Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH:44]4[CH2:46][CH2:45]4)[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:49][CH3:50].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:48]=[CH:47][C:27]([C:28]([NH:30][C@H:31]5[CH2:32][CH2:33][C@H:34]([N:37]6[CH2:42][CH2:41][N:40]([CH2:43][CH:44]7[CH2:46][CH2:45]7)[CH2:39][CH2:38]6)[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:49][CH3:50])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (0.065 g, 0.2 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.24 g, 0.6 mmol, 3 eq) and TFA (75 μL, 1 mmol, 5 eq) in TFE (6 mL) were heated to reflux together 40 hours. RM was concentrated in vacuo and the residue was partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic layer was separated, washed with saturated brine and concentrated in vacuo to a residue that was purified by preparative RP-HPLC-MS (Preparative—1) to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:15]([N:22]1[CH2:26][CH2:25][C@H:24]([O:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)O[C@H]2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A solution of 3-methoxy-4-nitro-benzoyl chloride (608 mg, 2.82 mmol) in 10 mL of CH2Cl2 was added to stirred solution of 500 mg (2.82 mmol) of (3S)-1-benzyl-pyrrolidin-3-ol and 1 mL of pyridine in 15 mL CH2Cl2 at room temperature. After stirring for 18 h, the reaction mixture was diluted with 20 mL of saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with 20 mL of brine, dried over MgSO4, filtered, and concentrated in vacuo to furnish 780 mg (71%) of the desired ester as a yellow oil, which solidified after drying under high vacuum. The resulting solid was further purified by trituration with 1:1 ether-hexane. 1H-NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.83 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=7.83 Hz, 1H), 7.2-7.4 (m, 5H), 5.44 (br.m, 1H), 4.02 (s, 2H), 3.69 (dd, J=30 Hz, J=13 Hz, 1H), 2.8-3.0 (m, 2H), 2.5-2.6 (m, 1H), 2.3-2.45 (m, 1H); 2.0-2.1 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[H][H]>C(O)C.[Ni]>[F:1][C:2]([F:14])([F:15])[CH:3]([OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccccc1C(O)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C(O)C(F)(F)F

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(2-nitrophenyl)ethane from Step 1 (5.45 g, 24.64 mmol) in 90 mL of ethanol was hydrogenated over 200 mg of Raney Nickel at 5 psi hydrogen over a 8 h period at 23° C. After removing the catalyst by filtration, concentration in vacuo afforded a quantitative yield of 1,1,1-trifluoro-2-hydroxy-2-(2-aminophenyl)ethane as a orange-yellow solid: 1H NMR (CDCl3) δ 4.32 (br s), 5.03 (q, J=6 Hz), 6.28 (br s), 6.67-6.78 (m), 7.08-7.23 (m); 13C NMR (CDCl3) 66.6 (q, J=33 Hz), 121.9, 124.9, 127.2 (q, J=280 Hz), 129.3, 130.1, 133.6; MS (EI) 191 (M+), 173, 122. IR (neat) 3395, 3325, 3400-3100. Anal. Calc'd. for C8H8NOF3: C, 50.26; H, 4.22; N, 7.33. Found: C, 50.47; H, 4.57; N, 7.05.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
tert-Butyl(cis-4-hydroxycyclohexyl)carbamate (2.00 g), phenol (1.14 g), and triphenylphosphine (3.17 g) were dissolved in tetrahydrofuran (40.0 mL). Then, to the solution, diisopropyl azodicarboxylate (6.49 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 63 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate-90/10) to obtain the title compound (1.80 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)[CH3:2].Cl[SiH:12]([CH3:14])[CH3:13].[Mg].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:13])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(Br)cn1
Reactant: C[SiH](C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc([SiH](C)C)cn1
Yield: 42.9 %

