Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH2:22][C:23](=O)[CH3:24])[CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10].[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27].C([O-])(=O)C.[NH4+]>O.C(O)(=O)C>[C:26]([CH:28]([CH:23]([CH3:24])[CH2:22][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:15])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
In 200 ml. of benzene was dissolved 50 g. of farnesyl acetone, and then 28 g. of ethyl cyanoacetate, 5 g. of ammonium acetate and 5 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours with removal of the produced water. The reaction mixture then was washed with water and dried. To this mixture there was added dropwise a solution of 4.3 g. of sodium borohydride in 50 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 50 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography to obtain 50.5 g. of the desired oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:11]1([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]([OH:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccnc(-c2ccccc2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
Preparation H1, Step 1: A mixture of 2-bromo-4-pyridinecarboxylic acid (1.1 g, 5.45 mmol), phenylboronic acid (1.3 g, 10.9 mmol), 2.0 M potassium phosphate (aq) (8.2 mL, 16.34 mmol), and DMF (10 mL) in a 20 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150° C. in the microwave for 30 min. The reaction mixture was filtered, the filtrate was concentrated in-vacuo, and the residue was dissolved in water (10 mL). The mixture was acidified to pH=6 with the addition of 1.0 N HCl, and the resulting precipitate was collected by filtration, rinsed with two portions of ice-cold water, and air dried to yield 575 mg of 2-phenylisonicotinic acid as an off-white solid. MS (ES+)=200 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:11]([O-])=O.[Na+].CC([O-])=O.[Na+].[CH2:20]([O:22][C:23](=[O:29])[CH:24]([Cl:28])C(=O)C)[CH3:21]>O.C(O)C>[Cl:28][C:24](=[N:11][NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])[C:23]([O:22][CH2:20][CH3:21])=[O:29]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=N[O-]
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of 2,4-dichloroaniline (1 g, 6.17 mmol) and concentrated hydrochloric acid (1.5 ml) in ice (1.5 ml) a solution of NaNO2 (0.460 mg, 6.68 mmol) in water (0.8 ml) is slowly added and the mixture is stirred for 1 h at 0-5° C. Then, this solution is added over a cold mixture of NaOAc (1.64 g, 19.6 mmol), ethanol (26 ml) and ethyl-2-chloro-3-oxobutanoate (1.0 g, 6.06 mmol) and let stirring for 1 hour until the formed precipitate is collected by filtration, washed with ethanol and dichloromethane and dried in vacuo to give the yellow solid ethyl 2-chloro-2-(2-(2,4-dichlorophenyl)hydrazono)acetate (70-80% yield), which is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:31]([C:33]1[C:34](=[C:49]([C:52]#[N:53])[C:50]#[N:51])[O:35][C:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:39]([F:42])([F:41])[F:40])[C:37]=1[CH3:38])#[N:32]>>[CH2:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16](=[CH:22][CH:23]=[CH:38][C:37]3[C:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:39]([F:42])([F:40])[F:41])[O:35][C:34](=[C:49]([C:52]#[N:53])[C:50]#[N:51])[C:33]=3[C:31]#[N:32])[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=O)CC(C)(C)C2)c(OC)c1
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 76 %

Procedure:
207 mg (0.51 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 175 mg (0.56 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile were dissolved, and the mixture was stirred with heating at 50° C. for 3 hours. The precipitate was separated by filtration and washed with ethanol. The residue was purified by silica gel column chromatography to give 274 mg of a dark brown crystal (yield: 76.8%; mp: 164-166° C.).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14]C1C=C2C(OC(=O)NC2=CC=1)=O>>[F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[N:11]([CH3:14])[C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Product: Cn1c(=O)oc(=O)c2cc(F)ccc21

Procedure:
By substituting 27 g of 5-fluoroisatoic anhydride for the 5-methylisatoic anhydride Preparative Example 13, there is obtained 5-fluoro-N-methylisatoic anhydride; mp 150°-155° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.[NH2:25][C:26]1[C:31]2[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:18]([NH:25][C:26]2[C:31]3[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=3[CH:29]=[CH:28][CH:27]=2)=[O:19])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CNC(=O)Nc2cccc3c2OCC(=O)N3)cc1
Temperature: 70 °C
Yield: 27 %

