Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[CH3:24].C([O-])([O-])=O.[K+].[K+].[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:39]([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)=[O:40])[CH2:34][CH2:33]1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:39](=[O:40])[C:41]2[CH:46]=[CH:45][C:44]([C:2]3[N:11]=[C:10]4[N:4]([CH2:5][CH2:6][C:7]5[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=5[CH:9]4[O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[C:3]=3[CH3:24])=[CH:43][CH:42]=2)[CH2:36][CH2:37]1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1ccc(B(O)O)cc1
Reactant: Cc1c(I)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(C(=O)NC3CCC(O)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 95 °C

Procedure:
To a solution of 2-iodo-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 133) (50 mg, 0.114 mmoles) in THF (0.7 mL) in a screw-capped vial under argon are added a 1M aqueous solution of K2CO3 (0.5 mL, 0.5 mmole), PdCl2(dppf)2 (4.5 mg, 6 μmole) and 4-(trans-4-hydroxycyclohexylcarbamoyl)phenylboronic acid (45 mg, 0.150 mmole). The reaction mixture is heated at 95° C. overnight. Water is added to the reaction mixture and the aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (98:2:0.2) to (96.5:3.5:0.35). The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1) to afford N-(4-hydroxycyclohexyl)-4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:25])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:7]=1
Reactant: Clc1cccc(COc2cncc(Cl)n2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Cl)nc(OCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 3-chloro-5-(3-chloro-benzyloxy)-pyrazine I-3l (500 mg, 1.97 mmol) in CHCl3 (10 ml) at 0° C. under a nitrogen atmosphere, was treated with 680 mg (3.94 mmol) m-chloroperbenzoic acid (mCPBA). The resulting mixture was allowed to warm to room temperature, stirred at 23° C. for 16 h, heated at reflux for 2 h and cooled to room temperature. The reaction mixture was treated with Ca(OH)2 (680 mg, 3.94 mmol), stirred at room temperature for 3 h and filtered. The solid was washed with CH2Cl2. The filtrate and washings were combined, dried over MgSO4 (anhydrous), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc-hexanes 4:6) to provide 465 mg of the title compound (I-3m) as a white solid (87%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:14][C:13]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][C:27]1[N:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:15]([C:16]([N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:17])[CH2:14][C:13]=2[N:26]=1
Reactant: CN(C(=O)N1Cc2ncn(Cc3ccccc3)c2C[C@H]1CO[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C(=O)N1Cc2nc(Br)n(Cc3ccccc3)c2C[C@H]1CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 1.23 g of (S)-1,4,6,7-tetrahydro-6-(t-butyldimethylsilyloxymethyl)-N-methyl-N-phenyl-1-(phenylmethyl)-5H-imidazo[4,5-c]pyridine-5-carboxamide and 10 mL of methylene chloride is stirred at room temperature and 0.45 g of N-bromosuccinimide is added. The reaction mixture is stirred for 20 min and concentrated. The residue is purified by flash chromatography on silica gel eluting with a 50% ethyl acetate-hexane mixture. The desired fractions are combined and concentrated to afford the desired product as an oil; TLC (SiO2) 50% EtOHc/hexane, Rf =0.35.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.O>CCOCC>[N:7]1([CH2:6][CH2:5][CH2:4][OH:3])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: CCOC(=O)CCn1cncn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: OCCCn1cncn1

Procedure:
To a solution of Ethyl-3-(1H-1,2,4-triazol-1-yl)propanoate (2.95 g, 17.5 mmol) in ether (90 ml), LiAlH4 (0.66 g, 17.5 mmol) was added. After heating to reflux for 60 h, 10 ml of 50%-methanol-water was added. The reaction mixture was filtered and the filter washed with 100 ml of methanol and twice with 100 ml of hot water. After evaporation the title product was obtained after purification using preparative HPLC.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9]([O:11]CC)=[O:10])=[N:5][N:6]([CH3:8])[CH:7]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[C:4]([C:9]([OH:11])=[O:10])=[N:5][N:6]([CH3:8])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1nn(C)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cn(C)nc1C(=O)O
Yield: 51.9 %

