Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH:10]1[CH:11]=[CH:12][C:13]2[C:26](=[O:27])[C:25]3[C:17]4[C:18]([CH:22]=[CH:23][N:24]=3)=[CH:19][CH:20]=[N:21][C:16]=4[C:14]=2[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:10]1[CH:15]=[C:14]2[C:16]3[C:17]4[C:25]([C:26](=[O:27])[C:13]2=[CH:12][CH:11]=1)=[N:24][CH:23]=[C:22]([Br:7])[C:18]=4[CH:19]=[CH:20][N:21]=3
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Reaction time: 0.5 h

Procedure:
A mixture of pyridinium bromide perbromide (390 mg, 1.2 mmol) and sampangine, (232 mg, 1.0 mmol) in chloroform (12 mL) was heated at reflux for 15 hours. Saturated sodium bicarbonate solution (100 mL) was added to the cooled reaction and the mixture stirred vigorously for 30 minutes. The two layers were separated and the aqueous phase extracted with chloroform (2×30 mL). The combined organic layers were dried over potassium carbonate and concentrated to dryness. The residual solid was applied to a 2×40 cm column of silica gel (Merck 230-400 mesh) and the pure product (200 mg, 64%) eluted with chloroform, mp 180° C. dec. IR (KBr) 1670, 1590, 1400, 1320, 1310, 1275, 1230, 980, 790, 755, 720 cm−1; 1H NMR (CDCl3) δ 9.28 (s, 1H), 8.99 (d, J=5.9 Hz, 1H), 8.85 (dd, J=7.9, 1.4 Hz, 1H), 8.46 (dd, J=7.9, 1.4 Hz, 1H), 7.96 (d, J=5.9 Hz, 1H), 7.86 (ddd, J=7.7, 7.9, 1.4 Hz, 1H), 7.72 (ddd, J=7.9, 7.9, 1.4 Hz, 1H); 13C NMR (CDCl3) 181.6 (0), 151.7 (0), 150.2 (1), 148.6 (1), 146.7 (0), 138.6 (0), 135.1 (0), 135.0 (1), 132.3 (0), 131.8 (1), 128.7 (1), 125.8 (1), 123.7 (0), 120.5 (0), 118.3 (1) ppm; HR MS calc. for C15H7BrN2O 309.9741, found 309.9747.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[H][H]>C(O)(=O)C.O=[Pt]=O>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NC1CCNCC1

Procedure:
A solution of the product of Example 2 (75 g) in 750 mL acetic acid was reduced over PtO2 catalyst at 60 psi hydrogen atmosphere at 60° C. for 7 hours. The solution was filtered, concentrated and triturated with ether to afford the title compound quantitatively as a white solid which was used directly in subsequent reactions.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([C:39]([OH:41])=O)[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]([C:39]([N:7]([CH3:8])[CH3:6])=[O:41])[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
TSTU (6.55 g, 21.74 mmol) was added to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7 g, 19.77 mmol) and DIPEA (3.79 mL, 21.74 mmol) dissolved in DCM (100 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 h. More TSTU (6.55 g, 21.74 mmol) and DIPEA (3.79 mL, 21.74 mmol) were added and stirring was pursued for a further 16 h. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM and a little MeOH. The combined organic phases were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 3 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (7.70 g, 102%) as a beige solid. Mass Spectrum: m/z [M+H]+=381.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH:42]=[O:43])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][CH:42]([OH:43])[CH2:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:40][CH2:39]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Yield: 62.7 %

Procedure:
50 ml of tetrahydrofuran was added to 3.80 g of N-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyl lithium·pentane solution was added dropwise thereto under an argon stream at -78° C. Subsequently, a solution of 3.50 g of (1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred until its temperature was returned to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.57 g of the title compound as white powder.
Reaction SMILES: [ClH:1].CN(C)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1.Br.CN(C)C1C=CC(NC2SC=C(C3C=C([C:48]([O:50]C)=S)SC=3C)N=2)=CC=1>>[ClH:1].[CH3:48][O:50][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1
Reactant: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(N(C)C)cc2)n1
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(N(C)C)cc3)n2)c(C)s1
Agent: Br
Agent: Cl
Product: COc1ccc(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)cc1
Yield: 22 %