Procedure:
To a solution of 4-tert-butylbenzylamine (2 mL, 11.36 mmol) in THF (30 mL) was added CDI (2.1 mol eq, 3.86 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×30 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (pale yellow oil, quantitative yield). The oil obtained (0.58 g, 2.28 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.30 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtOAc:petroleum ether) to obtain the product as a white solid (0.17 g, 27% Yield). 1HNMR (DMSO, 400 MHz) δ 1.26 (s, 9H), 4.24 (d, 2H, J=6), 4.60 (s, 2H), 4.45 (dd, 1H, J=2), 6.81 (t, 1H, J=10), 7.18 (d, 2H, J=8), 7.36 (d, 2H, J=8), 7.76 (dd, 1H), 8.06 (bs, 1H), 10.64 (bs, 1H). [M+1] 353.98 (C20H23N3O3 requires 353.41).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[NH:11][C:12]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CC(N(C)C)=O>[CH2:3]([C:10]1[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:13]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2nc(Cc3ccccc3)[nH]c2c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)nc(Cc1ccccc1)n2CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (18.31 mmole, 0.44 g, 60% in mineral oil) is added in small amounts under nitrogen to an ice cooled solution of 2-benzyl-5-methoxybenzimidazole (16.64 mmole, 3.96 g) in dry DMA (9 ml). The mixture is stirred at the same temperature for 30 minutes. 1-Bromo-2-methylpropane (18.31 mmole, 2.51 g) in DMA (4 ml) is added in several portions, and the mixture is allowed to stir at room temperature over night. The reaction mixture is added dropwise onto ice. The precipitate is collected and dissolved in dichloromethane. The organic solution is washed several times with water, is dried with Na2SO4, is filtered and is evaporated to give the title compound (R1=2-methylpropyl, R2=benzyl, R3=OCH3, n=1).
Reaction SMILES: Cl.[N+:2]([C:5]1N=C[C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.[CH2:31]([N:33](CC)CC)C>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:31][N:33]=3)[CH2:18][CH2:17]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cn3)CC2)cc1
Temperature: 60 °C

Procedure:
To a flask charged with 1-[2-(6-nitropyridin-3-yl)ethyl]piperazine hydrochloride (40 mg, 0.15 mmol) and and a stir bar was added 1-(2-bromoethyl)-4-nitrobenzene (40 mg, 0.18 mmol), DMF (2 mL), and triethylamine (0.082 mL, 0.59 mmol). The mixture was heated to 60° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 386 [M+1]+. (0.28 μM)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])=[CH:8][CH:9]=1
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone, was treated with acetylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[NH:10][N:9]=2)[CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:9]=2)[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:9]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:10]=[C:11]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[N:12]=2)[CH:3]=1
Reactant: Brc1ccnc(-c2n[nH]c(-c3cscn3)n2)c1
Reactant: Fc1ccccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cscn1
Product: Fc1ccccc1Cn1nc(-c2cscn2)nc1-c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)thiazole (1 eq) in DMF was added sodium hydride (2.1 eq). After 10 minutes, 1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction was stirred overnight at room temperature. Brine was used to quench the reaction. Methylene chloride was used to extract the aqueous layer. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. SiO2 chromatography yielded 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole in 1% yield as a solid and 4-(5-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiazole in 1% yield as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]3C=N[CH:21]=[N:22][CH:23]=3)[N:11]([CH2:24][C:25]([OH:27])=[O:26])[C:10]=2[CH3:28])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1C=NC=C[N:35]=1)CCC.[C:48]1([CH3:54])[CH:53]=CC=C[CH:49]=1>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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]3[CH:23]=[N:22][CH:21]=[CH:34][N:35]=3)[N:11]([CH2:24][C:25]([O:27][C:48]([CH3:54])([CH3:53])[CH3:49])=[O:26])[C:10]=2[CH3:28])=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1ccccc1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(-c3cncnc3)cccc2n1CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(-c3cnccn3)cccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of the product from Example 3 part (ii) (0.4 g) in toluene (4 ml) was added 2-tributylstannylpyrazine (0.32 g) and tetrakis(triphenylphosphine)palladium (0) (0.1 g). The reaction mixture was heated to 80° C. for 18 hours. The mixture was adsorbed onto silica and purified using column chromatography (33% EtOAc/hexane as eluent) to give the sub-title compound (160 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Reactant: CNc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-chloroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 168bp. 1H (500 MHz, CDCl3) δ 7.53 (d, J=7.7 Hz, 1 H), 7.35-7.41 (m, 3 H), 6.97 (s, 1 H), 6.94 (d, J=8.2 Hz, 1 H), 6.76 (d, J=8.2 Hz, 1 H), 6.56 (s, 1 H), 5.00 (s, 2 H), 3.39 (s, 3 H), 2.26 (s, 3 H). LCMS (ESI) m/z: 370.1
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39](OCC1SC=CN=1)=[O:40])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39]([O:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1)=[O:40])([CH3:29])[CH3:28]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Reactant: OCC1CCO1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC1CCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid.
Reaction SMILES: C(O)C.Cl[C:5]1[C:10]([Cl:11])=[N:9][CH:8]=[CH:7][N:6]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C(N(CC)CC)C>[Cl:11][C:10]1[C:5]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nccnc1Cl
Yield: 14.6 %