Procedure:
In the same manner as in Reference Example 52 and using ethyl 4-ethyl-1-methyl-1H-pyrazole-3-carboxylate (460 mg, 2.50 mmol), 8N aqueous sodium hydroxide solution (620 μL) and ethanol (3 mL) as starting materials, the title compound (200 mg, 53%) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.6 %

Procedure:
tert-Butyl ({3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate (0.27 g, 0.63 mmol) was dissolved in trifluoroacetic acid (1.5 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.12 g, 49%) as white crystals.
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH3:7].Br[C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1(C)C(C)=CC=CC=1>[CH3:7][C:6]1[CH:5]=[CH:4][N:3]=[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[C:10]=12
Reactant: C/C=C/C=NN(C)C
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 57.3 %

Procedure:
(E)-2-Butenal N,N-dimethylhydrazone, (3.70 g, 0.033 mol) in dry xylene (10 mL, Fisher) was added to a xylene solution (50 mL) of 2-bromo-1,4-naphthoquinone, (6.00 g, 0.025 mol) in a 200-mL, round-bottomed flask fitted with a condensor. The dark mixture was then heated at reflux for 6 h under a nitrogen atmosphere before decanting the solution into a 500-mL separatory funnel. The solids coating the wall of the flask were washed thoroughly with ethyl acetate (6×25 mL) and these washings added to the separatory funnel. The combined organic solutions were extracted with 2N sulfuric acid solution (1×100 mL followed by 2×75 mL). The acid layers were then combined, chilled in ice, and made basic (~pH 10 test paper) with sodium hydroxide before extracting with ethyl acetate (4×100 mL). The latter organic layers were dried over potassium carbonate and concentrated to dryness on a rotary evaporator. This material was applied to a 4×70 cm column of Silica gel (Merck 230-400 mesh) and the product Muted with ethyl acetate. Concentration of the appropriate column fractions yielded pure cleistopholine (3.20 g, 57%); mp 202°-204° C. (lit. mp 198°-201° C.). IR (KBr) 1680, 1660, 1590, 1300, 980, 720 cm-1 ; 1H NMR (CDCl3) δ8.86 (d, J=4.9 Hz, 1 H), 8.34-8.30 (m, 1 H), 8.24-8.19 (m, 1 H), 7.82-7.76 (m, 2 H), 7.47 (dd, J=4.9, 0.7 Hz, 1 H), 2.88 (br s, 3 H); 13C NMR (CDCl3) 184.7 (0), 181.9 (0), 153.4 (1), 151.5 (0), 150.0 (0), 134.5 (1), 134.1 (1), 133.8 (0), 132.5 (0), 131.2 (1), 129.1 (0), 127.3 (1), 127.1 (1), 2.28 (3) ppm.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25][CH3:26])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25][CH3:26]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OC
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Methyl 4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methoxypicolinate (209 mg, 0.55 mmol) was dissolved in CH3OH (10 mL), and acetyl chloride (194 μL, 2.73 mmol) was added dropwise to the mixture. The reaction mixture was allowed to stir at 25° C. for 3 h. Additional acetyl chloride (194 μL, 2.73 mmol) was then added, and the reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was concentrated to dryness and purified by flash chromatography (SiO2; 0-50% EtOAc/hexane gradient) to provide the title compound as an off-white solid (30 mg, 16%): mp 114-118° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J=8.5, 7.8 Hz, 1H), 7.22 (dd, J=8.6, 1.8 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 4.54 (s, 1H), 3.98 (s, 2H), 3.96 (d, J=0.8 Hz, 2H), 3.92 (s, 2H); ESIMS m/z 341 ([M+H]+), 339 ([M−H]−).
Reaction SMILES: [Mg].II.[CH3:4][N:5]([CH3:12])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:27](OC)(=[O:31])[C:28]([CH3:30])=[CH2:29]>CO>[C:27]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:5]([CH3:12])[CH3:4])(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: CN(C)CCOCCO
Reactant: C=C(C)C(=O)OC
Agent: II
Agent: [Mg]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=C(C)C(=O)OCCOCCN(C)C
Temperature: 25 °C

