Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]([CH2:21][CH2:22][Cl:23])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1cccc(Cl)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCl)Cc1cccc(Cl)c1
Yield: 44.7 %

Procedure:
Using 1.01 g of (3-chlorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 1.38 g of potassium carbonate, and 1.44 g of 1-bromo-2-chloroethane, and according to the process described in the Production Example 1, there was obtained 0.60 g of 2-(3-chlorobenzyl)-2-(2-chloroethyl)malononitrile (the present compound (63)).
Reaction SMILES: [CH3:1][O:2][P:3]([O:22][CH3:23])([C:5](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[O:4].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][P:3]([O:22][CH3:23])([C:5](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7])=[O:4]
Reactant: CCCCCCBr
Reactant: COc1ccc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Isopropyl 2-(dimethoxyphosphinyl)-3-(3-hydroxy-4-methoxy-phenyl)propenoate (2 g; 0.0058 mol; Table 1, No. 26), 1-bromohexane (0.85 ml; 0.006 mol), 30 ml of dimethylformamide (DMF) and potassium carbonate (ground, 0.89 g; 0.0065 mol) were mixed and stirred at room temperature for 6 hours. The filtrate after removal of the inorganic salts was evaporated under reduced pressure. Residues of DMF were removed from the resulting oily residue in a kugelrohr apparatus at 70° C./0.02 mm Hg, and it was then chromatographed on silica gel eluting with a dichioromethane:ethane acetate (8:2) mixture. This resulted in a pale oil. Yield: 3.6 g (72.5% of theory)
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:31])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:31][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: Cc1cc([C@H](N)CN2CCC2)ccc1Cl
Agent: Cl
Product: Cc1cc([C@@H](CN2CCC2)Nc2ncnc3c(C(N)=O)ccnc23)ccc1Cl

Procedure:
Compound 46 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [397 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.01 (s, 1H), 8.99 (d, J=4.5 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.17 (s, 1H), 7.45 (s, 1H), 7.39-7.24 (m, 2H), 5.34-5.17 (m, 1H), 3.20-2.98 (m, 5H), 2.83-2.71 (m, 1H), 2.29 (s, 3H), 2.01-1.84 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.CO.[BH4-].[Na+]>[OH-].[Na+].O>[CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6]([OH:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: CC1c2ccccc2CC(=O)Cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1c2ccccc2CC(O)Cc2ccccc21

Procedure:
12-Methyl-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-one (3.6 g., 15.3 mmole) in 25 ml. of methanol was treated with several drops of 1 M sodium hydroxide followed by 0.58 g. (15.3 mmole) of sodium borohydride in 5 ml. of water. The mixture was heated at reflux for 20 minutes, cooled, and concentrated in vacuo. The residue was slurried in water and extracted three times with chloroform. The chloroform fractions were washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo to give 3.7 g. of white solid, m.p. 142°-145° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH2:27])=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH:27][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:16]1
Reactant: NCCCc1c[nH]c2ccccc12
Reactant: ClCCOc1cccc2ccccc12
Product: c1ccc2c(OCCNCCCc3c[nH]c4ccccc34)cccc2c1
Yield: 85 %

Procedure:
This compound was prepared in the manner described above for Example 13 by replacing 2-(indan-4-yloxy)-ethylchloride with 2-(napthalen-1-yloxy)-ethylchloride (0.6 g, 2.8 mmol), and 3-(5-fluoro-1H-indol-3-y-)-propylamine with 3-(1H-indol-3-yl)-propylamine (1.35 g, 7.2 mmol) in 85% yield (1.42 g) as a yellow solid: mp 119-120° C.
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:16]=1[CH2:17]Br>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[CH2:17][C:16]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:29])[CH3:32]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture containing 3 g of benzyl 2-indolecarboxylate in 30 ml of anhydrous DMF and 500 mg of sodium hydride at 60% in oil is left stirring under a nitrogen atmosphere for 1 hour. 3 g of ethyl 6-bromohexanoate in 10 ml of DMF are added, at 0° C., and the mixture is left stirring overnight at RT. The solvents are evaporated off and the residue is taken up in EtOAc, washed with water, dried over MgSO4 and concentrated. The residue is chromatographed on a column of silica H, eluting with a heptane/toluene mixture (50/50; v/v) to give 4.17 g of the expected compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC=C)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22]C)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH2:34](N(CC)CC)C.C(O)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:34])([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(CC)c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2.00 g (4.12 mmol) of 2-[3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 371 are dissolved in 20 ml degassed dioxan and treated under argon with 97 mg of tetrakis(triphenylphosphine)-palladium(0) (0.084 mmol), 1.46 ml (10.44 mmol) of triethylamine and 0.32 ml (8.35 mmol) of formic acid and stirred for two hours at 85° C. The suspension is then allowed to cool to room temperature and the precipitated crystals are filtered off at the pump and washed with isopropanol. The mother liquor is concentrated in vacuo and treated with isopropanol, during which further crystals deposit, which are likewise suction-filtered and washed with isopropanol. Together 1.56 g (85% of theory) of the target compound are thus obtained.
Reaction SMILES: [F:1][C:2]([F:17])([N:8]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[N:9]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:18][C:19]1[C:28](Cl)=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:18][C:19]1[C:28]([NH:14][S:13]([C:10]2[CH:11]=[CH:12][N:8]([C:2]([F:1])([F:17])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:9]=2)(=[O:15])=[O:16])=[N:27][C:26]2[C:21]([N:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: CN(C)C(=O)C(F)(F)n1ccc(S(N)(=O)=O)n1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(F)(F)n1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)n1
Temperature: 0 °C
Yield: 69 %

