Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7](O)=O)[C:4]2[O:10][C:11]3C(C(O)=O)=CC=C[C:12]=3[C:3]=2[CH:2]=1.CC1C=CC(S([NH2:30])(=O)=O)=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O>[C:42]([C:41]1[C:11]2[O:10][C:4]3[C:5]([C:7]#[N:30])=[CH:6][CH:1]=[CH:2][C:3]=3[C:12]=2[CH:38]=[CH:39][CH:40]=1)#[N:37]
Reactant: O=C(O)c1cccc2c1oc1c(C(=O)O)cccc12
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cccc2c1oc1c(C#N)cccc12
Temperature: 200 °C

Procedure:
To a mixture of one equivalent of 4,6-dibenzofurandicarboxylic acid [H. Gilman and R. Young, J. Am. Chem. Soc. 57, 1121 (1935)] and 2.2 equivalents of p-toluenesulfonamide is added 4.5 equivalents of phosphorous pentachloride. When the initial reaction subsides the reaction mixture is heated to 200° C. and the solid residue remaining is cooled and treated with pyridine and water. The suspension is filtered, washed with water and suspended in dilute sodium hydroxide solution followed by filtration and washing with water to give 4,6-dicyanodibenzofuran which can be recrystallized from a dimethylformamide-water combination. In like manner 3,7-dicyanodibenzofuran is prepared from 3,7-dibenzofurandicarboxylic acid [H. Sugil and H. Shindo, J. Pharm. Soc. Japan 54, 829 (1934)].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][NH2:44].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:44][O:43][CH3:42])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C(=O)Nc1cc(C(C)(C)C)nn1-c1ccc(C)cc1)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 45 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and methoxyamine hydrochloride (50 eqv., 0.92 mmol, 77 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 8 mg of a white solid (76% yield; mixture of isomers). Expected mass=569. Observed mass=570.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(O)=[O:11].C([O-])=O.Cl>CC#N.CO>[OH:11][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=CO
Agent: Cl
Agent: O=C[O-]
Solvent: CC#N
Solvent: CO
Product: Cc1oc(=O)oc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 310.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): δ 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [C:1]1([NH:9][C:10]([NH:12][CH3:13])=[S:11])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].C(OC(O[CH2:21][CH3:22])CCl)C.[OH-]>Cl>[C:1]1([N:9]=[C:10]2[N:12]([CH3:13])[CH:22]=[CH:21][S:11]2)[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8]
Reactant: CCOC(CCl)OCC
Reactant: CNC(=S)Nc1ccc(C)cc1C
Agent: Cl
Agent: [OH-]
Product: Cc1ccc(N=c2sccn2C)c(C)c1
Temperature: 25 °C

Procedure:
19.4 g (0.1 mole) of N-2,4-xylyl-N'-methyl-thiourea and 15.2 g (0.1 mole) of chloroacetaldehyde-diethylacetal in 150 ml of 2N aqueous hydrochloric acid are refluxed for 1 hour. The clear light-yellow solution is subsequently cooled to room temperature; it is rendered slightly alkaline with 30% aqueous medium hydroxide solution, and extracted with ether. The ether extract is washed with water, dried with sodium sulphate and filtered, and the ether is then distilled off. The oily residue is distilled; b.p. 132°-134° C/0.3 Torr; yield: 20.2 g = 92% of theory.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[CH:31]=[C:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)[CH3:30]
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirring solution of DMSO (5.3 mL, 75 mmol) in methylene chloride (100 mL) at −78° C. under argon was added oxalyl chloride (4.6 mL, 53 mmol) dropwise. After stirring for 30 min., a solution of 1-benzhydryl-azetidin-3-ol hydrochloride (12) (10 g, 36 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. before triethylamine (18 mL, 128 mmol) was added. The ice bath was removed and the reaction quenched with saturated ammonium chloride (75 mL) at 0° C., then extracted with ethyl acetate (3×150 mL). The combined ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in ethyl acetate and hexane, filtered to give 1-benzhydrylazetidin-3-one (9 g, 33 mmol, 92%). To a stirring solution of the resulting 1-benzhydryl-azetidin-3-one (8.3 g, 30 mmol) in methylene chloride (120 mL) was added triethylamine (6.4 mL, 45 mmol), and carbethoxymethylene triphenylphosphorane (15.9 g, 45 mmol). This reaction mixture was stirred under argon at room temperature for 2 hrs., then quenched with acetone (1 mL), and concentrated in vacuo. The residue was stirred in 20% ethyl acetate in hexane (20 mL) as triphenyl phosphine oxide precipitated. The mixture was then filtered and concentrated. The crude product was chromatographed on silica gel, eluting with 50:40:10 methylene chloride:hexane:ether to give 9.3 g of the title compound.
Reaction SMILES: CC(C)(OC(N[C@H]([C:19]1[N:20](CC(=O)C2C=CC=CC=2)[CH:21]=[C:22](C2C=CC=CC=2)[N:23]=1)CC1C2C(=CC=CC=2)NC=1)=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:20]1[C:21]2[N:20]=[CH:21][CH:22]=[N:23][C:22]=2[NH:23][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cn1CC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(n1)NCN2
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Na+].Cl.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=[C:40]([C:42](N)=[O:43])[CH2:39][CH:38]=[CH:37]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.S[CH2:51][C@H:52]([C@@H:54]([CH2:56]S)O)O.C([O-])=O>C(O)C(N)(CO)CO>[OH:43][C@H:42]([CH2:40][CH2:39][C:38]1[CH:37]=[CH:56][CH:54]=[CH:52][CH:51]=1)[C:1]([OH:3])=[O:2]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C[O-]
Reactant: O[C@H](CS)[C@H](O)CS
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Na+]
Product: O=C(O)[C@H](O)CCc1ccccc1
Yield: 95 %