Procedure:
A magnesium methoxide solution was prepared by dissolving magnesium metal (4 g) in anhydrous methanol (100 ml) in the presence of a small amount of iodine (approximately 0.1 g). A portion of the resulting solution (18 ml) was placed in a 250 ml reaction vessel and then 2-(2-dimethylaminoethoxy)ethanol (23.6 g) was added, followed by the addition of phenothiazine (0.1 g) and methyl methacrylate (117 g). The mixture was stirred and heated until the methanol started to distill. When all of the methanol was collected, the mixture was cooled to room temperature and the solids were filtered off. The filtrate was subjected to fractionation under reduced pressure. The excess of methyl methacrylate was separated and then pure 2-(2-dimethylaminoethoxy)ethyl methacrylate was collected at 97-102° C./4 mmHg. Yield 22.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:27]([O-])(=[O:29])[CH3:28].[Na+].O>C(OC(=O)C)(=O)C>[C:27]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=2)[C:13]1=[O:26])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Cl)ccc3ncc21
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 80 mg, 0.22 mmol) and sodium acetate (27.06 mg, 0.33 mmol) was heated at 50° C. in acetic anhydride (2 ml) for 3 hours. Reaction mixture was cooled to RT. Water was added and extracted with chloroform. Chloroform layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 26 mg (29%); 1H NMR (CDCl3, 300 MHz): δ 9.796 (s, 1H), 8.039-8.070 (d, 1H, J=9.3 Hz), 7.764-7.792 (d, 2H, J=8.4 Hz), 7.499-7.537 (m, 3H), 6.861-6.868 (d, 1H, J=2.1 Hz), 2.822 (s, 3H), 1.83 (s, 6H); MS: m/z 405 (M+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:19][O:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:18])[C:7]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:21]=1[O:20][CH3:19])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCCCCC(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(CCl)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(Cc1cccc(OC)c1OC)(C(=O)OCC)C(=O)OCC
Yield: 73.1 %

Procedure:
To a suspension of 60% sodium hydride (440 mg, 11 mmol) in 5 ml of dimethylformamide was added a solution of 2.30 g (10 mmol) of n-pentylmalonic acid diethyl ester in 5 m of dimethylformamide under stirring and ice cooling, and the resultant mixture was stirred for 30 minutes. A solution of 1.86 g (10 mmol) of 2, 3-dimethoxybenzyl chloride in 5 ml of dimethylformamide was dropwise added to the mixture, which was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/12) to give 2.78 g of 2, 3-dimethoxybenzyl-n-pentylmalonic acid diethyl ester as a colorless oil. Yield, 73%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O>CC(O)=O.Cl.[Zn]>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH3:4]
Reactant: COc1ccc(C=O)c(O)c1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(C)c(O)c1
Temperature: 87.5 °C
Yield: 22 %

Procedure:
To a solution of 10.0 g (65.8 mmoles) of 2-hydroxy-4-methoxybenzaldehyde in 50 mL of HOAc and 50 mL of concentrated HCl, was added 17.2 g (263.2 mg atoms) of powdered zinc. The mixture was heated one hour at 85-90° C. and then extracted three times between EtOAc and saturtated NaCl solution. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and evaporated under vacuum. The crude product was purified via silica gel flash chromatography (0 to 20% EtOAc in hexane), giving 2.0 g (22.0%) of 3-hydroxy-4-methylanisole as an oil which crystallized on standing, melting at 34-35° C.
Reaction SMILES: BrC1N(CC=C(C)C)C(C(OC)=O)=C(C=O)N=1.[Br:18][C:19]1[N:20]([CH2:34][C:35]#[C:36][CH3:37])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:22]([C:24](OCC)=[O:25])[N:23]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:18][C:19]1[N:20]([CH2:34][C:35]#[C:36][CH3:37])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:22]([CH:24]=[O:25])[N:23]=1
Reactant: CC#CCn1c(Br)nc(C(=O)OCC)c1C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(=O)c1c(C=O)nc(Br)n1CC=C(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OCC

