed by tert-Butyl amine (70 mg). After stirring for 2 h, the mixture was partitioned between water and diethylether. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (4:1 Hexanes:ethylacetate) afforded 70 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide.
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2]1.COCC(Cl)=O.[CH:24]1(C(Cl)=O)[CH2:26][CH2:25]1>>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1)[CH2:3][CH2:2][CH2:25][CH2:24][CH3:26]
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: COCC(=O)Cl
Product: CCCCCCC1NCCc2cc(OC)c(OC)cc21

Procedure:
1,2,3,4-Tetrahydro-1-hexyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl-6,7- dimethoxyisoquinoline but substituting in the first step 2-methoxyacetyl chloride for cyclopropylcarbonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[N:24])[CH:22]=2)[CH:12]=[CH:11][C:10]=1[F:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH3:7].[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:22]=2)[C:23]#[N:24])[CH:12]=[CH:11][C:10]=1[F:25]
Reactant: CC(C)(C)OC(=O)NCc1cc(C#Cc2cncc(C#N)c2)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: N#Cc1cncc(C#Cc2ccc(F)c(CN)c2)c1
Reaction time: 1.5 h
Yield: 193.6 %

Procedure:
Dissolve [5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzyl]carbamic acid tert-butyl ester, (prepared as described in EXAMPLE 144), (390 mg, 1.11 mmol) in dichloromethane (7.5 mL) and treat with trifluoroacetic acid (2.57 mL, 33.3 mmol). After stirring for 1.5 h, dilute with dichloromethane and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 90:10 to 75:25 (98:2 dichloromethane:7 N ammonia in methanol):(9:2 acetonitrile:7 N ammonia in methanol), to give the title compound as a white crystalline solid (270 mg, 97%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C@@H:8]3[C:13]4[C:18]([CH2:19][C@@H:7]3[C:6]=2[CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2].[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[C@H:7]2[CH2:19][C:18]3[C:13]([C@@H:8]12)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CI
Reactant: CC(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2C
Reaction time: 2 h

Procedure:
A solution of cis-4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole (1.75 g, 7.0 mmol) in THF (10 cm3), was added to a suspension of sodium hydride (200 mg, 1.2 equivalents) in THF (7 cm3), at 0° C. The reaction was stirred for two hours and iodomethane (0.53 cm3, 1.2 equivalents) was added. The reaction was stirred overnight, and then quenched with a saturated solution of ammonium chloride. The organic phase was separated, and the aqueous phase extracted with diethyl ether. The combined organic phases were dried (Na2SO4), and solvent removed in vacuo to yield the title compound as a colourless gum which was purified by bulb to bulb distillation. Yield: 1.0 g (54%). B.p. 200° C. at 0.4 mmHg. 1H NMR (CDCl3) δ: 1.22 (6H, d,), 2.81 (1H, septet,), 2.94 (3H, s,), 3.09 (1H, dd,), 3.43 (1H, dd,), 4.15 (1H, ddd,), 4.90 (1H, d,), 6.32 (1H, d,), 6.93 (1H, dd,), 7.02 (1H, br,), 7.1-7.5 (4H, m,).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])=[O:25]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, 0.22 ml (3.3 mmol) of pyridine and 15 ml of anhydrous THF was prepared. 10 ml of a solution of 0.26 ml (3.3 mmol) of methyl chloroformate in anhydrous THF was added dropwise at 0° C. over a period of 15 minutes and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into 150 ml of ice water and extracted with 30 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solids thus obtained were recrystallized from ethyl acetate to provide 600 mg of red crystals. Yield: 79% m.p.: 184°-185° C.; 1H-NMR (300 MHz, DMSO-d6 /TMS; δppm): 8.64 (brs, 1H), 6.98 (d, 1H), 6.80 (d, 1H), 6.63 (brs, 1H), 3.92 (s, 3H), 3.79 (brs, 3H), 2.59 (s, 3H), 2.42 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][C:18]=1C.[CH2:26](OCC)C>>[OH:1][C:2]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][C:21]=2[CH3:26])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc([Mg]Br)cc1C
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10 mmol) in diethyl ether (100 mL) was chilled to 0° C., and a solution of (4-methoxy-3-methylphenyl)magnesium bromide (0.5 M in ether) (20 mL, 10 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 12 h. The reaction mixture was then quenched with a saturated NH4Cl solution and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and then evaporated under reduced pressure to provide the desired product (2.3 g, 71%); 1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J=8.0 Hz, 1H), 6.75-6.61 (m, 2H), 4.83 (s, 1H), 3.85-3.77 (m, 2H), 3.71 (s, 3H), 3.17 (d, J=5.0 Hz, 2H), 2.51 (s, 3H), 1.82-1.73 (m, 4H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1.O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:30][CH2:29][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCC1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (6 g, 25 mmol) in DMF (100 mL) was cooled to 0° C. Triethylamine (10.0 mL, 74.4 mmol) was added, and then tetrahydro-2H-pyran-4-ylmethylamine (see U.S. Patent Application Publication No. 2004/0147543 (Hays et al.) Examples 477-480) (3.4 g, 0.030 mol) was added slowly. Additional DMF was added, and the reaction was stirred at room temperature for one hour and cooled to 0° C. Water (300 mL) was added, and the mixture was maintained at 0° C. for 30 minutes. A precipitate was present and was isolated by filtration and washed sequentially with water and diethyl ether to provide 7 g of 2-chloro-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([CH3:8])([CH3:7])[CH3:6].C.[H][H]>[O-2].[Zn+2].[Pd]>[C:5]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH2:1][C:2](=[O:3])[CH3:4])=[CH:12][CH:11]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Agent: [Pd]
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)CCc1ccc(OC(C)(C)C)cc1
Yield: 43.1 %

