Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[C:9]3[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=2)[CH:22]=[CH:26][CH:25]=[CH:24]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2n1-c1ccc(-n2cccc2)cc1
Yield: 0 %

Procedure:
A solution of 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (0.4 g, 1.59 mmol) and 2,5-dimethoxytetrahydrofuran (0.50 g, 3.78 mmol) in 15 mL of glacial acetic acid was heated at 90° C. for 1.5 hours. After removing the solvent the residue was purified by by semi-preparative HPLC to afford the title compound (0.095 mg, 20%) as a beige solid: 1H NMR (DMSO-d6) δ 6.32 (s, 2H), 7.08 (d, J=8.4 Hz, 1H), 7.15-7.25 (m, 1H), 7.25-7.35 (m, 1H), 7.40-7.55 (m, 5H), 7.60-7.70 (m, 3H), 12.82 (br s, 1H); MS (ESI) m/z 303 (MH+); MS (ESI) m/z 301 ([M−H]−); HRMS calcd for C19H15N2O2: 303.1122; found (ESI+): 303.1124; Anal. calcd for C19H14N2O2.0.1H2O: C, 75.0; H, 4.71; N, 9.21. Found: C, 74.90; H, 4.42; N, 9.33.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=O)[C:19]#[CH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:19]=[CH:20][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
To a solution of 1-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (740 mg, 2.5 mmol) in ethanol (20 mL) was added cyclopentyl guanidine hydrochloride (600 mg, 3.7 mmol), followed by solid potassium carbonate (510 mg, 3.7 mmol). The resulting solution was heated at 80° C. for 12 hours. The reaction mixture was concentrated to a solid. Water and dichloromethane were added. The phases were separated and the organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was crystallized from acetonitrile, to give 4-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (600 mg, 59%) as a white solid. 1H NMR (CDCl3) δ 9.48 (d, 1H), 8.11 (d, 1H), 7.68 (q, 2H), 7.42 (d, 1H), 7.11 (t, 2H), 6.86 (t, 1H), 6.40 (d, 1H), 5.28 (d, 1H), 4.35 (m, 1H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −113.0; MS m/z 408 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH2:24][O:25][CH3:26])=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:28]1([NH:34][C:35]([NH2:37])=[NH:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH2:24][O:25][CH3:26])=[CH:20][N:37]=[C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:36]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCc1cnc(Nc2ccccc2)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 90 °C
Yield: 2.7 %

Procedure:
4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (0.27 mmol) was combined with phenyl guanidine (73 mg) in N,N-dimethylacetamide (2 mL) and the resulting suspension was heated at 90° C. for 35 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by prep HPLC (Gilson: Column=CombiHT SB-C189 5 μM, 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) to afford III-a-164 as a yellow solid (3.2 mg). LC/MS(m/z) 444.16 (M+1), 442.19 (M−1); HPLC Method B, Rt=5.16 minutes: 1H NMR consistent with structure.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]=[CH:6][CH2:5]2)[CH2:3][O:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[O:2]1[CH2:3][C:4]2([CH2:8][CH:7]3[CH:6]([CH:11]3[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5]2)[CH2:1]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C1=CCC2(C1)COC2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2CC3(COC3)CC21
Yield: 83.1 %

