Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].[Cl-:14].[NH4+:15]>CO>[ClH:14].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:15])=[NH:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N#Cc1ccc(C(=N)N)cc1

Procedure:
From 1,4-dicyanobenzene and sodium methylate in methanol followed by ammonium chloride there is obtained 4-cyano-benzamidine hydrochloride, which is used in the next step without further purification, and therefrom with diethyl (2-methoxy-phenoxy)-malonate there is obtained rac.-4-[5-(2-methoxy-phenoxy)-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-benzo-nitrile as a yellow product with a melting point >250° C. With PCl5 and POCl3 this compound yields 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-benzonitrile as a brownish material of melting point 179-180° C. from EtOAc. Reaction with 4-tert.-butyl-benzenesulphonamide K finally yields 4-tert.-butyl-N-[6-chloro-2-(4-cyanophenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:21]([OH:22])[OH:20])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
A solution of 2.0 gm (9.6 mMol) 4-bromoisoquinoline in 30 mL tetrahydrofuran was cooled to −100° C. To this solution were added dropwise 6.3 mL (10.1 mMol) n-butyl-lithium (1.6 M in hexane) dropwise, and the resultant solution was stirred for 30 minutes. To this solution was then added dropwise a solution of 4.4 mL (19.2 mMol) triisopropylborate and the reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was sonicated in a mixture of hexane:ethyl acetate. The resulting suspension was filtered to provide 0.57 gm (34%) isoquinolin-4-ylboronic acid as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:12]([OH:13])=[C:11]([C:14](=O)[CH3:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>CS(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([NH:29][NH:28][C:26]([C:25]3[CH:30]=[CH:31][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=3)=[O:27])[CH3:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)nn(-c2ccc(Cl)nn2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(Cl)nn3)N=C2C)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
0.2 mmol of 1-[1-(6-chloro-3-pyridazinyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]ethanone and 0.2 mmol of 4-methoxycarbonylbenzhydrazide were dissolved in 2 ml of DMSO and heated at 100° C. for 8 hours with stirring. After the solvent was removed by evaporation, the crude product was dissolved in chloroform and recrystallized from ether to obtain 55 mg of the desired product, methyl 4-[(2-{1-[1-(6-chloro-3-pyridazinyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]-ethyl}hydrazino)carbonyl]benzoate (yield 64%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[O:1]([CH2:8][CH2:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH:14]=[O:15])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCOc1ccccc1)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C[C@@H]1CCCN1C(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A mixture of N-(3-phenoxy)propionyl-prolinol (1.4 g) and triethylamine (1.7 g) was dissolved in anhydrous dimethyl sulfoxide (16 ml), and to the stirred solution, a solution (16 ml) of sulfur trioxide-pyridine complex (2.6 g) in dimethyl sulfoxide was added. After stirring the mixture at room temperature for 10 minutes, the reaction solution was poured into iced water (150 ml) and subjected to extraction with ethyl acetate. The extract was washed successively with 10% aqueous citric acid, water, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under vacuum, the resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (1.2 g).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C.CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][CH:17]([OH:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.34 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methanol (10 mL), sodium borohydride (0.047 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 100%).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[C:29]([F:32])[CH:28]=[C:27]([Cl:33])[CH:26]=2)=[O:22])=O)(C)(C)C.[ClH:34].[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>O1CCOCC1>[ClH:33].[Cl:34][C:28]1[C:29]([F:32])=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][C@H:9]1[NH:8][C:6]([C:43]1[S:44][C:38]3[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=3[N:42]=1)=[O:5])=[O:22])=[CH:31]2
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3c(F)cc(Cl)cc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4c(F)c(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(6-chloro-4-fluoroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:23]([NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:24]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: S=C=Nc1ccccc1
Solvent: c1ccccc1
Product: S=C(Nc1ccccc1)NC1CCN2CCc3ccccc3C2C1
Yield: 56.7 %