Procedure:
A mixture of 18.2 g (0.09 mol) of 2-ethoxy-5-bromopyridine (can be obtained from 2,5-dibromopyridine and sodium methanolate in DMSO), 11.4 g (0.12 mol) of chlorodimethylsilane and 50 ml of anhydrous tetrahydrofuran (THF) is added dropwise to 2.4 g (0.10 mol) of magnesium turnings in 10 ml of anhydrous THF, a strongly exothermic reaction occurring. The reaction is completed by refluxing for two hours. The mixture is then poured into water and extracted repeatedly with n-hexane, The extracts are washed with water and saturated sodium chloride solution, dried and evaporated, and the residue is distilled. 7 g (43%) of 2-ethoxy-5-dimethylsilylpyridine are obtained as a colorless oil of boiling point 7=140°-150° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of (2-nitro-4-trimethylsilanylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F1) (3.54 g, 10.6 mmol) in MeOH (10 mL) and THF (20 mL) at 0° C. was added 1N NaOH (13 mL) and stirring was continued at 23° C. for 30 min. Poured into cold 5% citric acid, extracted with EtOAc (300 mL), washed with sat. NaHCO3-sol. and brine, dried over MgSO4. Removal of the solvent in vacuum left a dark brown oil, which was purified by silica gel column chromatography with hexane/EtOAc 19:1. Obtained as a yellow solid (2.4 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC>>[CH:6](=[N:7][CH:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(C)C
Agent: [Li]CCCC
Product: CC(C)C(N=Cc1ccccc1)C(C)C

Procedure:
treating (4-bromobenzylidene) (1-isopropyl-2-methylpropyl)amine with n-butyllithium to give para-lithiated (benzylidene) (1-isopropyl-2-methylpropyl)amine,
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]3[C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][N:15]=[C:9]3[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:30]1[N:35]=[C:34]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:32][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:30]4[N:35]=[C:34]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:33]=[CH:32][CH:31]=4)=[CH:14][N:15]=[C:9]3[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Brc1cccc(-c2cccnc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(Cn3cncn3)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1cncc(-c2cccc(-c3cnc4nc(Cn5cncn5)ccn34)n2)c1

Procedure:
To the degassed solution of 7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was added 6-bromo-2,3′-bipyridine (prepared according to Example 49) (0.39 g, 1.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.10 mmol) and the mixture heated at reflux for 3 h. The crude reaction was adsorbed onto silica and purified by chromatography on silica gel eluting with a dichloromethane, methanol, aqueous ammonia (33%) mixture in the volume ratios of 90:5:0.5 respectively to give 6-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,3′-bipyridine as a hygroscopic solid following crystallisation from dichloromethane/ethyl acetate. Addition of an excess of 1M HCl in ether to a solution of the product in a methanol/ether solvent mixture gave 50 mg of the dihydrochloride salt as a white solid: δH (360 MHz, CDCl3) 5.62 (2H, s), 6.96 (1H, d, J 7), 7.47 (1H, dd, J 4.7 and 4.7), 7.66 (1H, d, J 7.7), 7.78 (1H, d, J 7.9), 7.91 (1H, t, J 9), 8.05 (1H, s), 8.23-8.27 (1H, m), 8.36 (1H, s), 8.41 (1H, s), 8.71-8.72 (1H, m), 9.25 (1H, s), 10.30 (1H, d, J 7.2); m/z (ES+) 355 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3](=[O:42])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:30][NH:31]C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>[Pd].CO>[CH3:43][N:2]([CH3:1])[C:3](=[O:42])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:30][NH2:31])[CH2:15][CH2:16][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(CNC(=O)OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Agent: [Pd]
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCC(CN)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Yield: 52 %

Procedure:
3-(4-((Benzyloxycarbonylamino)methyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate (0.140 g, 0.239 mmol) from example 19, step E, Pd/C (10% Pd/C, Pearlman), and methanol (5 mL) were combined and hydrogenated overnight at 1 atmosphere. The reaction was filtered through celite, concentrated under vacuum, and purified by neutral phase prep-HPLC to give the title compound as the acetate salt in 52% yield.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH2:6])[CH3:2].[F:7][C:8]([F:15])([F:14])[C:9]([O:11]CC)=O.O>C(#N)C>[F:15][C:8]([F:7])([F:14])[C:9]([NH:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCNCCN
Solvent: CC#N
Solvent: O
Product: CCNCCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of N-ethylethylenediamine (10.0 g, 113.4 mmol) and ethyl trifluoroacetate (32.0 mL, 261 mmol) in the mixture of acetonitrile (110 mL) and water (2.5 mL, 139 mmol) was refluxed with stirring overnight (˜18 h). Solvents were evaporated in vacuo. Residue was re-evaporated with i-PrOH (3×100 mL). Residue was dissolved in dichloromethane (500 mL) and left overnight at room temperature. The formed crystals were filtered, washed with dichloromethane (100 mL) and dried in vacuo to provide compound JJ (24.6 g, 82.4 mmol) as white solid powder.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:24]=1[CH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:22][CH:21]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: CC1=C(Cc2ccc(C(C)C)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 58 %