Procedure:
To a solution of 2-oxaspiro[3.4]oct-6-ene (1.0 g, 9.2 mmol) and copper sulfate (145 mg, 0.907 mmol) in toluene (5 mL) was added a solution of ethyl 2-diazoacetate (2.64 g, 22.7 mmol) in toluene (20 mL) at 100° C. over 16 h. The reaction mixture was concentrated, and the resulting residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to afford product as a brown oil (1.5 g, 84% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20].[OH-].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:20]/[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:21])=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCCC2)c(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(N3CCCC3)c(-c3cccs3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
4-Pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde (400 mg, 1.55 mmol) from Ex-20B and 4-acetylbenzoic acid (255 mg, 1.55 mmol) were dissolved in dimethylformamide (30 mL). Sodium hydroxide solution (5 N, 1.25 mL) was added in one portion, and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography (100% ethyl acetate) followed by recrystallization from ethanol provided 80 mg (13%) of the title compound as a solid, m.p. 212–214° C. with decomposition. 1H-NMR (300 MHz, CDCl3) δ 8.21 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.80 (d, 1H, J=15.3 Hz), 7.58 (d, 1H, J=1.9 Hz), 7.52 (dd, 1H, J=8.5 and 1.9 Hz), 7.33 (m, 1H), 7.32 (d, 1H, 15.3 Hz), 7.01–7.06 (m, 2H), 6.82 (d, 1H, 7.9 Hz), 3.12 (m, 4H), 1.84 (m, 4H). MS m/z=403 ([M]+, 100%). HRMS (EI) Calcd. for C24H21NO3S: 403.1242. Found: 403.1251.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9](=[O:17])[O:8]2)[CH2:4][O:3]1.[Si]([C:23]([F:26])([F:25])[F:24])(C)(C)C.[F-].C([N+](CC)(CC)CC)C>C1COCC1.O>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9]([C:23]([F:26])([F:25])[F:24])([OH:17])[O:8]2)[CH2:4][O:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@H]([C@H]2OC(O)(C(F)(F)F)[C@H]3OC(C)(C)O[C@@H]23)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1000 mL three neck round bottom flask, a solution of (3aS,6R,6aS)-6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)-2, 2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (30 g, 116.2 mmol, 1eq) in THF (600 mL) was treated with TMSCF3 (2M in THF, 122 mL, 244 mmol, commercially available from Sigma Aldrich, India) and tetraethylammonium fluoride (TEAF, 2.48 g, 23.24 mmol, Apollo scientific, UK) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 30 minutes and additional TEAF (24.8 g, 232.4 mmol, Apollo scientific, UK) was added to the reaction mixture. The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf 0.6), the reaction mixture was diluted with water (1000 mL), and it was then extracted with EtOAc (500 mL×2). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes) to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(trifluoromethyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol, as a yellow semi solid mixture of two isomers (27.3 g, 71.8%): 1H NMR (400 MHz, CDCl3) δ 4.95 (m, 2H), 4.78 (d, J=8 Hz, 1H), 4.61-4.32 (m, 2H), 4.23 (dd, J=8, 4 Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=8.0, 4.0 Hz, 2H), 3.98 (m, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 19F NMR (376.17 MHz, CDCl3) δ −78.24 & −82.32 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26]([NH:1][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=3)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2c1=O
Yield: 6.9 %

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 1-(4-amino-phenoxy)-3-dimethylamino-propan-2-ol (18 mg, 0.083 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 34 mg, 0.083 mmol). 3.1 mg of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.50 (br, 1H), 7.40 (d, 2H), 7.28 (m, 3H), 7.19 (d, 1H), 6.66 (br, 2H), 4.40 (q, 2H), 4.05 (m, 1H), 3.90 (d, 2H), 3.10 (m, 4H), 2.52 (dd, 1H), 2.33 (m, 7H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N5O5: 544.25 (M+H), Found: 544.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionyl chloride (8.7 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 3 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propionamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (13 mg, 28%). ESI-MS m/z calc. 456.5, found 457.5 (M+1)+; retention time 3.22 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (109) (100 mg, 0.27 mmol) was coupled to 3-fluoro-phenylboronic acid (41 mg, 0.29 mmol) using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:17](=[O:18])[CH2:16][C:15]([CH2:14][CH2:12][CH3:13])=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
From the reaction of 4-nitrophenylhydrazine and ethylbutyrylacetate, 2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazol-3-one, Mp 211° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([CH3:23])=[CH:18][N:17]=1>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]2)[C:19]([CH3:23])=[CH:18][N:17]=1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1C1(C(N)=O)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (2.29 g, 12.4 mmol), 2,4-dichloro-5-methylpyrimidine (2.62 g, 16.1 mmol), CuI (0.047 g, 0.25 mmol) and PdCl2(PPh3)2 (0.087 g, 0.12 mmol) in dioxane (25 mL) was bubbled with N2 for 10 minutes. Et3N (10 mL) was added and the mixture was stirred under nitrogen at 70° C. for 1 hour. The reaction mixture was cooled and adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 120 g SiO2, 0-10% MeOH in CHCl3) gave the title compound A39 as a yellow oil (1.85 g, 48%). LCMS-D: rt 3.24 min; m/z 312 [M+H]+.
Reaction SMILES: [CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18]([O:20]CC2C=CC=CC=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)CC)(=O)[CH2:32]C>Br.C(O)(=O)C.CCOCC>[CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18](=[O:20])[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Reactant: CCC(=O)OC(=O)CC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2.6 g (0.0063 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cycloheptylamide were dissolved in 15 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated from the solution. The ether phase was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.6 g (0.0126 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated. The solid residue was taken up in 100 ml of chloroform and the solution was washed with sodium chloride solution and dried over magnesium sulphate. The chloroform was removed by evaporation to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution. There was obtained 1.85 g (88.1%) of N-propionyl-L-alanyl-L-proline cycloheptylamide of melting point 155°-156° C. [α]D20 =-119.4° (c=0.91% in methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:22][NH2:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:23][N:22]=[C:8]2[CH2:9][CH2:10][CH3:11]
Reactant: NN
Reactant: CCCC(=O)c1cc(Br)ccc1F
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: CCCc1n[nH]c2ccc(Br)cc12
Temperature: 65 °C
Yield: 52.3 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)butan-1-one (2.0 g, 8.1 mmol) in THF, anhydrous hydrazine (11 mL) in THF was added and heated at reflux (60-70° C.) for 5-6 hours. Xylene was added to the reaction mixture and heated at reflux for 20-24 hours. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography using 15% ethyl acetate/pet-ether as eluents to afford 5-bromo-3-propyl-1H-indazole (1.02 g, 52.3%) as a solid. 1H NMR (CDCl3): δ 7.9 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 2.9 (t, 2H), 1.8 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:9]([C:6]2[NH:5][C:4]3[CH:3]=[CH:2][S:1][C:8]=3[CH:7]=2)=[O:11])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1cc2sccc2[nH]1
Reactant: C1CNCCN1
Product: O=C(c1cc2sccc2[nH]1)N1CCNCC1
Yield: 35 %

