Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH2:35]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:35][N:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[CH2:30][CH2:31]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=O
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.20 g, 0.72 mmol) obtained in Example A1, Step 1 in ethanol (10 mL) was added with 1-tert-butoxycarbonylpiperazine (0.16 g, 0.87 mmol), and 37% aqueous formaldehyde (0.068 g, 0.87 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.22 g, 63%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)C[C@@H](C(=O)c1cc(F)c(F)cc1F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of 3 g (S)-methyl 3-(dibenzylamino)-4-oxo-4-(2,4,5-trifluorophenyl)butanoate in 100 ml ethanol, was added 0.5 g of 10% Pd/C under an atmosphere of nitrogen. The atmosphere of nitrogen was replace with an atmosphere of hydrogen, and the reaction was carried out at 25° C. for 5 h. After completion of the reaction, the reaction mixture was filtered through diatomite. The filtrate was concentrated, and the pH was adjusted to 5˜6 by addition of 10% hydrochloric acid. The aqueous layer was washed with ethyl acetate, and then concentrated to obtain 1.47 g (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid as white solid, with a yield of 93.2%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCOc1ccc(C)nc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCCOc1ccc(CBr)nc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 2.16 gm (9.0 mmol) of acetic acid 2-(6-methyl-2-nitro-pyridin-3-yloxy)-ethyl ester 94, 1.76 gm (9.9 mmol) of N-bromosuccinimide in 125 mL of CCl4 was added 0.074 gm (44.9 μmol) of AIBN and the reaction was heated to reflux for 1 h. After 1 h a 500 watt sun lamp was used to irradiate the refluxing solution for an additional 4 h. The mixture was poured into 300 mL of CCl4 and washed with water twice (150 mL), saturated brine and the organic layer was dried (anhydrous Na2SO4) and the solvents removed at reduced pressure. Column chromatography of the residue using 50%-30%-10% CH2Cl2-hexanes yielded 1.06 gm (37%) of a light yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.06 (s, 3H), 4.31 (t, 2H, J=4.1 Hz), 4.41 (t, 2H, J=4.1 Hz), 4.48 (s, 2H), 7.49 (d, 2H, J=8.5 Hz), 7.65 (d, 2H J=8.5 Hz).
Reaction SMILES: [OH-].[Na+].C=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6].Cl[CH2:14][C:15]([CH3:17])=[CH2:16].[C:18]1(C)C=CC=CC=1>>[CH2:17]([O:6][C:5](=[CH2:18])[CH2:4][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:15](=[CH2:16])[CH3:14]
Reactant: Cc1ccccc1
Reactant: C=C(C)CCl
Reactant: C=C(CO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)COC(=C)Cc1ccccc1

Procedure:
Into a 3 liter reaction flask equipped with stirrer, thermometer, reflux condenser, addition funnel and heating mantle is placed 240 grams of a 50% aqueous solution of sodium hydroxide; 15 grams of ALIQUAT®336 and 200 ml toluene. The resulting mixture is heated to reflux and over a period of ten minutes, 268 grams of beta-methylene phenylethyl alcohol having the structure: ##STR155## is added followed by addition of 190 grams of 3-chloro-2-methyl-propene over a 25 minute period while refluxing the reaction mass at 104°-110° C. The reaction mass is then continued to be refluxed at a temperature of between 95° and 110° C. for a period of eleven hours. At the end of the eleven hour period, the reaction mass is washed with water. The organic phase is then distilled on a 10" Goodloe column yielding the following fractions:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.C(N([CH2:22][CH3:23])CC)C.[C:24](=[S:26])=[S:25].C(I)C>CO.O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH2:22][CH3:23])=[S:25]
Reactant: CCN(CC)CC
Reactant: S=C=S
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Solvent: CO
Solvent: O
Solvent: CCI
Product: CCSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1C
Yield: 78.1 %