Procedure:
A solution of sodium 2-oxo-4-phenyl butanoate (601 mg, 3.0 mmol) and sodium formate (0.34 g, 5 mmol) in Tris buffer (5 mM; pH adjusted to 7.5 with 2M HCl). NADH (43 mg, 0.06 mM), dithiothreitol (7.5 μl of a 1M aqueous solution), formate dehydrogenase from yeast (Boehringer; 20 mg, 10 U) and R-lactate dehydrogenase from Staphylococcus epidermidis (Sigma; 31 mg, 500 U) were added successively to the solution at room temperature under nitrogen. The mixture was stirred under nitrogen for 77 hours, with periodic addition of dilute HCl (0.5 m; 3.9 ml) to maintain the pH in the range of 7.4-7.6. After acidification to pH2 and saturation with sodium chloride, the mixture was filtered under gravity. The filtrate was subjected to a normal ethyl acetate (4×70 ml) work-up with brine wash (70 ml ) to afford (R)-2-hydroxy-4-phenyl butanoic acid (7) as an amorphous white solid (513 mg, 95%) having identical spectroscopic properties to the (S)-enantiomer (compound 14). The title compound gave a melting point of 113°-115° C. and an [α]D22 value (c=2.21, EtOH) of -8.4°. 1H-NMR and capillary GC analysis of the Mosher derivative of the corresponding methyl ether indicated that homochiral (>99% ee) product had been obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.N1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:16]2[CH2:18][CH2:17]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-2-methylbenzoic acid and SOCl2 was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 30 mL CH2Cl2 and combined with cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0 mmols). The solution was stirred for 18 hours and then diluted with EtOAc before being washed with 5% aqueous HCl, saturated NaHCO3, and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure leaving the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: BrCc1cccnc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (423 mg) in DMF (5 mL) was added potassium carbonate powder (868 mg) and 3-(bromomethyl)pyridine hydrogen bromide (615 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (15%-60% EtOAc/hexanes) to yield the title compound as a green solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:29][CH2:30][CH3:31])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1>C(O)C.[Pd]>[CH2:29]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]2[C:3]([N:4]=1)=[CH:2][N:10]=[CH:9][N:8]=2)[CH2:30][CH3:31]
Reactant: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2cncnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
6-Chloro-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine (0.030 g) was dissolved in ethanol (2 ml) and was stirred under an atmosphere of hydrogen in presence of Pd-C(10%) (0.01 g) for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness giving the pure desired product as a glass like solid (0.020 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.I[CH3:27].[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:25]([CH3:27])[CH:24]=[N:23][N:5]2[C:6](=[N:17][CH2:18][C:19]([F:21])([F:20])[F:22])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: CI
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1cnn2c(=NCC(F)(F)F)c(-c3c(F)cc(F)cc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.78 mmol) in 4 mL of dimethylsulfoxide at room temperature is added iodomethane (146 μL, 2.34 mmol) followed by sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol). The mixture is then stirred at room temperature for 18 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides N-[5-chloro-3-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-ylidene]-2,2,2-trifluoroethanamine as a white solid (76 mg). MS: m/z 396.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[CH3:25])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH:26]1([CH2:29][NH:30][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[CH3:25])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
Temperature: 120 °C
Yield: 9.6 %

