Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[Br:15]Br.S([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([Br:15])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: BrBr
Reactant: Cc1ccc(C)c2c1SCCC2(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2(C)C
Yield: 87.1 %

Procedure:
100 ml of methylene chloride was added to 13.2 g (0.064 mol) of 4,4,5,8-tetramethylthiochroman, 10.2 g (0.064 mol) of bromine was dropwise added at room temperature, and then the mixture was allowed to react for 2 hours. After the completion of the reaction, 70 ml of a 2% sodium hydrogensulfite aqueous solution was added, excessive bromine was removed, and the reaction mixture was liquid-separated. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 15.9 g (yield 87%) of 4,4,5,8-tetramethyl-6-bromothiochroman.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([NH2:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>C(O)(C)C>[CH2:17]([NH:18][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:19][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CO1
Reactant: NCCCCCCCCCCN
Solvent: CC(C)O
Product: CCCCC(O)CNCCCCCCCCCCNCC(O)CCCC
Yield: 13.7 %

Procedure:
In a manner similar to that of Example 1, condensation of 1-hexene oxide (34.8 g.) and 1,10-decanediamine (30 g.) and recrystallization of the resulting product from isopropyl alcohol gave N,N'-(1,10-decylene)-bis[2-hydroxyhexylamine] (I: R= CH3 (CH2)3R' = H, X= (CH2)10, Z= H) (8.9 g., m.p. 127.0°-137.0° C.).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:55][C:56]1[CH2:57][CH2:58][CH2:59][CH2:60][N+:61]=1[O-:62]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:62][N:61]4[CH2:60][CH2:59][CH2:58][CH2:57][C@:56]4([CH3:55])[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Reactant: CC1=[N+]([O-])CCCC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@@]4(C)CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 18.6 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 25 ml of toluene is added 0.201 g of 2,3,4,5-tetrahydro-6-methyl-pyridine 1-oxide and the reaction mixture heated at reflux for 12 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:2 ethyl acetate-hexanes to give 0.108 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](I)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:30][CH:31]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(OCc5ccccc5)cc4)cnc3[nH]2)c1
Yield: 64.2 %

Procedure:
0.38 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (example 7) and 0.342 g of 4-benzyloxyphenylboronic acid are dissolved in 16 ml degassed dioxane. Then a solution of 0.276 g of potassium carbonate and 0.85 g of lithium chloride in 13 ml of degassed water and 0.115 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 20 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–26:1). Concentration of the chromatographically pure fractions and crystallisation from ethyl acetate gives 0.28 g of the title compound as a colourless solid of m.p. 161–162° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 437.3 and 894.2 Da.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].O.Cl.[C:10]([NH2:16])(=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:16][C:10](=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)CC(=N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC(=N)CC(C)C
Yield: 93.3 %

Procedure:
78.8 parts of methyl chloroformate and a mixture of 46.8 parts of potassium hydroxide in 215 parts of water are added via two inlets to a mixture of 113.8 parts of isovaleramidine hydrochloride in 530 parts of methylene chloride, at from 0° to 10° C., in the course of 25 minutes, while stirring. The mixture is stirred at 25° C. for 30 minutes, the phases are separated and the aqueous phase is extracted once with methylene chloride. The solvent is removed from the organic extract to give 123 parts (93.3% of theory) of N-methoxycarbonylisovaleramidine of melting point 82°-86° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.C(OC)(OC)OC.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>CO>[CH2:24]([NH:32][CH2:1][C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCc1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Reaction time: 3 h
Yield: 48 %

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (200 mg, 0.87 mmol), (MeO)3CH (1.2 mL), phenethyl amine (0.142 mL, 130 mol %) and methanol (1.7 mL). Stir the resulting mixture for 3 hours, and then add sodium borohydride in portions. Stir for few hours. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (5 mL) and CH2Cl2 (7 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the product through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound (139 mg, 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]CC)=[C:4](F)[C:3]=1F.[CH2:13]([Li])[CH2:14][CH2:15]C.CCCCCC>C1COCC1>[CH2:2]([CH:7]1[CH2:3][CH2:4][C:5](=[O:8])[CH2:6]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1CCC(=O)C1
Reaction time: 1.5 h