Procedure:
As starting materials for the coupling reaction menadione and 4-isopropylphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 395 mg (1.30 mmol, 58% yield) of P_TM100 were isolated as yellow solid.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[C:31]3=[O:39])=[C:23]2[CH:22]=[N:21]1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:34][CH2:33][NH:32][S:35]([CH3:38])(=[O:37])=[O:36])[C:31]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=3)=[O:39])=[C:23]2[CH:22]=[N:21]1
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)N1CC[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](CCNS(C)(=O)=O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Trimethylaluminium (2M in hexane) (0.164 mL, 0.33 mmol) was added to 5-methylpyridin-2-amine (33.8 mg, 0.31 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-1-(methylsulfonyl)pyrrolidin-2-one (Intermediate AC1) (116 mg, 0.28 mmol) in toluene (1 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid and sodium potassium tartrate solution (sat.) and stirred vigorously for 45 mins. The mixture was separated and the aqueous re-extracted with ethyl acetate, the organic layer was dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (52.0 mg, 35.4%). 1H NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.37-2.55 (2H, m), 2.98 (3H, s), 3.35-3.55 (2H, m), 4.95-5.10 (1H, m), 6.04 (1H, t), 7.44-7.58 (4H, m), 7.60-7.65 (1H, m), 8.07-8.15 (2H, m), 8.44 (1H, s), 8.61 (1H, s), 8.69 (1H, s); m/z (ES+) (M+H)+=516.28; HPLC tR=1.84 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]>[Pd].O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1ccc(CCC(=O)O)cc1

Procedure:
4-Ethoxycinnamic acid (2) is hydrogenated at 40 p.s.i. with catalytic 5% palladium on carbon in tetrahydrofuran solvent to obtain 3-(4-ethoxyphenyl)propionic acid (3). A sample is recrystallized from ethyl acetate/hexane to obtain an analytically pure sample (m.p. 101-103° C.).
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)([CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][C:5](OCC)=[O:6])#[N:2].CCO.C([O-])(O)=O.[Na+]>O>[Cl:26][C:21]1[CH:20]=[C:19]([C:3]2([CH2:10][CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:1][NH:2][C:5](=[O:6])[CH2:4]2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CCOC(=O)CC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Yield: 83.8 %

Procedure:
A solution of 8 g of the compound obtained in step B in 100 ml of 100° EtOH, 5 ml of water and 0.6 g of NaHCO3 is hydrogenated at atmospheric pressure and at RT. The catalyst is filtered off and the filtrate is evaporated under vacuum. The residue is extracted with DCM, the extract is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 6 g of the expected product.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20]=2[CH2:21][O:22][CH3:23])=[C:17]([O:24][C:25]2[N:30]=[CH:29][CH:28]=CN=2)[CH:16]=[CH:15][CH:14]=4)[O:5][N:4]=1)[CH3:2].ClC1C=C[C:35](OC2C=CC=C3C=2C2C(COC)=C(C4ON=C(CC)N=4)N=CC=2N3)=[N:36]C=1.C(OC(C)C)(C)C>CCO>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20]=2[CH2:21][O:22][CH3:23])=[C:17]([O:24][C:25]2[CH:35]=[N:36][CH:28]=[CH:29][N:30]=2)[CH:16]=[CH:15][CH:14]=4)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ncccn5)c4c3c2COC)n1
Reactant: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cn5)c4c3c2COC)n1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCc1noc(-c2ncc3[nH]c4cccc(Oc5cnccn5)c4c3c2COC)n1

Procedure:
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methoxymethyl-5-(2-pyrimidinyloxy)-β-carboline, mp 175°-176° C. (EtOH), 5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-3-(3-ethyl1,2,4-oxadiazol-5-yl)-β-carboline, mp 144°-146° C. (diisopropyl ether).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Product: Nc1ccccc1C(=O)Nc1ccc(CCCC(=O)O)cc1