Procedure:
Prepared analogously to 1c from 20.00 g (58.28 mmol) diethyl 2-bromo-1-(but-2-ynyl)-1H-imidazole-4,5-dicarboxylate with 70 ml (70 mmol) diisobutylaluminium hydride in 300 ml of tetrahydrofuran.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1.O=[C:26]1CCSCC1C(OCC)=O.Cl>C(O)C>[OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][CH2:26][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCOC(=O)C1CSCCC1=O
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h
Yield: 68 %

Procedure:
A solution of 6.4 g. (0.027 mole) of 5-(3-methyl-2-octyl-resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate [prepared according to the method of Bennett and Scorah, J. Chem. Soc., 194 (1927)] in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured onto a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the desired compound, m.p. 153°-155°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2>>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:16][N:15]=[CH:14]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(Oc1nncc2cc(Br)ccc12)C(F)(F)F

Procedure:
This compound was prepared according to the procedure described in Example 2b, but starting with 1,1,1-trifluoropropan-2-ol, sodium hydride and 6-bromo-1-chlorophthalazine. MS (ESI, pos. ion) m/z: 321.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(O)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]([N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2N(C)c1ccccc1
Reaction time: 8.5 h
Yield: 55.2 %

Procedure:
5.0 g. (0.016 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 50 ml. of ethanol. To the solution 3.5 ml. (0.032 mole) of N-methyl-aniline are added and the reaction mixture is boiled for 8-9 hours in a nitrogen gas atmosphere. 50 ml. or 5% by weight hydrochloric acid solution is then added to the solution and shaken out three times with 25 ml. of dichloromethane. The combined organic layers are dried above calcinated sodium sulfate and evaporated at reduced pressure. The residue is dark oil which crystallizes upon the addition of some methanol. 3.0 g. (55.2%) of 6-methyl-9-(N-methyl-anilino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are obtained. Melting point: 175°-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[I-:11]>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[NH2:1]
Reactant: [I-]
Reactant: Nc1ccc2c(c1)CCC2
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: Nc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A mixture of 5-aminoindan (423 mg, 3.17 mmol), silver sulfate (990 mg, 3.17 mmol) and iodide (805 mg, 3.17 mmol) in methanol (20 mL) was stirred at room temperature overnight. The mixture was filtered and the solid was washed with a small amount of methanol. The filtrate was quenched with saturated Na2S2O3 and then diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. Flash chromatography (Si, hexanes/EtOAc) of the residue yielded 6-iodoindan-5-amine (354 mg, 43%). LCMS calc.=258.99; found=260.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.69 (s, 1H), 3.97 (br, s, 2H), 3.02-2.90 (m, 1H), 2.81 (d, J=7.1 Hz, 3H), 2.12-2.02 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1.[H][H].N#N>CCO.[Pd]>[CH3:20][O:19][C@H:17]1[CH2:16][NH:15][CH2:14][C@@H:13]([CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:18]1
Reactant: [H][H]
Reactant: CO[C@@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To cis-phenylmethyl (3RS,5SR)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-(methyloxy)-1-piperidinecarboxylate (210 mg, 0.51 mmol) in EtOH (20 mL) was added Pd/C (50 mg; 10%). The reaction was hydrogenated on a Parr apparatus at 45 psi of H2 for 3 h. The hydrogen was displaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst which was washed with additional EtOH (50 mL). The filtrate was then concentrated under reduced pressure to give the desired compound (125 mg; 90%) as a colorless oil which was used without further purification.