Procedure:
In the same manner as described in Example 13 by using (1S, 3S)-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (1.08 g), triethylamine (1.01 g), CS2 (0.76 g), ethyl iodide (1.56 g), methanol (25 ml) and water (2.5 ml), there is prepared the title compound (1.25 g, 78%) as white powder, [α]D20 +176.0° (c=1, methanol). NMR (CDCl3, δ): 1.38 (t, J=7.3 Hz, 3H, CSSCH2CH3), 1.62 (d, J=6.8 Hz, 3H, C1 --CH3), Mass m/e: 320 (M+), 291 (M+ --C2H5), 258 (M+ --C2H5SH).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[N:14]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[CH3:24][C:21]1[N:20]=[CH:19][C:18]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][N:14]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:10][C:9]=2[OH:8])=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of 5-(benzyloxy)-6-(6-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.44 g, 3.60 mmol) in EtOH (50 mL) and EtOAc (50 mL) is added Pd/C (500 mg, 10% wt) under N2. The resulting mixture is degassed by evacuation and backfilled with nitrogen. Then the reaction mixture is stirred at RT under H2 atmosphere overnight. The reaction mixture is filtered. The filtrate is concentrated to give the product (982 mg, 88.0% yield). MS (m/z): 310.1 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 191 (4.02 g, 16.46 mmol) are treated with 4M HCl in dioxane (60 ml, 240 mmol) and the mixture is stirred at room temperature for 1 h. The white precipitate is filtered off, washed with ether and dried under high vacuum. The mother liquor is concentrated and treated with ether. The white solid is filtered off and dried under high vacuum.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=[CH:20][CH:19]=1.O=[C:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]1>C(O)C>[CH2:19]([CH:26]1[C:25]2[NH:16][C:13]3[C:12](=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:15][CH:14]=3)[C:30]=2[CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27]1)[CH3:20].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][C:26]2=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccncc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCC1CC(C(=O)O)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Product: O=C(O)C1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 50 °C
Yield: 85.8 %

Procedure:
To a suspension of 3.242 gm (12.93 mMol) 4-benzyloxyphenylhydrazine hydrochloride in 80 mL ethanol were added 1.05 mL (12.93 mMol) pyridine. The resulting mixture was heated to 50° C. for about 20 minutes and then 1.87 mL (11.75 mMol) ethyl 4-oxocyclohexanecarboxylate were added. The resulting mixture was stirred at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 35% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to give 3.38 gm (83%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl.O>[CH3:15][S:14]([C:10]1[N:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc(N)nc2C)n1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Yield: 17.2 %

Procedure:
To a suspension of 4′-Methyl-2-methylsulfanyl-[4,5]bipyrimidinyl-2′-ylamine (19) (380 mg, 1.629 mmol) in DCM (3.258 mL) was added mCPBA (402 mg, 1.629 mmol). The reaction turned to a brown solution, and immediately the reaction was complete. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 2-10% MeOH in DCM to give the desired product (70 mg, 17%). MS (ES+): m/z=250.1 (100) [MH+]. HPLC: tR=0.64 minute over 3 minutes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccc1Br)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC(Cc1ccccc1-c1ccccc1)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
1-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-1-phenyl-ethanol (0.50 g, 1.0 equiv. prepared according to Example 15a below) and phenylboronic acid (0.402 g, 3.0 equiv., available from Aldrich Chemical Company) were suspended in a mixture ethanol/water (2/1, 7.5 mL) and Pd(Ph3)4 (0.022 g, 0.04 equiv.), then K2CO3 (0.654 g, 4.30 equiv.) were added. The mixture was heated to 80° C. under nitrogen atmosphere. After 16 hours, the reaction was cooled down to room temperature and filtered through Celite, then extracted with ethyl acetate. The organic layers were combined, dried with MgSO4, filtered and concentrated in vacuo yielding a yellow oil, which was purified by column chromatography on silica gel (10% EtOAc:Hexane) to give 0.491 g (98%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=[C:6]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=1.Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CN(C)[C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:38]1([CH2:37][O:36][C:34](=[O:35])[CH2:33][N:1]([C:2]2[CH:3]=[C:4]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=[C:6]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=2)[CH2:33][C:34](=[O:35])[O:36][CH2:46][C:55]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CCCCCCCCCC(=O)Nc1cc(N)cc(NC(=O)CCCCCCCCC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 2 %

Procedure:
A mixture of 1.92 g (4.45 mmol) of N,N'-(5-amino-1,3-phenylene)bisdecanamide, 10.6 ml (0.061 mol) of benzyl bromoacetate, 2.4 g (11.1 mmol) of 1,8-bis(dimethylamino)-naphthalene and 0.19 g (1.25 mmol) of sodium iodide in 50 ml of acetonitrile and 15 ml of DMF was stirred and refluxed under an argon atmosphere for 36 hours. The solvents were removed at reduced pressure and the residue was dissolved in ethyl acetate. The extract was washed with 0.05N HCl, with NaHCO3 solution, dried and concentrated to a brown solid. Purification by HPLC using 25% ethyl acetate-hexane gave 0.9 g which was recrystallized from acetone-hexane to give 0.064 g (20% yield, mp 127°-129°) of N-[3,5-bis[(1-oxodecyl)amino]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:14]([N:18]=[C:19]=[O:20])[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:14]([NH:18][C:19](=[O:20])[NH:6][C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=1)=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN=C=O
Reactant: Cc1ncc([N+](=O)[O-])cc1C(N)=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NC(=O)c1cc([N+](=O)[O-])cnc1C
Yield: 43.1 %

