Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)(=N)C1C=CC=CC=1.[C:10]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[BH4-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(O)(=O)C>[CH2:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH2:17]1
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C(N)c1ccccc1
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: C1=Cc2ccccc2CC1

Procedure:
Scheme 12 outlines the preparation of tetralins having an acetic acid residue at C2 and an amide linked benzamidine at C6. In the first step, tetralone 81 is reduced with NaBH4 and the resultant unstable alcohol is dehydrated with TsOH in benzene giving dihydronapthalene 82. Osymylation of 82 affords diol 83 which is then subjected to the action of TsOH in refluxing benzene. The unstable 2-tetralone thus formed is not isolated but rather allowed to react with the sodium salt of tert-butyl diethylphosphonoacetate giving unsaturated ester 84 as a mixture of olefin isomers. This material is subjected to hydrogenation over palladium which effects saturation of the olefin and removal of the CBz group providing aniline 85. Acylation of 85 with 4-cyanobenzoic acid is accomplished with the aid of EDCI and the resulting amide 86 is transformed into the Boc protected amidine 87 using conditions previously described in Scheme 1. Removal of the Boc moiety and cleavage of the tert-butyl ester is accomplished with TFA giving 88. ##STR67##
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:31][CH:32]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3=CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CC=C(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), N,N-dimethylglycine (27 mg, 0.26 mmol), EDCl (50 mg, 0.26 mmol), HOBt (35 mg, 026 mmol), and N,N-diisopropylethylamine (124 μL, 0.71 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 24 mg (20%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.96 (s, 1 H), 7.81 (d, 1 H), 7.61 (s, 1 H), 7.27-7.37 (m, 5 H), 7.14 (dd, 1 H), 7.03-7.10 (m, 1 H), 6.80-6.84 (m, 1 H), 5.65 (s, 2 H), 4.25 (d, 2 H), 3.69 (dt, 2 H), 3.13 (d, 2 H), 2.63-2.70 (m, 1 H), 2.53-2.60 (m, 1 H), 2.17 (m, 6 H); ES-MS m/z 507.17 [M+H]+, HPLC RT (min) 1.36.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=O.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>C(O)C>[OH:19][N:18]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: NO
Reactant: N#Cc1ccc(C=O)c(OCC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(OCC(F)(F)F)c1

Procedure:
In analogy to example 106.2, 4-formyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile was reacted with hydroxylamine hydrochloride and sodium acetate in ethanol to give 4-(hydroxyimino-methyl)-3-(2,2,2-trifluoro-ethoxy)-benzonitrile as a yellow solid.
Reaction SMILES: C(=O)=O.C(O)(C)C.[CH2:8]([C:11]1[S:12][C:13]2[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=2[C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1)=O)[CH:9]=[CH2:10].B(Br)(Br)Br.O>C(Cl)Cl>[C:16]1([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:15]2[C:14]3[CH:26]=[CH:27][CH:28]=[CH:29][C:13]=3[S:12][C:11]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=CCc1sc2ccccc2c1C(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: Oc1ccc(-c2cccc3sc4ccccc4c23)cc1
Yield: 57.4 %

Procedure:
To a mechanically stirred, cold (-74° C. dry ice-isopropanol bath) solution of (2-allyl-benzothiophen-3-yl)-(4-methoxy-phenyl)-methanone (11.27 g, 36.5 mmol) in anhydrous methylene chloride (112 mL) was added a 1 M solution of boron tribromide in methylene chloride (146 mL, 146 mmol, 4 eq) dropwise over a period of 1.25 hours under a dry nitrogen atmosphere. The reaction mixture was stirred in the warming bath overnight and at ambient temperature for 6 days. The reaction mixture was diluted with methylene chloride (total volume 500 mL) and added cautiously to water (1 L) with cooling in an ice bath. The layers were separated and the aqueous phase was extracted with ether (500 mL). The organic phases were combined, washed with a dilute aqueous solution of sodium bisulfite (2×1 L), and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (82/18 petroleum ether/ethyl acetate) and chased with benzene and petroleum ether to provide the title compound as a white solid (5.79 g, 57%): mp 117-119° C.; NMR (CDCl3): δ 7.84 (dd, J=8, 1 Hz, 1H), 7.82 (dm, J=8 Hz, 1H), 7.45 (dd, J=8, 8, 1 Hz, 1H), 7.37-7.31 (multiplet with overlapping doublet at 7.33, J=8 Hz, 3H), 7.25 (s, 1H), 7.24 (dd, J=7, 1 Hz, 1H), 7.22 (dm, J=7 Hz, 1H), 7.10 (ddd, J=8, 7, 1 Hz, 1H), 7.01-6.98 (multiplet with overlapping doublet at 6.98, J=8 Hz, 2H); MS (EI): [M+] 276 (100%); Anal. Calc. for C18H12OS: C, 78.23, H, 4.38, N, 0.00. Found: C, 77.83, H, 4.22, N, 0.05.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:30][S:31][CH3:32])[C:25]([F:29])=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:4](=[O:33])[O:3]1.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CC(OCC)=O)=CC=1>>[F:29][C:25]1[C:24]([CH2:30][S:31][CH3:32])=[C:23]2[C:28]([C:20]([CH:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=3)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:33])=[CH:21][NH:22]2)=[CH:27][CH:26]=1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)c(F)ccc12
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)c(F)ccc12