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.766 g) and phenyl isothiocyanate (0.563 g) were condensed together in benzene (50 ml) in a manner analogous to that of Example 1 to give the title compound (0.724 g). Crystallization from EtOH/HCl afforded the hydrochloride (0.950 g), m.p. 213.5° C. C20H23N3S.HCl requires C, 64.25; H, 6.47; N, 11.24% Found: C, 63.94; H, 6.56; N, 11.16%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]([CH2:16][CH2:17][C:18](Cl)=[O:19])([O:14][CH3:15])=[O:13]>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:18](=[O:19])[CH2:17][CH2:16][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.3 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (26.9 g, 0.202 mol) in dichloromethane (415 mL) at 5° C. under nitrogen was added dropwise neat bromobenzene (10.0 mL, 0.0950 mol), and the mixture was stirred briefly. To the mixture was added dropwise a solution of 3-carbomethoxypropionyl chloride (12.9 mL, 0.105 mol) in dichloromethane (200 mL) over 70 minutes, and the mixture was allowed to slowly warm to room temperature. After 4 days, the mixture was recooled to 5° C. and quenched with the dropwise addition of water (600 mL). The organics were washed with additional water (200 mL), aqueous sodium bicarbonate, water, and brine. The organics were dried (Na2SO4), and rotary evaporated to an oil, which crystallized. The residue was dissolved in chloroform, and the solution was purified by chromatography on silica gel (435 g, 230-400 mesh), eluting with hexanes-acetone (9:1, 10×400 mL; 8:1, 7×400 mL),to give 21.2 g of 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester as an off-white solid; mp 49-51° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>[Ni].C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN(CCC#N)Cc1ccccc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCCN(CCCN)Cc1ccccc1
Reaction time: 48 h
Yield: 89.7 %

Procedure:
A mixture of 43.3 g (0.203 mol) of N-benzylbis(2-cyanoethyl)amine, 7.8 g of a 50% aqueous slurry of Raney nickel and 90 mL of a 1.4 M solution of NaOH in 95% ethanol was hydrogenated in a Parr apparatus for 48 h. The catalyst was removed by filtration and washed with 80 mL of 95% ethanol. The combined filtrates were concentrated by rotary evaporation. A solution of the residue in 100 mL of hexane/chloroform (1:1, v/v) was dried over Na2SO4, filtered and concentrated by rotary evaporation. Removal of solvent residues under vacuum (0.5 mm) afforded 40.3 g (90%) of product as a yellow oil. 1H NMR (CDCl3/TMS) δ7.31 (m, 5 H), 3.52 (s, 2 H), 2.70 (t, J=6.8 Hz, 4 H), 2.45 (t, J=6.8 Hz, 4 H), 1.60 (quint., J=6.8 Hz, 4 H), 1.26 (s, 4 H). 13C NMR (CDCl3) δ139.5, 128.3, 127.7, 126.3, 58.3, 50.9, 40.0, 30.6. IR (film, cm−1) 3360 (br), 3270 (br), 3070 (w), 3050 (w), 3020 (m), 2920 (br. s), 2850 (s), 2800 (s), 1600 (s), 1485 (s), 1450 (s), 1360 (m), 1110 (br), 1070 (m), 1020 (m) 730 (m), 690 (m).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C[O:30][C:31](=[O:40])[CH:32](Br)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:7]2[CH:6]=[N:5][N:4]([CH:32]([CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:31]([OH:30])=[O:40])[C:3](=[O:15])[CH:2]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1ccccc1C1CCCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C2CCCCC2)cc1=O
Yield: 72 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-cyclohexylphenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 2-[4-(2-cyclohexylphenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentylpropionic acid (17.1 g, 72%) as a white solid; LC-MS [M+H+]=411.2; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), 254 nm, 95.8%, 214 nm, 97.2%. 1H-NMR (CDCl3, 300 MHz) δ 1.04-1.77 (m, 19H), 2.05-2.11 (m, 1H), 2.22-2.31 (m, 1H), 2.59-2.66 (t, 1H), 5.27-5.32 (dd, J=10.2 Hz, 4.8 Hz, 1H), 5.88-5.89 (d, J=2.4 Hz, 1H), 6.98-7.00 (m, 1H), 7.19-7.26 (m, 2H), 7.34-7.37 (m, 1H), 7.84-7.85 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[OH:6].[CH2:16](OC(OCC)C)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[O:6][CH:16]([CH3:17])[O:14]1)=[O:15]
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1Cl
Reactant: CCOC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1OC(C)O[C@@H]1c1ccccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
Dichloromethane (MC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate at room temperature. 1,1-Diethoxyethane (8 ml) and p-toluenesulfonic acid (0.27 g) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with MC, washed with H2O, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (3.6 g, 70˜95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.061 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CCOS(C)(=O)=O)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.03 M) solution of methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from Step 2, Amine 31 and Hunig's base (1.5 eq.) was added at 0 methanesulfonyl chloride (1.3 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was subsequently quenched with 10% aq. HCl. The aqueous wash was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[C:17]([O:28][CH3:29])[CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][O:28][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 130 °C
Yield: 17.3 %