Procedure:
4-(2-{[4-(Dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (50 mg, 0.10 mmol) was treated as described in Example 154, step (b) to give 9.4 mg (22% yield) of 4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J=9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92 (bs, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:51]([C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1)#[N:52]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([N:62]3[CH2:61][CH2:60][N:59]([C:55]4[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=4)[C:51]#[N:52])[CH2:64][CH2:63]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(N2CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.4 g, 1.8 mmol) in anhydrous dimethylformamide (3 ml) is treated with HATU (0.7 g, 1.8 mmol) and diisopropylethylamine (0.6 ml, 3.3 mmol). The reaction mixture is stirred 10 mins. at ambient temperature before being treated with a solution of 1-(3-cyanophenyl)piperazine (0.3 g, 1.6 mmol) in dimethylformamide (5 ml). The reaction mixture is stirred at ambient temperature for 18 hours, concentrated under vacuum and the residue partitioned between dichloromethane (2×40 ml) and saturated aqueous sodium bicarbonate (40 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (ethyl acetate) to give the title compound as a yellow oil (0.33 g). 1H NMR (CDCl3, 500 MHz) δ8.82 (s, 1H), 8.61 (s, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.39 (m, 4H), 7.16 (m, 3H), 3.95 (br m, 2H), 3.63 (br m, 2H), 3.30 (br m, 4H), EI MS M++H: 393.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>CS(C)=O.CCOC(C)=O>[CH3:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: C[C@@H]1CCCCN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol) and (R)-(−)-2-methylpiperidine (3.1 mL, 26.4 mmol) was prepared in DMSO (10 mL) and heated at 100° C. under nitrogen for 12 hours. The reaction mixture was diluted with EtOAc, and then washed with water, a saturated aqueous solutions of NaHCO3 and a saturated aqueous solution of NH4Cl. The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow oil, which was used without further purification in the next step. HPLC (Method A) Rt 5.65 min (82.6%). LC/MS (Method B): 269.1 (M+H)+.
Reaction SMILES: [IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](SC)=[NH:14])=[C:6]2[N:5]=[N:4]1.Cl.[NH2:18][CH2:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21]>>[IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:14])[NH:18][CH2:19][C:20](=[O:21])[C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[C:6]2[N:5]=[N:4]1
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Reactant: NCC(=O)c1cccs1
Agent: Cl
Agent: I
Product: Cn1nnc2c(C(=N)NCC(=O)c3cccs3)ncn2c1=O
Yield: 66 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and 2-amino-1-(thiophen-2-yl)ethanone hydrochloride, using a reaction time of 16 hours for the amidine formation. Yield 66%. δH (DMSO-d6): 9.76-9.73 (1H, m), 9.69 (1H, s), 9.49 (1H, bs), 9.22 (1H, s), 8.16 (1H, dd, J=4.9, 1.1), 8.12 (1H, dd, J=3.8, 1.1), 7.37 (1H, dd, J=4.9, 3.8), 5.17 (2H, d, J=6.3), 4.06 (3H, s).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]2[N:37]=[C:38]([CH:40]=O)[N:39]=[C:32]2[N:31]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:20][CH:21]=3)[O:11][C:10](=[O:12])[C:9]([CH2:40][C:38]3[N:39]=[C:32]4[N:31]=[C:30]([CH3:29])[CH:35]=[C:34]([CH3:36])[N:33]4[N:37]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: Cc1noc(C)c1-c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(-c5c(C)noc5C)cc4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione (Example A(18)) to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:22]1[C:31]([C:32]([F:35])([F:34])[F:33])=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:36][CH3:37])[CH:28]=2)[N:23]=1>>[CH3:37][O:36][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=1)[C:31]([C:32]([F:35])([F:33])[F:34])=[N:30]2
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CCOC(=O)C1CC=C(c2nc3ccc(OC)cc3nc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
Followed the coupling procedure similar to that described in Compound VIII-2 (Example 65), where the starting materials were ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and where the reaction here was stirred under N2 atmosphere at 100° C. for 3 hours. Ethyl 4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)cyclohex-3-enecarboxylate was isolated (800 mg, yield 55%) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].C1C(=O)N([Br:22])C(=O)C1.C(O)(=O)C>C(Cl)Cl>[Br:22][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)=[N:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(-c2nccs2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(-c2ncc(Br)s2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 2-(4-ethoxyphenyl)thiazole (1.03 g, 5.00 mmol) in DCM (30 mL) were added NBS (0.98 g, 5.50 mmol) and acetic acid (0.3 mL) with stirring at rt under N2. The reaction was stirred at 48° C. for 3 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (1.34 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH3:13][C:14](=[CH2:16])[CH3:15]>ClCCl.OS(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=[CH:5]2
Reactant: C=C(C)C
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: -39 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 6-bromo-2-hydroxynaphthalene (1.5 g, 6.72 mmol) and liquefied iso-butylene (6 mL) in dry dichloromethane (6 mL) at −78° C. was added triflic acid (6 drops). The resulting solution was stirred for 4 hours as it warmed from −78 to 0° C. The reaction was quenched by adding excess saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with 25% ether/hexanes gave the title compound (1.64 g, 80%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C.O.N>[C:20]([C@@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: Clc1nnc(CCc2cccnc2)c2ccccc12
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2nnc(CCc3cccnc3)c3ccccc23)CC1