Procedure:
4-(4-(2-aminobenzoyl)aminophenyl)butyric acid was prepared using Method F starting from isatoic anhydride and 4-(4aminophenyl)butyric acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:9]=1.Cl.[CH2:21]([NH:23][CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22].[I-].[K+].C(OCC)C>CN(C)C=O>[CH2:21]([N:23]([CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:9]=1)[CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH3:22]
Reactant: O=C(CCCBr)COc1cccc(-c2ccsc2)c1
Reactant: CCNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(C/C=C/C#CC(C)(C)C)CCCC(=O)COc1cccc(-c2ccsc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
50 mg of 5-bromo-1-[3-(3-thienyl)phenoxy]-2-pentanone was dissolved in 1.8 ml of dimethylformamide, and 125 mg of a (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 29 mg of potassium iodide were added. The mixture was stirred at 40° C. for 1 hour, and then ethyl ether and ice water were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane→chloroform] to give 20 mg (yield 27%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1
Reactant: NCCSCc1ccco1
Reactant: COc1ccc(C(=O)O)cc1C
Product: COc1ccc(C(=O)NCCSCc2ccco2)cc1C
Yield: 58 %

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and 2-(furan-2-ylmethylthio)ethanamine. Yield 58%. 1H NMR (500 MHz, CDCl3) 2.23 (s, 3H), 2.76 (t, 2H, J=6.37 Hz), 3.59 (q, 2H, J=12.2 Hz), 3.76 (s, 2H), 3.86 (s, 3H), 6.22 (dd, 1H, J=3.49 Hz, J=2.67 Hz), 6.30 (dd, 1H, J=3.04 Hz, J=1.78 Hz), 6.46 (m, 1H, broad), 6.83 (d, 1H, J=8.51 Hz), 7.34 (dd, 1H, J=1.97 Hz, J=1 Hz), 7.56 (d, 1H, J=1.72 Hz), 7.61 (dd, 1H, J=8.53 Hz, J=2.25 Hz). MS (M+H, 306).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([SH:9])[N:6]2[N:10]=[C:11]([CH3:13])[N:12]=[C:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:9][C:7]3[N:6]4[N:10]=[C:11]([CH3:13])[N:12]=[C:5]4[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=3)[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nc2nc(CO)cc(S)n2n1
Agent: N
Solvent: O
Solvent: CC#N
Product: Cc1nc2nc(CO)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 120 ml of acetonitrile were suspended 9.8 g of 5-hydr- oxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine and 13.6 g of 7-aminocephalosporanic acid, and 22 ml of boron trifluoride-ethyl ether complex was added to the suspension and the mixture was stirred at 50° C. for 3 hours. After cooling the reaction mixture, 250 ml of water was added thereto and the mixture was adjusted to pH 2 with conc. aqueous ammonia. Precipitated crystal was collected by filtration, washed with water, washed with acetone and then dried to obtain 11.6 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([O:14][C:23](=[O:25])[CH3:24])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)c2c1cc(C)c(O)c2C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To an ice-cold solution of indoline 11a (219 mg, 1 mmol) dissolved in methylene chloride (5 mL) were added sequentially pyridine (1 mL) and acetic anhydride (0.12 mL, 1.1 mmol), and the resulting mixture was stirred over a range of 0° C. to room temperature for 18 h. The reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were washed with 5% aq. hydrochloric acid and brine then dried (MgSO4). Removal of solvents and chromatographic purification of the residue using 3:7 ethyl acetate:hexanes as eluent gave the acetate 12a (228 mg, 87% yield) as a pale yellow solid. This was recrystallized from hexanes-methylene chloride to afford a colorless solid, mp 128°-130° C. Spectral data: 1H NMR: δ 1.23 (d, 3H, J=7 Hz), 2.04 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 3.61 (dd, 1H, J=10.2, 2.3 Hz), 4.13 (t, 1H, J=9.53 Hz), 7.96 (s, 1H); 13C NMR: δ 12.3, 16.7, 20.4, 20.7, 24.8, 33.9, 57.4, 116.4, 125.7, 129.3, 133.7, 139.5, 144.2, 168.5, 169.1; HRMS: calcd. for C15H20NO3 (M+H+) 262.1443, fnd. 262.1446.