Procedure:
THF (40 ml) was added to 1-bromo-4-ethoxy-2,3-difluorobenzene-(3.56 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −78° C. n-Butyllithium (1.65 M, in a hexane solution) (9.1 ml) was added dropwise at a temperature of −70° C. or lower. The stirring was continued at −78° C. for another 1.5 hour and 3-butyl-cyclopentanone (2.1 g) obtained in the first step, in a THF (20 ml) solution was added dropwise at a temperature of −70° C. or lower. After the mixture had been stirred at −78° C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) to give 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(O)(=O)C>[C:27]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)(=[O:29])[CH3:28]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone, glacial acetic acid and acetic anhydride.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16]>O1CCOCC1.CCOC(C)=O>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16]
Reactant: COC(=O)Cl
Reactant: N[C@H](C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g, 3.31 mmol) in dioxane at 0° C. was added NaOH (5.46 g, 10.92 mmol) followed by dropwise addition of methyl chloroformate (0.51 mL, 6.62 mmol) and the solution was warmed to room temperature with stirring over 1 h. Diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and removed solvent in vacuo to give the title compound (0.35 g, 1.673 mmol, 51%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][C:28]([CH3:30])=[CH2:29])=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:29]=[C:28]([O:27][C:25]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[O:26])[CH3:30]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)OC(=O)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1 g, 5 mmol) and DIEA (1.76 ml) in DCM (10 ml) at 0° C. was added isopropenyl chloroformate dropwise. After the addition, the reaction mixture was allowed to warm up to room temperature and was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added and the organic layer was collected, washed with water and dried over sodium sulfate. After removal of solvent, the crude product (1.8 g) was used directly for the next step reaction.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[N:20]=[C:21]([CH2:23][CH2:24][OH:25])[CH:22]=[C:12]3[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[N:20]=[C:21]([CH2:23][CH2:24][OH:25])[CH:22]=[C:12]3[C:11]=2[CH:10]=1
Reactant: O=c1[nH]c2ccc(OCc3ccccc3)cc2c2cc(CCO)nn12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(O)cc2c2cc(CCO)nn12
Temperature: 25 °C

Procedure:
29.2 g (0.1 mole) of 9-(benzyloxy)-2-(2-hydroxyethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one and 0.5 g 10% palladium-on-carbon in 200 ml ethanol containing 0.2 moles of hydrogen chloride are hydrogenated on a Parr shaker, with cooling, at ambient temperature. The reaction is stopped after 0.3 moles of hydrogen are absorbed or when hydrogen uptake ceases, whichever comes first. The reaction is diluted with chloroform, filtered and the filtrate evaporated. The residue is suspended in methylene chloride and shaken with excess aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[CH:25]4[OH:31])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](Cl)(C(C)(C)C)(C)[CH3:33].N1C=CN=C1>CN(C)C=O>[CH3:33][N:10]([CH:8]1[CH2:9][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]1[C:12]2[N:23]=[N:22][N:21]([CH:24]3[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[CH:25]3[OH:31])[C:13]=2[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product of step d) (1.79 g), tert-butyldimethylsilylchloride (1.22 g) and imidazole (1.10 g) in N,N-dimethylformamide (3 ml) was stirred at ambient temperature for 24 hours. Further tert-butyldimethylsilylchloride (1.0 g) was added and the mixture stirred for a further 6 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate: hexane 1:20 as eluant) to afford the sub-title compound (2.43 g).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:29]=[CH:28][C:13]([CH2:14][C:15]3[C:16]([CH2:26][CH3:27])=[N:17][N:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[N:20][C:19]=34)=[CH:12][CH:11]=2)[CH:9]=1)C.Cl>O1CCOCC1>[CH2:26]([C:16]1[C:15]([CH2:14][C:13]2[CH:28]=[CH:29][C:10]([N:8]3[CH:9]=[C:5]([CH:4]=[O:3])[N:6]=[N:7]3)=[CH:11][CH:12]=2)=[C:19]2[N:20]=[C:21]([CH3:25])[CH:22]=[C:23]([CH3:24])[N:18]2[N:17]=1)[CH3:27]
Reactant: CCOC(OCC)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(-n2cc(C=O)nn2)cc1

Procedure:
A solution of 3-[4-(4-diethoxymethyl-[1,2,3]triazol-1-yl)-benzyl]-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (21) (2.19 g, 5.04 mmol) and 4N HCl (50 ml, 200 mmol) in 30 ml of dioxane was stirred at r.t. for 2 h. The reaction mixture was quenched with sat aq NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2 SO4, filtered and concentrated under HV.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12](O)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:35]>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([NH2:35])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(N)=O)n1Cc1ccccc1Cl

