Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].Cl>C(O)C.O>[C:19]1(/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Yield: 24.5 %

Procedure:
To a slurry of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (4.0 mmol, 1.0 g), and benzaldehyde (4.0 mmol, 0.41 ml) in ethanol (10 ml) was added sodium methoxide (4.8 mmol, 260 mg). The solution was heated to reflux for 1.5 hours, then more benzaldehyde was added and the mixture was heated another 1.5 hours, then cooled, diluted with water (60 ml), acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isopropanol to give title product as a pale yellow solid (0.33 g, 24%); m.p. 147°-149° C.
Reaction SMILES: [H-].[Na+:2].ClC1C=C(C=CC=1)N.[CH3:11][C:12]1[CH2:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]>O1CCCC1>[CH3:11][C:12]1[CH:16]([Na:2])[C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: [Na+]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Nc1cccc(Cl)c1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (0.80 g) and m-chloroaniline (0.064 g) were added to the solution of tetramethylcyclopentadiene (1.34 g; purity: 91.3%; pure compound: 1.22 g) dissolved in tetrahydrofuran (6.73 g), and stirred at 50° C. for one hour. Thus, tetramethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:9][C:10]1[CH:17]=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[C:14]([F:19])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: C[C@@H]1NCC[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (300 mg), 2,4,6-trifluorobenzonitrile (882 mg) and lithium carbonate (276 mg), the title compound was obtained as a colorless solid (yield: 263 mg, yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].I[CH3:17]>CN(C=O)C.C1CCN2C(=NCCC2)CC1>[CH3:17][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:15]
Reactant: CI
Reactant: O=C(O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To an ice cooled solution of (E)-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoic acid (2.4 g, 0.01 mol) in dry DMF (80 mL), DBU (1.5 mL, 0.01) was added dropwise on stirring, under nitrogen atmosphere. To the resulting stirred solution iodomethane (3.1 mL, 0.05 mol) dissolved in dry DMF (20 mL) was added dropwise over 20 min. The resulting solution was stirred at 0° C. for 1 hour and 3 hours at room temperature. The resulting reaction mixture was poured into ice-water on stirring, and the precipitate was filtered, washed with water and then with hexane. Recrystallization from diisopropyl ether/hexane provided the pure ester (2.2 g, 86%), pale yellow needles, mp. 108-109°.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]([Cl:32])=[CH:23][C:22]=1[Cl:33].[O:34]1CC[CH2:36][CH2:35]1>>[Cl:33][C:22]1[CH:23]=[C:24]([Cl:32])[C:25]2[C:30](=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:21]=1[CH2:20][CH2:36][CH:35]=[O:34]
Reactant: ClCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=CCCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyl lithium in hexane (3.2 ml, 4.3 mmoles) was added dropwise (3 minutes) to a solution of diisopropylamine (0.45 g, 4.5 mmoles) in dry tetrahydrofuran (10 ml) with cooling (ice bath). After stirring under nitrogen for 15 minutes, ethylidene cyclohexylimine (0.55 g, 4.3 mmole) was added dropwise (5 minutes) at 0° C. The mixture was stirred for 15 minutes and then the ice bath was replaced by a dry-ice-acetone bath. A solution of 1-chloromethyl-2,4,7-trichloronaphthalene (1.0 g, 3.8 mmoles) in tetrahydrofuran (15 ml) was added (5 minutes) at -75° C. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature overnight (20 hours) and then concentrated to dryness in vacuo. The residual oil was taken up in ether (100 ml) and 5% aqueous oxalic acid (100 ml) and the mixture stirred at room temperature for 31/2 hours. The layers were separated and the aqueous phase extracted (2X) with ether. The ether extracts were combined, washed with cold water and brine, and dried over MgSO4. The solution was filtered and concentrated in vacuo to give a red-brown oil (1.1 g). This material was chromatographed using a 50 mm flash column containing 150 g of silica gel (230-400 mesh) eluting with 30% methylene chloride in hexane (v/v) to give 0.21 g of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CCO>C(OCC)(=O)C>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCNCC1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: CCOC(C)=O
Product: NCC1CCN(c2ncccc2Cl)CC1
Temperature: 95 °C
Yield: 72.8 %

Procedure:
A stirred mixture of 2,3-dichloropyridine (20 g), 1-(piperid-4-yl)methylamine (30 g), sodium carbonate (30 g) and 3-methyl-1-butanol (100 ml) was heated at 95° C. for 16 hours, then cooled to ambient temperature, diluted with ethyl acetate (200 ml), and filtered. The solvents were removed in vacua, and the residual oil distilled to give 1-[1-(3-chloropyrid-2-yl)piperid-4-yl]methylamine as a colourless oil (22.2 g), b.p. 115°-140° C. at 0.13 mbar.
Reaction SMILES: [CH:1]1([N:5]2[C:10]3[N:11]=[C:12](S(C)=O)[N:13]=[C:14]([CH3:15])[C:9]=3[CH:8]=[C:7]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1.[N:28]1C2NC(=O)C=CC=2C=N[CH:29]=1>>[CH:1]1([N:5]2[C:10]3[N:11]=[C:12]([NH:28][CH3:29])[N:13]=[C:14]([CH3:15])[C:9]=3[CH:8]=[C:7]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1ccc2cncnc2[nH]1
Reactant: COc1ccc(-c2cc3c(C)nc(S(C)=O)nc3n(C3CCC3)c2=O)cn1
Product: CNc1nc(C)c2cc(-c3ccc(OC)nc3)c(=O)n(C3CCC3)c2n1
Yield: 35 %