Procedure:
To a solution of 8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 113, 40 mg, 0.114 mmol) in NMP (3 mL) was added cyclopropanemethylamine (0.1 ml, 1.140 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was diluted with aqueous saturated NaHCO3 (20 mL) and EtOAc (2×20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in EtOAc to give the title compound (4.2 mg, 10%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:17][CH2:16]2)=[CH:21][CH:20]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
A solution of 1-[2-(4-nitrophenyl)ethyl]piperazine (300 mg, 1.3 mmol), 1-bromo-4-(2-bromoethyl)benzene (400 mg, 1.5 mmol), and triethylamine (0.89 mL, 6.4 mmol) in DMF (5 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product. The desired product was purified by silica gel chromatography (10% MeOH in EtOAc). LC-MS (IE, m/z): 420 (M+1)+.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]3=[CH:24][CH:25]=[N:26][N:19]3[CH2:18][CH:17](O)[C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(Cl)Cl>[C:35]([O:34][C:32]([N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]3=[CH:24][CH:25]=[N:26][N:19]3[CH:18]=[CH:17][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1C(O)Cn1nccc1-2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (0.5 mL) was added to a solution of methyl 8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 8, 0.290 g) in triethylamine (0.7 mL) and DCM (10 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was washed with 1M aqueous hydrochloric acid and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.280 g) as a gum.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=3)[C:20]2=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])[CH3:33].Cl.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CC#N.CCOC(C)=O>[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:28]([C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH:19]([CH2:18][CH2:17][CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:16][CH2:15]3)[C:20]2=[O:31])=[CH:25][CH:24]=1)=[O:29])[CH3:33]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)CCNC(=O)c1ccc2c(c1)C(=O)C(CCC1CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A slurry of 1-4 (0.45 g, 1.2 mmol), β-alanine ethyl ester·HCl (Aldrich) (0.184 g, 1.2 mmol), in CH3CN (2 mL) was treated with N-methylmorpholine (0.4 mL, 3.6 mmol) and BOP reagent (0.8 g, 1.8 mmol) and stirred at room temperature for 24 h. The solution was diluted with EtOAc, washed with H2O, 10% KHSO4 and brine, dried (MgSO4), filtered, concentrated and chromatographed (30% EtOAc/Hexanes) to give 1-5 as a tan solid. Rf (30% EtOAc/Hexanes) 0.22 1H NMR (300 MHz, CDCl3) δ 8.14 (d, 1H), 8.03 (s, 1H), 7.59 (d, 1H), 7.3 (m, 5H), 6.92 (m, 1H), 5.12 (s, 2H), 4.2-4.1 (m, 4H), 3.75 (dd, 2H), 3.4 (m, 1H), 2.92 (dd, 1H), 2.78 (m, 2H), 2.17 (t, 2H), 2.41 (dd, 1H), 2.0 (m, 1H), 1.7 (m, 3H), 1.6- 11 (m, 6H), 1.3 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[N:14]1[CH:18]=[C:17]([CH:19]=O)[NH:16][CH:15]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:22]1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:19]([C:17]1[N:16]=[CH:15][NH:14][CH:18]=1)[C:22]1[NH:21][C:29]2[C:24]([C:23]=1[CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=Cc1cnc[nH]1
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2c[nH]cn2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with 3H-imidazole-4-carbaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as pale brown solid. MS: 455.0 ([M+H]+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([C:26]#N)[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1.Cl.C([O:32]C(C)C)(C)C>C1(C)C=CC=CC=1.CO>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([CH:26]=[O:32])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1
Reactant: CC(C)OC(C)C
Reactant: Cn1cc(C2(C#N)CCCC2)c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1cc(C2(C=O)CCCC2)c2ccccc21

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 94.4 cm3 (0.0944 mol) of a 1N toluene solution of diisobutylaluminium hydride are added at -60° C. to a solution of 13.3 g (0.059 mol) of 1-(1-methyl-3-indolyl)-cyclopentanecarbonitrile in 230 cm3 of toluene. The temperature of the mixture is thereafter allowed to rise to room temperature, and the reaction is then stopped by adding 50 cm3 of methanol and then 230 cm3 of 3N hydrochloric acid to the reaction mixture. The mixture is extracted with dichloromethane, the organic extract is washed with water, dried over sodium sulphate and filtered and the filtrate is evaporated. In succession, the residue obtained is taken up with diisopropyl ether, some insoluble matter is removed by filtration, the solvent is evaporated and the residue is crystallised in hexane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.F[C:19]1[C:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([CH:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of 4-(benzo[d]thiazol-2-ylamino)phenol (91 mg, 0.38 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol), and cesium carbonate (123 mg, 0.38 mmol) in DMSO (0.85 mL) was heated at 80° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 3% MeOH in EtOAc, followed by reverse-phase preparative HPLC using a Germini C18 5 uM column, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 15 min, then neutralize with Si carbonate resin, to provide 1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl) as a white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1). IC50 (uM) +++++.