Procedure:
(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid, prepared in Example 2, is treated with thionyl chloride and then ammonium hydroxide, as described in Example 57, to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[N:13]1([C:5]2[N:4]=[C:3]([NH2:18])[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Agent: [Cs+]
Agent: [F-]
Product: Nc1nc(-n2cccn2)nc(-n2cccn2)c1-c1nccs1
Temperature: 80 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
A mixture of 8.9 mg (13.1 μmol) of Pd-PEPPSI-IPr-catalyst, 0.1 g (0.33 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine (Example 1), 0.1 g (0.65 mmol) of cesium fluoride and activated, crushed 4 Å molecular sieves (33 mg) in a glass vial was purged with argon and 1 ml of dioxane was added. 0.15 (0.39 mmol) of 2-tributylstannylthiazole was then added and the reaction was stirred at 80° C. for 24 h. The mixture was filtered throw celite/CsF. The solvent was removed in vacuum. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as eluent to give 47.9 mg (47.2%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH2:42]O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH2:42][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][C:7]=3[S:8][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:12])=[CH:18][CH:17]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OCC1CCCCN1Cc1ccccc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCCN3Cc3ccccc3)cc2)cc1
Yield: 36 %

Procedure:
The product from Step 2 (600 mg) was coupled with (1-benzyl-piperidin-2-yl)-methanol (379 mg) as is Example 10, Step 3 to yield the title compound (320 mg) after silica gel chromatography with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as the gradient eluant.
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].[CH3:13]O>>[C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([O:3][CH3:13])=[O:2]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CO
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 2-carboxy-indane (2.5 g, 15.4 mmol) in methanol and cool to 0° C. Saturate with hydrogenchloride gas then add 2,2-dimethoxypropane (2-3 mL). Stir overnight then evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 methylene chloride:hexane) to give 2-carbomethoxy-indane as a water white oil (2.04 g, 75%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([F:27])[C:3]=1[C:4]#[N:5].C1(C)C=CC=CC=1.[H-].[Na+].CN([CH:40]=[O:41])C>CO>[F:27][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:9]=[C:2]([O:41][CH3:40])[C:3]=1[C:4]#[N:5]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C(C)C)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (360 mg, 0.96 mmol) was azeotroped with toluene (2×12 mL). The resulting residue was taken up in 7.5 mL of CH3OH as a suspension. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was added to a chilled (ice bath) solution of CH3OH (12.5 mL) under nitrogen portion-wise. After completion of addition, the ice bath was removed. The resulting mixture was stirred at ambient temperature for 10 minutes (concentration of CH3ONa was assumed to be 0.52 mmol/mL). A 2.25 mL portion (1.17 mmol, 1.2 equiv) of this mixture was added to the above suspension at room temperature in one portion. The resulting suspension was stirred at room temperature for 2 hours. LCMS showed no conversion. After another 1 h, 5 mL of DMF was added to the mixture, which became milky. The mixture was stirred at room temperature for another 16 hours, upon which time, it became a clear solution. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (20 mL) as a suspension, which was sonicated briefly, and then filtered. The solids collected were dried under house vacuum at room temperature for 1 hour. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (350 mg) as a foam. LC-MS (ES) m/z=386 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([O:22][CH3:23])=[CH:6][CH:5]=2.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: COc1ccc2[nH]c(C)c(C(=O)c3ccccc3C(=O)O)c2c1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]c(C)c(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)c2c1
Yield: 91.5 %

Procedure:
A mixture of 2.0 g (0.006 mole) of 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]benzoic acid, obtained as described in part A above, 1.1 g (0.0067 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and six ml of acetic anhydride were interacted at 50°-55° C. in a manner similar to that described in Example 2, part B to obtain 2.5 g of 3-[2,4-bis(dimethylamino)-phenyl]-3-(2-methyl-5-methoxy-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =OCH3), as a light pink-colored solid melting at 196°-198° C. with decomposition. The infrared spectrum, showing a significant maximum at 1740 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum were in accord with the structure. A toluene solution of this product spotted on a phenolic resin coated paper developed an intense violet-colored image.
Reaction SMILES: [Br-].[C:2]([N:5]([CH:23]1[CH2:25][CH2:24]1)[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N+:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[CH3:26][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.CO>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([N:5]([CH:23]2[CH2:25][CH2:24]2)[C:2](=[O:4])[CH3:3])=[CH:7][CH:8]1[CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)N(c1cc[n+](Cc2ccccc2)c2ccccc12)C1CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(C1=CC(C)N(Cc2ccccc2)c2ccccc21)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a mixture of 4-(acetyl-cyclopropyl-amino)-1-benzyl-quinolinium bromide (9.6 g) in tetrahydrofuran (200 ml), under nitrogen and under cooling at 0° C., a solution of methyl magnesium chloride 1 Mol/l (12 ml) was added during 15 minutes. After 2 hours, a solution of ammonium chloride in methanol (100 ml) was added. The solvent was removed under reduce pressure and then washed with dichloromethane and water. The organic layer was separated and the solvent was removed under reduce pressure. The crude compound was purified by flash chromatography on silicagel with an eluent of dichloromethane/methanol (98/2) to give the N-(1-benzyl-2-methyl-1,2-dihydro-quinolin-4-yl)-N-cyclopropyl-acetamide (7.9 g, 98.6% yield).