Procedure:
Following the procedure described in Example 22, using 8-cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one in place of 6-(6-methoxypyridin-3-yl)-4-methyl-2-ethylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, the title compound was obtained in 35% yield.
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1.[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[O:17][N:16]=1.[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O>[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=3)=[O:12])[CH2:30][CH2:31]2)=[O:23])[O:17][N:16]=1
Reactant: O=C(CCc1cc(O)no1)NCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCc1cc(O)no1)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3,5-dichlorobenzyl carbonochloridate (331 mg, 1.380 mmol) and 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide (step 2) (200 mg, 0.690 mmol) in DCM (7 ml) was added 2M NaOH solution (6.90 ml, 13.80 mmol) and the mixture stirred vigorously at RT for 16 hrs. The mixture was diluted with EtOAc (50 ml) and acidified with 2M HCl. The organics were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in MeOH/EtOAc and dry loaded onto silica (10 g). This was applied to a 12 g silica cartridge, eluting with 1% AcOH/EtOAc. The product fractions were combined and concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.N1C=CC=CC=1.[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH:34][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 104 %

Procedure:
2-Amino-4-chloropyridine (500 mg, 0.446 mmol) was dissolved in N-methylpyrrolidone (5.0 ml); pyridine hydrochloride (750 mg) and 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol) was added thereto; the reaction mixture was stirred at 100° C. for 6.5 hours. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system). The obtained pale yellow oil was solidified with diethyl ether; and the crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (188 mg, 0.464 mmol, 35.7%) as pale yellow crystals.
Reaction SMILES: N[C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3].[OH:31][Li].O>CO>[CH3:27][C:26]([O:25][C:23]([N:5]1[C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8][C@@:4]1([CH3:30])[C:2]([OH:31])=[O:3])=[O:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Reactant: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(=O)O
Yield: 93.4 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D7, 0.977 g, 2.29 mmol) and LiOH.H2O (192 mg, 4.59 mmol, dissolved in 7 ml H2O) in methanol (7 ml) was heated in a microwave synthesizer for 1 hour at 100° C. After evaporation of methanol, the aqueous phase was acidified to pH 3 with 1M HCl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (white solid, 880 mg, 93%); R (cyclohexane:ethyl acetate=6:4): 0.24; Rt (HPLC): 6.07 min. MS: (ES/−) m/z: 410 [M−H]; C24H29NO5 requires 411; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 12.92-12.23 (br. s, 1H); 7.48-7.40 (m, 4H); 7.40-7.33 (m, 2H); 7.31 (t, 1H); 6.92 (t, 2H); 5.08 and 5.06 (s, s, 2H); 4.85 and 4.76 (d, d, 1H); 2.48-2.34 (m, 1H); 2.19-2.05 (m, 1H); 1.81-1.72 (m, 1H); 1.64-1.57 (m, 1H); 1.46 and 1.43 (s, s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18](OC3CCOCC3)[C:19]=2[N:20]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:41][CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[C:19]=2[N:20]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Hunig's base (6.53 mL, 37.5 mmol) was added to a suspension of 4,6-dichloropyrido[3,2-d]pyrimidine (intermediate 1, 5.00 g, 25.0 mmol) and tert-butyl-4-aminopiperidine-1-carboxylate (6.00 g, 30.0 mmol) in 1,4-dioxane (250 mL) at room temperature. The reaction mixture was refluxed for 1 h, and cooled to room temperature. The solvent was removed under reduced pressure, EtOAc and water were poured into the residue, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give a pale yellow solid which was washed with MeOH afforded tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (8.72 g, 96%) as a off white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.50-1.62 (2H, m), 2.10-2.15 (2H, m), 2.98-3.01 (2H, m), 4.01-4.25 (2H, m), 4.25-4.40 (1H, m), 6.86 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=8.8 Hz), 8.04 (1H, d, J=8.8 Hz), 8.62 (1H, s).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([CH3:40])([OH:39])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:40][C:11]([OH:39])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:18][CH:19]=1)[CH2:10][CH2:9][OH:8]
Reactant: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(CCO)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 79.9 %

Procedure:
4-Benzyloxy-2-methyl-1-(4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenoxy)butan-2-ol (2.43 g, 4.5 mmol), ethanol (24 ml) and 20% palladium hydroxide on carbon (0.24 g) were mixed and stirred at 50 to 60° C. under the hydrogen pressure of 1 atm for 4 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless powder (1.68 g, 80%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:12]([NH:14][NH2:15])=O)([CH3:8])[CH3:7].[OH-].[Na+]>C(O)C>[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([C:12]2[N:2]([CH3:1])[C:3](=[O:4])[NH:15][N:14]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:8])[CH3:7]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n[nH]c1=O
Temperature: 25 °C
Yield: 29.6 %