Procedure:
1.30 g of 2,2-difluoro-N,N-dimethyl-2-(3-sulfamoylpyrazol-1-yl)acetamide, 1.16 g of 2,3-dichloroquinoxaline and 670 mg of potassium carbonate in about 16 ml of dried DMA are heated at 100° C. (bath temperature) under nitrogen in a flask until the sulfonamide has reacted virtually completely (HPLC check, about 3 hours). The cooled reaction solution is poured into about 200 ml of ice-water, with a precipitate depositing after some time. This is filtered off with suction and discarded. The filtrate is adjusted to pH 4-5 using saturated citric acid solution. A further precipitate deposits, which is filtered off, washed with water and dried, giving 1.44 g of 2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamide as pale-beige solid (yield 69%, content 99.8%). MS-FAB (M+H+)=431.0. Rf (polar method): 1.98 min. This is employed without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[CH:25]=[CH:26]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (500 mg, 1.77 mmol) in dioxane (15.0 mL) and water (5.0 mL) were added K2CO3 (730 mg, 5.31 mmol) and N-methylindole-5-boronic acid (140 mg, 1.95 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (100 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude title compound. Crude product was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:22])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c[nH]c3ncc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Aluminum trichloride (2.7 g, 20.0 mmol) and methylene chloride (30 mL) were combined under an atmosphere of nitrogen and 5-bromo-7-azaindole (67, 400.0 mg, 2.30 mmol) in methylene dichloride (20 mL) was added. The reaction was stirred at room temperature for 70 minutes. 4-Methoxybenzoic acid chloride (0.38 g, 2.2 mmol) (prepared from the corresponding carboxylic acid using the protocol described in Example 1, Scheme 13, Step 4) in methylene dichloride (7.0 mL) was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the compound (116, 250 mg, 34%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:34](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
35.0 ml (0.25 mol-1.8 equiv.) of triethylamine were added dropwise to a solution, cooled to 0° C., of 33.18 g (0.14 mol) of 4-nitrobenzyl acetoacetate and 30.40 g (0.15 mol) of p-toluenesulphonyl azide in 280 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 2 hours, and the resultant precipitate was then filtered off under suction, washed with ether and dried in a high vacuum over P4O10. 20.3 g (55% of theory) of the title compound were obtained as colorless crystals, melting point: 132° C. A further 6.3 g (17% of theory) of the title compound were obtained by chromatography of the filtrate solution on 400 g of silica gel (toluene:ethyl acetate=9:1), Rf =0.35 (toluene:ethyl acetate=9:1).
Reaction SMILES: [NH:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11]I>C(O)C>[CH3:11][N:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)Nc1ccccc1
Reactant: CI
Solvent: CCO
Product: CC(O)N(C)c1ccccc1
Reaction time: 8 h

Procedure:
In a 250 ml container, take 50 g (0.365 mole) of 2 N anilinoethanol, 52.5 g (0.35 mole) of methyl iodide and 66 ml of ethanol. The solution is left overnight under ethanol reflux.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:8](Br)([CH3:11])([CH3:10])[CH3:9]>CCCCC>[C:8]([C:2]1([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:1]=[CH:5][CH:4]=[CH:3]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)Br
Reactant: C1=CCC=C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Product: CC(C)(C)C1(C(C)(C)C)C=CC=C1
Reaction time: 0.75 h

Procedure:
In this example, freshly distilled cyclopentadiene, a 50 wt % aqueous solution of potassium hydroxide, and tertiary-butyl bromide in the molar ratio of 1:40:5 were stirred together in a reactor. The quaternary ammonium halide, Adogen® 464 is added in the amount of one gram per mole of the potassium hydroxide. These reactants were stirred together and heated to 60° for 75 minutes and then at 100° for an additional 45 minutes. During the reaction foaming may occur which should be controlled. The reaction mixture is then cooled, diluted with pentane, washed with water and dried over magnesium sulfate. The pentane is then removed by vacuum. The crude residue contains the product and the Adogen® 464. Chromatography of the crude material over silica gel yielded di(tert-butyl)-cyclopentadiene. The overall calculated yield is 90 wt % based on the starting cyclopentadiene material.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH:22][C:34](=[O:36])[CH3:35])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)no1
Yield: 51.5 %