Procedure:
Under N2-atmosphere, 500 mg (1.85 mmol) 1-chloro-4-[2-(pyridin-3-yl)ethyl]phthalazine and 1.25 g (8 mmol) of 4-tert.-butylcyclohexylamine (trans/cis mixture) are heated at 150° C. for 2.5 h. The reaction mixture is diluted with ethyl acetate, water and conc. NH3-solution (=1 ml), then the aqueous layer is separated off and extracted 2× with ethyl acetate. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; ethyl acetate to ethyl acetate/ethanol 10:1) yields the trans isomer followed by the cis isomer of the title compound. trans 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: m.p. 155-157° C.; 1H-NMR (DMSO-d6) 8.50 (s, 1H), 8.38 (d, 1H), 8.35 (d, 1H), 8.06 (d, 1H), 7.83 (m, 2H), 7.74 (d, 1H), 7.30 (m, 1H), 6.89 (d, HN), 4.08 (m, 1H), 3.38 (t, 2H), 3.10 (t, 2H), 2.12 (m, 2H), 1.81 (m, 2H), 1.35 (q, 2H), 1.14 (q, 2H), 1.07 (m, 1H), 0.88 (s, 9H); FAB-MS (M+H)+=389. cis 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: 1H-NMR (DMSO-d6) 8.48 (m, 2H), 8.38 (d, 1H), 8.08 (m, 1H), 7.84 (m, 2H), 7.73 (m, 1H), 7.29 (m, 1H), 6.49 (d, HN), 4.33 (sb, 1H), 3.39 (m, 2H), 3.10 (m, 2H), 2.18 (d, 2H), 1.6-1.4 (m, 6H), 1.06 (m, 1H), 0.87 (s, 9H); FAB-MS (M+H)+-=389.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[CH:24])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:25]([NH2:27])=[O:26])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.[Si]([N:32]=[N+:33]=[N-:34])(C)(C)C>>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]5[N:32]=[N:33][NH:34][CH:24]=5)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:25]([NH2:27])=[O:26])=[CH:12][N:11]=2)[C:5]([F:8])([F:6])[F:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3c[nH]nn3)ccc12
Temperature: 25 °C

Procedure:
1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-ethynyl-5H-pyrido[4,3-b]indole-4-carboxamide (0.13 g, 0.36 mmol) in TMS-azide (4 mL, 30 mmol) was heated to 150° C. for 18 h, cooled to room temperature, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.73 (s, 1H); 8.50 (d, 1H); 8.48 (s, 1H); 8.30 (br s, 1H); 8.22 (s, 1H); 7.93 (br s, 1H); 7.72 (d, 1H); 7.26 (br s, 1H); 6.98 (d, 1H); 4.85 (m, 1H); 1.58 (m, 1H); 0.72 (m, 1H); 0.62 (m, 1H); 0.51 (m, 1H); 0.31 (m, 1H). LRMS (APCI) calc'd for (C19H16F3N7O) [M+H]+, 416.1. found 416.1.
Reaction SMILES: C(O)(=O)C.[C:5](#[N:9])[CH2:6][C:7]#[N:8].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[C:10]1(=[C:6]([C:5]#[N:9])[C:7]#[N:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#CCC#N
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#CC(C#N)=C1CCCCC1
Temperature: 25 °C