Procedure:
Methyl isocyanate (1.02 g, 18 mmol) is added dropwise to a solution of the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (2.35 g, 8.9 mmol) in absolute ethanol (100 ml). The reaction mixture is stirred at room temperature, concentrated, and poured into ice water. The precipitate (1.2 g) is collected by filtration and dissolved in two equivalents of 1N NaOH. The reaction mixture is refluxed for three hours, and then is cooled and neutralized. The product is extracted into ethyl acetate. Pure 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one (0.8 g, 30%) is obtained by recrystallization from methanol, mp 308°-312° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][NH:8][C:7]=1[CH2:17][CH2:18][NH2:19])=[O:5])C.O.[OH-].[Li+].O.[CH2:24]([OH:26])C>>[O:5]=[C:4]1[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH:24]=[O:26])[NH:8][C:7]=2[CH2:17][CH2:18][NH:19]1
Reactant: CCO
Reactant: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
A stirred solution of 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester, lithium hydroxide monohydrate (840 mg, 20 mmol) in ethanol (20 ml) was heated to reflux under an argon atmosphere for 3 hours. The mixture was added with cold water (150 ml), stirred for 10 minutes, extracted with dichloromethane:methanol=5:1(50 ml×7), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from dichloromethane and methanol to give 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (280 mg, 38.9%) as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33]Cl)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Na]c1ncc[nH]1
Reactant: Cc1cc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.7 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.2 g of imidazolyl sodium are heated to 80° C. in 30 ml of DMF and the mixture is stirred for 5 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine having an m.p. of 158°-160° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:30])[CH3:29])[CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[O:19])[CH:15]=[CH:16][C:9]2=1)([OH:3])=O.C(OC(C1C=CC=C2C=1[NH:43]C1CN(CC(NC(C(C)C)C(O)C(F)(F)F)=O)C=CC2=1)=O)C>>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:29])[CH3:30])[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:19])[CH:15]=[CH:16][C:9]2=1)(=[O:3])[NH2:43]
Reactant: CC(C)C(NC(=O)CN1C=Cc2c([nH]c3c(C(=O)O)cccc23)C1)C(O)C(F)(F)F
Reactant: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(C)C)C(O)C(F)(F)F)C=C3
Product: CC(C)C(NC(=O)CN1C=Cc2c([nH]c3c(C(N)=O)cccc23)C1)C(=O)C(F)(F)F

Procedure:
2-(8-Carboxy-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide. 2-(8-Ethoxycarbonyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a hydrolysis procedure similar to that outlined in Example 3 to give the title compound as a white solid;
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[C:3]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)=[O:12])=[CH:43][CH:42]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccc(Cl)cc2)C2CCC(C2)C1=O
Reaction time: 2 h

Procedure:
2.0 g (0.0058 mol) of 4-chloro-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one, 0.07 g of dimethylaminopyridine (0.00058 mol) and 1.61 ml of triethylamine are dissolved in 15 ml of methylene chloride. At 25° C., 0.092 g (0.0064 mol) of 4-chlorothiophenol are added. After 2 hours at 22° C., the reaction mixture is evaporated and purified over silica gel (hexane/ethyl acetate 2:1). Recrystallization (hexane/acetic acid at −25° C.) gives pure 4-(4-chlorophenylsulfanyl)-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one: m.p. 130-131 ° C.
Reaction SMILES: C([O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[NH:12][C:11]2=[O:18])[CH2:7][CH:6]1[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C1CCN2C(=NCCC2)CC1>>[OH:4][CH:5]1[O:9][CH:8]([N:10]2[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[NH:12][C:11]2=[O:18])[CH2:7][CH:6]1[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)OC1OC(n2cc(C)c(=O)[nH]c2=O)CC1[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CC([Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(O)O2)c(=O)[nH]c1=O

Procedure:
Compound 97 is treated as per the protocol of Baptistella et. al., Synthesis 1989, 436 with DBU to give the title compound, 98.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3O)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.P(Cl)(Cl)([Cl:29])=O>C(#N)C>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:29])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture containing 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2-ethylquinolin-4-ol (1.78 g, 4.36 mmol, Intermediate 32: step c) and phosphorus oxychloride (1.8 mL, 20 mmol) in acetonitrile (15 mL) was heated to 90° C. After 3 hours, the flask was allowed to cool to 23° C. The mixture was concentrated. Dichloromethane (100 mL) and ice (50 mL) were added to the residue. Concentrated aqueous ammonia solution was added dropwise with stirring until the pH was 9 by litmus paper test. The biphasic mixture was stirred at 23° C. for 30 minutes. The layers were separated. The aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined and the combined solution was dried with sodium sulfate. The dried solution was filtered. Celite® (8 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with hexanes initially, grading to 25% ethyl acetate-hexanes provided the title compound as an off-white solid.