Procedure:
58 g (1 mole) of acetone and 36 g (0.2 mole) of p-tert.-butoxy-benzaldehyde are introduced into a 300 ml stirred autoclave, 5 g of zinc oxide and 1 g of 1% strength palladium on active charcoal are added and the mixture is heated to 160° C., with vigorous stirring, under 20 bar hydrogen pressure. After a reaction time of 2 hours, the reaction mixture is cooled, freed from catalyst by filtration, and subjected to fractional distillation. 19 g of 1-(4-tert.-butoxy-phenyl)-butan-3-one (yield: 43%) are obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH3:20][C:21]1[O:14][C:13]([C:12]2[CH:17]=[CH:18][N:19]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[CH:11]=2)=[N:15][N:16]=1
Reactant: CSc1ccc(Nc2cc(C(=O)NN)ccn2)cc1
Reactant: CCOC(C)(OCC)OCC
Product: CSc1ccc(Nc2cc(-c3nnc(C)o3)ccn2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide (511 mg, 1.86 mmol) and triethyl orthoacetate (10 mL) was stirred at 120° C. overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (441 mg, yield 80%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)/[C:7]([CH3:21])=[C:6]2[CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)/[C:7]([CH3:21])=[C:6]2[CH2:22][C:23]([Cl:29])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccc(SC)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(SC)cc1

Procedure:
(Z)-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (70 mmol) in absolute THF (500 ml) is heated with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) at reflux (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH3:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH3:43])=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 84.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.17-8.16 (m, 1H), 8.13-8.09 (m, 2H), 8.00-7.96 (m, 1H), 7.59-7.57 (m, 1H), 7.31-7.29 (m, 1H), 4.74 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.36 (s, 3H), 1.97 (s, 3H), 1.35 (t, 6H))
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>C1C=CC=CC=1.CN(C)C=O>[Cl-:22].[CH2:1]([O:8][C:9](=[O:18])[CH:10]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)CC(C(=O)O)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
9.7 grams of the thus-obtained isobutylmalonic acid monobenzyl ester were dissolved in 120 ml of absolute benzene. The solution was treated with 40 drops of dimethylformamide and subsequently, at 0°, with 6.64 ml of oxalyl chloride. After stirring at 0°-5° for 1 hour and for 30 minutes at 20°, the mixture was evaporated under reduced pressure and the residue re-evaporated once with benzene to yield isobutylmalonic acid monobenzyl ester chloride as an orange-red oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#N.[CH3:14]I.C[N:17]([CH3:20])C=O>>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([CH3:12])([CH3:14])[C:20]#[N:17]
Reactant: CI
Reactant: N#CCc1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(F)cc1Br
Yield: 65 %

Procedure:
Add sodium hydride (1 g, 42.1 mmol) to a stirred solution of (2-bromo-4-fluoro-phenyl)-acetonitrile (3 g, 14 mmol) in 10 mL of dimethyl formamide (DMF) at 0° C. Stir the mixture at 0° C. to RT for half an hour. Add methyl iodide (6 g, 42 mmol). Stir for another 30 min. Quench the reaction with water. Extract the product into DCM. Dry the organic phase over sodium sulfate and concentrate to give an oily residue. Purify the residue by flash column chromatography (FCC) (hexane to 20% ethyl acetate in hexane as gradient elute) to give the title compound as a white solid (2.2 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.41-7.47 (m, 2H), 7.03-7.08 (m, 1H), 1.88 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](N2C=CN=C2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:15][CH:16]=[CH:17][C:3]=12.C(N(C(C)C)C(C)C)C.Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:9])=[CH:6][N:5]=[C:4]2[NH:15][CH:16]=[CH:17][C:3]=12
Reactant: O=C(c1cnc2[nH]ccc2c1Cl)n1ccnc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 4-chloro-5-(1H-imidazol-1-ylcarbonyl)-1H-pyrrolo[2,3-b]pyridine(300 mg) in N,N-dimethylformamide (3 ml) were added N-ethyl-N-isopropylpropane-2-amine (0.64 ml) and glycine methylester hydrochloride (305 mg) at ambient temperature. The mixture was warmed immediately to 60° C. and stirred at 60° C. for 2 hours. After to the reaction solution was added water, the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to obtain methyl N-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl]glycinate (267 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.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>[C:19]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-2-(phenylsulfonyl)pyridine (6.00 g), ethynylbenzene (2.87 mL), dichlorobis(triphenylphosphine)palladium (II) (140 mg) and CuI (38 mg) in DMF (90 mL) was added triethylamine (8.42 mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3 to CHCl3-EtOAc 10:1) to give 5-(phenylethynyl)-2-(phenylsulfonyl)pyridine (6.33 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:26][NH2:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:27][CH2:26][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: NCc1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Reactant: C=CC(=O)Cl
Product: C=CC(=O)NCc1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from 4-(8-amino-3-(aminomethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 44) and acryloylchloride, to afford the title compound (1.7 mg, 4%). Data: UPLC(C) Rt: 1.22 min; m/z 414.2 (M+H)+.