Procedure:
4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (50 mg, 0.30 mmol) was coupled with piperazine according to Procedure D to provide the title compound (25 mg, 35%) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C11H13N3OS, 235.08; m/z found, 236.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): 7.33 (d, J=5.3 Hz, 1H), 6.98 (dd, J=5.2, 0.7 Hz, 1H), 6.89 (d, J=0.6 Hz, 1H), 4.08 (t, J=5.3 Hz, 4H), 3.50-3.20 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH:17]=[O:18])[N:6]=[CH:5]1)[CH2:2][CH3:3].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>>[C:11]1([C:10]#[C:9][C:8]2[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][N:6]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:34][N:35]=[N:36][N:37]=4)=[CH:23][CH:22]=3)[C:7]=2[CH:17]=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCn1cnc(C=O)c1C#Cc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCN1CN(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C(C=O)=C1C#Cc1ccccc1

Procedure:
3-n-Propyl-4-(phenylethynyl)imidazole-5-carboxaldehyde was alkylated with 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl by the procedure described in example 1, parts D and I, to yield the entitled product. NMR (CDCl3) δ 9.88 (s,1H): 8.03 (m,1H); 7.57-7.27 (m,8H); 7.17 (m,2H); 7.01 (m,2H); 5.55 (s,2H); 2.61 (t,2H); 1.75 (m,2H); 0.99 (t,3H).
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:19]([CH3:29])[CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C@H:19]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:22](=[O:24])[NH:21][CH2:20]1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (4.9 g, 12 mmol) was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (18.3 mL) at 0° C. After removal of the ice bath, the solution was stirred for 30 min, and evaporated under reduced pressure. The residue was dissolved in methanol (40 mL), then after addition of saturated sodium bicarbonate solution (90 mL) the mixture was stirred for 20 h at room temperature. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel with hexane/ethyl acetate (1:1) yielded the title compound as a white solid (2.9 g, 90%). M.p.: 201–204° C., EI-MS: m/e=268.2 (M+), αD20=+7.5
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[CH2:11](O)[CH2:12][CH2:13]O>C1CCCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:10][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: OCCCO
Reactant: Cc1ccccc1B(O)O
Solvent: C1CCCCC1
Product: Cc1ccccc1B1OCCCO1

Procedure:
A mixture of 1.75 g of 2-methyl phenylboronic acid trimer, 30 ml of cyclohexane, and 0.5 ml of 1,3-propanediol is heated under reflux for 6 hours. The mixture is washed with water and extracted with pentane. The organic phases are dried and concentrated under reduced pressure. In this way 1.8 g of desired product is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O>CO>[CH3:12][O:13][CH:14]1[C:15]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:16][CH2:17][CH2:18][CH2:19]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC1CCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC1CCCC=C1c1c[nH]c2ccccc12
Yield: 29.9 %

Procedure:
Add 5 ml dry MeOH to a flask under N2 containing indole (1 g, 8.5 mmol, 8.5 eq) and potassium hydroxide (202 mg, 3.59 mmol, 1 eq). Add to this solution 2-Methoxy-cyclohexanone (834 mg, 6.5 mmol, 6.5 eq). Heat reaction to 63° C. for 18 hours. Cool reaction and purify crude material by silica gel chromatography to give 442 mg (30% yield) of 3-(6-Methoxy-cyclohex-1-enyl)-1H-indole as a waxy yellow solid. Mass Spectrum (m/e): 228.02 (MH+).