Procedure:
Acetic acid was added at room temperature to a stirring mixture of malononitrile (2.65 mL, 42.1 mmol), cyclohexanone (5.03 g, 51.3 mmol) and NH4OAc (6.49 g, 84 mmol) in toluene (200 mL). The resulting mixture was heated at reflux under a Dean-Stark trap for 2 hours (6 mL water collected), then cooled to room temperature. The mixture was concentrated under vacuum, and the residue was distilled under vacuum (air bath 110-130° C./˜10 mm) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.61-1.74 (m, 2H), 1.81 (ddt, J=6.5, 6.2, 5.8 Hz, 4H), 2.66 (dd, J=6.5, 6.2 Hz, 4H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[NH:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:24]1[CH:28]=[CH:27][C:26]([NH:29][CH2:18][C:17]2[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=2)[O:14][CH2:13][CH:12]([OH:23])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:25]1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OC(COc1cccc(CNc2cc[nH]n2)c1)CN1CCc2ccccc2C1
Temperature: 60 °C
Yield: 11 %

Procedure:
To a solution of 3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)benzaldehyde (200 mg, 0.64 mmol) in DCM (15 mL) was added 1H-pyrazol-3-amine (80 mg, 0.96 mmol). The solution was heated at 60° C. for 0.5 h. NaBH(OAc)3 (204 mg, 0.96 mmol) was then added into the reaction mixture which was heated at 60° C. for another 1 h. The reaction mixture was quenched by adding 1 N HCl aqueous solution and diluted with DCM and washed with NaHCO3 aqueous solution. The separated organic layer was concentrated and the crude product was purified by preparative HPLC purification. (26 mg, yield 11%). MS (ESI+) e/z: 379.1 [M+1]. 1H NMR (MeOD, 400 MHz), δ ppm: 7.33-7.18 (m, 7H), 7.00-6.96 (m, 2H), 6.84-6.80 (m, 1H), 4.48-4.44 (m, 3H), 4.28 (s, 1H), 4.06-3.98 (m, 2H), 3.59-3.56 (m, 2H), 3.42-3.39 (m, 2H), 3.20-3.15 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN([CH:14]=[O:15])C>>[CH2:3]([O:15][CH2:14][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the above alcohol (430 mg, 3.0 mmol) in DMF (10 mL) was added NaH (144 mg of a 60% dispersion in mineral oil, 3.60 mmol) and the mixture was then cooled in an ice bath. Benzyl bromide (437 uL, 3.60 mmol) was then added and the mixture was stirred at room temperature for 3 h. After normal aqueous work-up and short column chromatographic purification, 600 mg of desired benzyl ether was obtained.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)s1
Yield: 33.5 %

Procedure:
A solution of 5-formylthiophene-2-carboxylic acid (350 mg, 2.24 mmol), tert-butyl 2-aminophenylcarbamate (467 mg, 2.24 mmol) and triethylamine (470 μL, 340 mg, 3.36 mmol) and BOP (1.1 g, 2.68 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography using 25% EtOAc in hexanes as an eluent, yielding 260 mg (33%) of the title compound. 1H NMR (CDCl3) 9.95 (s, 1H), 9.7 (br. s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.74 (m, 2H), 7.15 (m, 2H), 6.72 (s, 1H), 1.56 (s, 9H). LRMS: (calc) 346.1; (found) 369.1 (M+Na)
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>ClCCl>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N5CCN(C(C)=O)CC5)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 300 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 181 mg of 1-acetylpiperazine, and 3.0 mL of dichloromethane was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was washed with ethanol and water in this order to obtain 305 mg of methyl 4-{2-[4-({[2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.