Procedure:
To a solution of Example 40D (265 mg, 0.76 mmol) in tetrahydrofuran (5 mL) at room temperature, was added diisopropylethyl amine (400 uL) followed by acetic anhydride (150 μL, 1.59 mmol). After an hour the reaction was quenched with methanol and stirred for additional hour. The solvent was removed under vacuum and the product was purified via silica-gel column chromatography using a gradient of 25 to 75% ethyl acetate in hexane to provide the title compound (152 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.90 (s, 1H) 7.17-7.25 (m, 2H) 6.89-6.99 (m, 2H) 6.09 (d, J=7.72 Hz, 1H) 5.33-5.53 (m, 1H) 4.54 (heptet, J=6.0 Hz, 1H) 2.08 (s, 3H) 1.62 (d, J=7.0 Hz, 3H) 1.36 (d, J=6.0 Hz, 6.0H).). MS (DCI): m/z 389 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[S:4]([C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:8]=1[CH3:22])(=[O:6])=[O:5])[CH3:2].[NH2:24][C:25]1[C:26]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36][CH2:35]3)=[N:27][C:28](Br)=[CH:29][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:23])(=[O:5])=[O:6])=[C:8]([CH3:22])[CH:9]=2)=[N:27][C:26]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[NH:37][CH2:36][CH2:35]2
Reactant: CCN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: Nc1ncc(Br)nc1-c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1C
Yield: 28.6 %

Procedure:
A solution of N-ethyl-2,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (140 mg, 0.42 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.38 mmol) Pd(PPh3)4 (13.2 mg, 0.011 mmol) and 2.0 M aq. Na2CO3 (0.38 mL) in n-butanol (2 mL) was microwave heated at 150° C. for 10 min to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-ethyl-N,2-dimethylbenzenesulfonamide (49 mg, 29% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.04 (s, 1H), 7.93-8.02 (m, 3H), 7.82 (d, J=8.28 Hz, 1H), 7.67-7.77 (m, 2H), 6.62 (s, 2H), 3.43 (td, J=6.40, 2.51 Hz, 2H), 3.18 (q, J=6.94 Hz, 3H), 3.00 (t, J=6.53 Hz, 2H), 2.76 (s, 3H), 2.59 (s, 3H), 1.08 (t, J=7.15 Hz, 3H). MS (EI) m/z: 452 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq NH4OAc, 4 min gradient) tR=2.14 min, 100% integrated area.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)(=O)C>[O:7]=[C:1]1[CH:2]=[CH:3][C:4](=[O:6])[N:8]1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: NCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
A solution of maleic anhydride (5.00 g, 0.0561 mol) in acetic acid (70 ml) was added dropwise to a solution of β-alanine (5.50 g, 0.0561 mol) in acetic acid (25 ml) and the mixture was stirred at room temperature for three hours. 50 mL of acetic acid was added to the white suspension and the mixture heated up to 115° C. After 1 h a limpid colourless solution was observed. The mixture was then stirred at this temperature overnight and the colour turned to orange. The solvent was then removed under reduced pressure and 30 mL of toluene was then added to the resulting orange oil. This was then evaporated under reduced pressure and this operation was repeated 3 times. The orange residue was then purified by flash chromatography (CC, SiO2, CH2Cl2/ethyl acetate 9:1) to give the product as a white solid (3.86 g, 0.0228 mol, 41%). m.p. 105-107° C. IR (neat): 3092, 2883, 2537, 1695, 1445, 1411, 1373, 1337, 1305, 1230, 1151, 1081, 1043, 924, 830, 773, 694, 618 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=2.69 (t, J=7.3 Hz, 2H, CH2), 3.82 (t, J=7.3 Hz, 2H, CH2), 6.71 (s, 2H, CHvinyl) 10.07 (bs, 1H, COOH). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=32.62 (1C, CH2), 33.36 (1C, CH2), 134.38 (2C, CHvinyl) 170.48 (1C, C), 176.64 (2C, C). Anal. Calcd. for C7H7NO4: C, 49.71; H, 4.17; N, 8.28. Found C, 49.35; H, 4.19; N, 7.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:8]1[CH:7]=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1cccc(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(NC(C)=O)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
N-(3-Methoxy-phenyl)-acetamide (17.7 g, 107 mmol) in methylene chloride was cooled to zero degrees C., and acetyl chloride (19.0 ml, 268 mmol) was slowly added, followed by aluminum chloride (35.7 g, 268 mmol) in small portions over 15 min. The reaction mixture was stirred 15 minutes at zero degrees, then allowed to warm to room temperature with stirring. The reaction mixture was poured into ice, stirred 35 minutes, and filtered. The solid was washed with water. The filtrate was extracted with EtOAc and solvent was removed under reduced pressure. The combined solids gave N-(4-Acetyl-3-methoxy-phenyl)-acetamide (16.5 g., 74%) as a solid.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C@H:16]1[NH:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:17]1.C(O)(=O)C>CO>[CH3:22][C@H:20]1[N:21]([CH3:1])[C@@H:16]([CH3:15])[CH2:17][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
Sodium triacetoxyborohydride (5.30 g, 25.00 mmol) was added to ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.62 g, 10 mmol), and acetic acid (1.145 mL, 20.00 mmol) in methanol (15 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with saturated NaHCO3 (15 mL) to pH7 and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (1.960 g, 70.9%) as a yellow oil. MS: m/z 277 (MH+).