Procedure:
The title compound was prepared starting from 3.82 g (7.71 mmol) of the compound from Example 22A in analogy to the synthesis of the compound from Example 47A. 3.05 g (90% of theory) of the title compound were obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH-].[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>O1CCCC1.O>[CH2:21]([O:28][C:29]([NH:2][C@@H:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Hydrochloride (1.00 g, 3.64 mmol) of ethyl (S)-2-amino-3-(4-nitrophenyl)propionate was dissolved in a mixed solution of tetrahydrofuran (10 ml), water (10 ml) and a 1N aqueous sodium hydroxide solution (3.64 ml) and a solution of benzyloxycarbonyl chloride (0.57 ml, 3.99 mmol) dissolved in tetrahydrofuran (3.5 ml) and a 1N aqueous sodium hydroxide solution (3.64 ml, 3.64 mmol) were simultaneously added dropwise under ice-cooling, which was followed by stirring at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give 743 mg of ethyl (S)-2-(benzyloxycarbonylamino)-3-(4-nitrophenyl)propionate as a colorless solid (55%). This solid (724 mg, 1.94 mmol) was dissolved in a mixture of ethanol (120 ml) and water (30 ml), and zinc (6.40 g, 97.9 mmol) and calcium chloride (2.00 g, 18.0 mmol) were added. The mixture was refluxed under heating for 3.5 hours. The reaction mixture was cooled to room temperature and filtrated. The filtrate was concentrated and water (100 ml) was added to the filtrate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 572 mg of ethyl (S)-3-(4-aminophenyl)-2-(benzyloxycarbonylamino)propionate as a pale-yellow oil (86%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([OH:38])[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1.[CH2:39]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:38][CH:52]3[CH2:53][CH2:54][N:49]([C:47]([O:46][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:48])[CH2:50][CH2:51]3)[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(O)cc2n1Cc1ccc(C#N)c2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methyl-6-hydroxy-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (2.8 g) in THF (50 mL) was first added N-benzyloxycarbonyl-4-hydroxypiperidine (1.7 g), PPh3 (1.9 g), and then DEAD (1.2 mL) in a dropwise fashion. After stirring at ambient temperature for 1 hour the solvent was removed and the residue was separated by silica gel chromatography (hexane/ethyl acetate, gradient) to afford 2-methyl-6-(N-(benzyloxycarbonyl)piperidin-4-yloxy)-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.Cl.O.C(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:24])=[C:4]([CH:3]=1)[C:25]([NH:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])=[O:37]
Reactant: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 4-[(5-chloro-3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-2-methylphenyl)(ethyl)amino]piperidine-1-carboxylate (140 mg, 0.26 mmol) in 1,4-dioxane (5 ml) at room temperature was added HCl (4M in dioxane) (1.32 ml). A gum formed after stirring for a short time which then dissolved upon the addition of deionized water (2 ml). The reaction was stirred for 21 h before being concentrated under reduced pressure to give a thick oil. DCM (3 ml) was added and a solid formed. This mixture was concentrated to give 105 mg of a yellow solid which was stirred in DCM (10 ml) for 1 hour before being filtered and dried under high vacuum in a vacuum oven for 24 hours. The sample was then dissolved in deionized water (0.2 ml) and lyophilized to give 86 mg (70%) of the title compound as a beige solid. LC-MS 100%, m/z=431.2/433.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.44 (bs, 1H), 7.26 (bs, 1H), 6.69 (bs, 1H), 4.55 (s, 2H), 3.53-3.34 (m, 3H), 3.28-3.08 (m, 2H), 3.01 (t, J=11.8 Hz, 2H), 2.51 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H), 2.16-1.96 (m, 2H), 1.91-1.76 (m, 2H), 0.92 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: NCCC1CCOCC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCC3CCOCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(tetrahydropyran-4-yl)-ethyl-amine to afford the title compound. MS: m/e=370 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]1([OH:31])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:26][CH2:27][C:28]4([OH:31])[CH2:30][CH2:29]4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: OC1(CCBr)CC1
Reactant: CCCSc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)n(CCC3(O)CC3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione (124 mg, 0.34 mmol) in DMF (7 mL) was added 1-(2-bromoethyl)cyclopropanol (67.3 mg, 0.41 mmol, intermediate 46), followed by potassium carbonate (141 mg, 1.02 mmol). The reaction was stirred at 70° C. for 5 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude yellow oil product (100 mg, 66.9% yield). LCMS MH+ 449.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: Cc1ccc(CN)cc1
Solvent: CO
Product: Cc1ccc(CN=C(NC#N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.30 g, 1.9 mmol) was dissolved in methanol (10 ml), p-methylbenzylamine (0.25 g, 2.1 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.41 g, 1.6 mmol, yield: 91%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.O>[CH2:13]([O:15][C:16](=[O:23])[C:17](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C=O)cc1OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OC)c(OC)c1)C(=O)OCC