Procedure:
A degassed mixture of 6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (350 mg, 0.78 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium carbonate solution (8 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-25% methanol in DCM) to afford the title compound as an off-white solid (61 mg, 17%). 1H NMR (DMSO-D6, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 2.44-2.34 (m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].O>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Fc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)ccc1Sc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a mixture of 3-fluorothiophenol (8.36 g, 65.2 mmol) and potassium carbonate (9.81 g, 71.0 mmol) in 115 mL of dry acetonitrile is added 2,5-difluoronitrobenzene (7.00 mL, 64.55 mmol). The mixture is allowed to stir at room temperature for 2 hours. Water and CH2Cl2 (120 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organics are dried over MgSO4, filtered, and concentrated to give a bright yellow solid. The solid is triturated with hexane to give 17.1 g (99%) of the title compound as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.[OH-].[Na+]>CO>[C:18](/[C:17](/[C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:19]
Reactant: N#CCc1cccnc1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1
Reaction time: 3 h
Yield: 57.9 %

Procedure:
To a stirred mixture of 4-methoxybenzaldehyde (2 g, 14.69 mmol) and 3-pyridylacetonitrile (1.58 ml, 14.84 mmol) in methanol (30 ml) was added 50% w/v sodium hydroxide (1 ml). The reaction was stirred for 3 hours. The reaction mixture was quenched with water (20 ml), acidified with 2N HCl, then rebasified with dilute NaOH (aq), and the reaction product was extracted successively into dichloromethene (3×20 ml). The organic solutions were dried over anhydrous MgSO4 and the solvent removed. Purification by column chromatography (SiO2, Hexane/Ethylacetate 8:2; 1:1) gave 2.01 g (58% yield) of the title compound as a straw coloured solid: 1H-NMR (CDCl3) 8.80 (d, 1H), 8.50 (m, 1H), 7.80 (m, 3H), 7.45 (s, 1H), 7.25 (m, 1H), 6.90 (m, 2H), 3.80 (s, 3H). 13C NMR (CDCl3) 161.9, 157.6, 157.5, 149.5, 146.9, 143.3, 133.1, 131.4, 130.9, 126, 123.5, 117.7, 114.5, 105.2, 55.4. Mass Spectrum m/e (M+1) 237.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][O:43][NH:44][CH3:45]>C(Cl)Cl.O>[CH3:42][O:43][N:44]([CH3:45])[C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To the solution of 166 (170 mg, 0.69 mmol) in DCM (5 mL) was added EDC.HCl (190 mg, 1 mmol), HOBt (160 mg, 1 mmol), TEA (0.3 mL) and N-methoxymethanamine hydrochloride (100 mg, 1 mmol). The mixture was stirred at RT overnight. The mixture was poured into water, extracted with EtOAc, washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography affording 140 mg (85%) of 1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide (168) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:4](=O)[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:3].[C:12](O)(=O)C.[CH:16]([NH2:18])=[NH:17]>C(O)CCC>[C:2]([C:4]1[C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:12][N:18]=[CH:16][N:17]=1)([CH3:11])([CH3:3])[CH3:1]
Reactant: N=CN
Reactant: CC(C)(C)CC(=O)C(C)(C)C
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)c1cncnc1C(C)(C)C
Temperature: 130 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
A 100 mL reaction flask is charged with 2,2,5,5-tetramethyl-hexan-3-one (10 g, 0.06 mol), formamidine acetate (33 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4,5-di-tert-butyl-pyrimidine (˜5 g) is obtained.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.CO>[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COc1cc(Br)cc(CC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CCN)c1
Temperature: 80 °C

Procedure:
A borane-tetrahydrofuran complex (1 M, 73.6 mL) was added to a THF (36.8 mL) solution of Intermediate 3 at room temperature and the resulting mixture was stirred to reflux at 80° C. for 2 hours. Methanol (26 mL) and 1 N hydrochloric acid (26 mL) were added to the reaction mixture solution and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was neutralized with 1 N aqueous sodium hydroxide solution followed by the addition of ethyl acetate (100 mL) to extract the reaction mixture, the organic layer was dried, and then the solvent was evaporated under reduced pressure to give the title compound (8.76 g).