Procedure:
To an ethanol solution (10 mL) of 2,3-dichloropyrazine (1.0 g), glycine ethyl ester hydrochloride (940 mg) and triethylamine (1.9 mL) were added and the mixture was irradiated with microwave (150° C., 10 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium bicarbonate solution was added and the product was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (hexane:ethyl acetate=10:1) to give 212 mg (15% yield) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].O[CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH3:37]>C1(C)C=CC=CC=1>[CH3:37][N:28]1[C:29](=[O:36])[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CN1C(=O)c2ccccc2C1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2ccccc2C(=O)N1C
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
11.5 g of ethoxycarbonylmethylenetriphenylphosphorane are added to a suspension of 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one in 110 cm3 of toluene. The reaction mixture is refluxed with stirring for 16 hours and then cooled to a temperature in the region of 20° C. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residual oil is taken up in 50 cm3 of diethyl ether. The precipitate formed is filtered off and then washed twice with 10 cm3 of diethyl ether. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give an orange-colored oil, which is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 20-45 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (70/30, 65135, 60/40 by volume). The fractions comprising the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 30° C. 4.1 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a yellow oil. (Rf=0.25, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[K+]>CO.Cl.O>[CH3:20][C:12]1[N:11]=[C:10]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH2:23])=[O:21])=[CH:3][CH:4]=2)[CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc(N(C)c2ccc(NC(N)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (48 mg, 0.18 mmol) in 250 uL of methanol and 750 uL of 1N HCl was added potassium cyanate (50 mg, 0.62 mmol) in 500 uL of water, and the mixture was stirred overnight at room temperature. The precipitated product was collected by filtration under vacuum, washed with 1 mL of cold water and dried to give the title compound (12.3 mg, 0.04 mmol, 22%). 1H NMR (DMSO): 8.75 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 6.99-7.13 (m, 4H), 5.92 (s, 2H), 3.45 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCO
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Yield: 45.6 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (60 mg, 0.17 mmol); 1-azido-4-nitrobenzene (42 mg, 0.26 mmol); CuSO4 (4.4 mg, 0.03 mmol); NaAsc (22 mg, 0.11 mmol); TBTA (20.0 mg, 0.04 mmol); in t-BuOH/EtOH/H2O (2:2:1); afforded the 45 as an orange solid (40 mg, 45.6%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.8 Hz); 8.77-8.74 (t, 1H); 8.73 (s, 1H); 8.63-8.61 (d, 1H, J=8.17 Hz); 8.47-8.44 (d, 2H, J=9.13 Hz); 8.21-8.19 (d, 2H, J=9.13 Hz); 7.36 (d, 1H, J=1.78 Hz); 4.71-4.65 (q, 1H); 4.42-4.40 (d, 2H, J=5.50 Hz); 4.20-4.09 (m, 2H); 3.66-3.65 (d, 1H, J=1.75 Hz); 3.52-3.53 (d, 1H, J=1.75 Hz); 3.28-3.06 (m, 2H); 1.22-1.17 (t, 3H). 13C NMR (CDCl3, 100 MHz): 170.25, 167.14, 165.00, 153.70, 152.87, 146.77, 146.68, 140.89, 125.70, 121.59, 120.42, 115.86, 61.60, 53.09, 52.61, 51.40, 34.32, 33.12, 13.94.