Procedure:
3,4-dimethoxybenzaldehyde (Veratraldehyde) (9.13 g, 55 mM) was heated with malonic acid diethyl ester (8.00 g, 50 mM), acetic acid (0.29 ml) and piperidine (0.74 ml) in benzene (100 ml) in an apparatus equipped with a water separator (Dean-Stark tube) until 50 mM water was separated. After washing the benzene solution with water, it was dried over anhydrous magnesium sulfate. After drying, benzene was evaporated under reduced pressure to obtain a crude product (15.40 g). The crude product thus obtained is pure enough, and can be used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:49]1(C(OC(C)(C)C)=O)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:49]6[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (40 mg, 0.062 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (115.37 mg, 0.619 mmol, 10 eq) and acetic acid (3.55 μL, 0.062 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in a VX-2500 Multi-Tube Vortexer overnight at room temperature. MP-triacetoxyborohydride (195 mg, 0.482 mmol, 7.78 eq) was then added and the mixture was stirred again in the VX-2500 Multi-Tube Vortexer overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock (Artisian Scientific, Champaign, Ill., USA, http://www.artisan-scientific.com/51413.htm) in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) and hydrochloric acid (5 μL) were then added and the vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator over the weekend at 60° C. The reaction mixture was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on a Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 16.4 mg (41.1%) of the title compound. LC-MS m/z 716 (M+H)+, 1.25 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 80.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: O[C:2]1[NH:3][SH:4](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[NH:3][SH:4](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(O)N1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(Cl)N1
Yield: 73 %

Procedure:
A solution of 13.84 g (0.049 mole) of 3-hydroxy-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide of Example 7 in 50 ml of phosphorus oxychloride was refluxed for 30 minutes and then excess reagent was evaporated under vacuum. The residue was taken up in chloroform and the solution was washed once with water, dried over magnesium sulfate and evaporated to an oil. The residue crystallized on trituration with ethanol to obtain 10.8 g (73%) of 3-chloro-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 117°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[NH:4][NH2:5].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9][CH:8]=1>CO>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:5][NH:4][C:3]([O:2][CH3:1])=[O:6])=[CH:9][CH:8]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: COC(=O)NN
Solvent: CO
Product: COC(=O)NN=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of 2.70 gm (0.03 mole) of methylcarbazate, 4.72 gm (0.03 mole) of 4-quinolinecarboxaldehyde and 100 ml of anhydrous methanol is refluxed 8.5 hr. The hot solution is filtered. The filtrate is diluted with water until cloudy. The mixture is cooled to room temperature then chilled. The crystals are collected, washed with ether and dried to give 5.88 gm (86%) of the title compound, having a melting point of 83.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17]>C(OCC)(=O)C.O>[Cl:21][C:20]([Cl:23])([Cl:22])[CH2:19][O:18][C:16](=[O:17])[NH:10][C:8]1[N:7]([CH2:11][CH3:12])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCn1nc(C(C)(C)C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.75 h
Yield: 7.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-ethyl-1H-pyrazole-5-amine (0.500 g, 2.99 mmol) in ethyl acetate (7.5 mL) and 1 M aqueous NaOH (7.5 mL, 7.5 mmol), cooled in an ice bath, was added 2,2,2-trichloroethyl chloroformate (0.453 mL, 3.29 mmol) and the mixture was stirred for 45 min. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated. The residue was crystallised from pentane-diethyl ether (1:1) to give the title compound (0.078 g) as a white solid. The mother liquors were evaporated and purified by column chromatography (0-40% EtOAc/cyclohexane) to give the title compound (0.817 g) as a colorless oil (Total yield 0.895 g, 87%). LCMS (Method 3): Rt 4.09 min, m/z 342/344/346 [MH+]. 1H NMR (300 MHz, CDCl3): 1.44 (12H, m), 4.78-4.83 (2H, m), 4.88 (2H, s), 6.53 (1H, s), 9.82 (1H, s).