Procedure:
A mixture of 0.9 g of 2-methyl-5-nitronicotinamide and 0.9 g of n-butylisocyanate in 40 ml of anhydrous toluene was refluxed for 18 hours. Unreacted nicotinamide (0.2 g) was filtered off and the filtrate was chromatographed over silica gel to give 0.6 g of the desired product. mp 111° - 112° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])=[O:17].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.N1C=CC=CC=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:32][N:31]=[N:30][N:23]=2)[CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(NC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of 10 mmol of 3-(3-(2-quinolinylmethyloxy)benzoylamino)benzonitrile, 50 mmol of sodium azide, and 50 mmol of pyridine HCl in 30 ml of DMF is heated at 100° C. for 2 days. The reaction mixture is poured into water, and the product is collected on a filter. Recrystallization from ethyl acetate and DMF gives 5-(3-(3-(2-quinolinylmethyloxy)benzoylamino)phenyl)tetrazole.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:33])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=3[Cl:19])[NH:12][C:11]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccc(F)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (1.2 g, 2.35 mmol) in methylene chloride. Add trifluoracetic acid and stir for 2 hours. Concentrate the reaction in vacuo and recrystallize the residue from hot ethyl acetate/hexane to yield the title compound (720 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C1C[O:18]CC1>[OH-].[Na+].O>[Cl:1][C:2]1[N:11]=[C:10]([OH:18])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(O)nc(Cl)nc2c1
Reaction time: 4 h
Yield: 63 %

Procedure:
2,4-dichloro-7-methoxyquinazoline (500 mg, 2.183 mmol) was suspended in 2% aqueous NaOH (6 mL). THF (1 mL) was added and the reaction was stirred for 4 h. The reaction was diluted with water and the solid that remained was filtered off. The aqueous phase was diluted with 1 N HCl. The precipitate that formed was filtered, washed with water and dried to give 2-chloro-7-methoxyquinazolin-4-ol (288 mg, 63% yield). MS: MS m/z 211.1 (M++1).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=O)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH2:16]([N:19]1[C:11](=[O:13])[CH:6]2[CH:5]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]2[CH:8]=[CH:9]3)[C:14]1=[O:15])[CH2:17][N:18]1[C:11](=[O:13])[CH:6]2[CH:5]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]2[CH:8]=[CH:9]3)[C:14]1=[O:15]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCCN
Product: C=CCC12C=CC(C1)C1C(=O)N(CCN3C(=O)C4C5C=CC(CC=C)(C5)C4C3=O)C(=O)C12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
204 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are initially taken and 30 g of ethylenediamine are added dropwise, with stirring. The temperature rises to 130° C. The temperature is increased to 180° C.; in the course of this 14 ml of water distil off. Heating is then continued for a further 2 hours at 200° C. and under a pressure of 9.3 Pa. This gives 210 g of a yellow resin, solid at room temperature and having a softening point of 56° C., measured on a Kofler heated stage.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.CN(C=O)C.[H-].[Na+]>O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-(3-methoxyphenylthio)picolinonitrile (214 mg, 0.666 mmol), 3-bromophenol (138 mg, 0.800 mmol), and DMF (6 mL). NaH (24.0 mg, 0.999 mmol) was added and reaction stirred at room temperature for 24 hours. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (225 mg, 81.7% yield).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[CH:26][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:30][CH:31]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.00 g) was refluxed for twenty-four (24) hours in 400 ml of toluene that contained morpholine (3.50 g) and 4-trifluoromethylbenzaldehyde (4.35 g). At this time, an additional 2.0 g of aldehyde was added and reflux was continued for another sixteen (16) hours. At the end of this time the reaction mixture was concentrated and the residue was purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.46 g of analytically pure product, m.p. 203°-205° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2Sc3ccccc3NC(=O)C2CO)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C2Sc3ccccc3NC(=O)C2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
3 g of 2,3-dihydro-3-hydroxymethyl-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 3 was dissolved in 15 ml of pyridine. 1.3 g of methanesulfonyl chloride was added to the solution and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from dichloromethane-n-hexane to obtain 3.3 g of 2,3-dihydro-3-[(methylsulfonyloxy)methyl]-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 207° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>O1CCOCC1.CO.O>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][C:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
To a solution of 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.515 g, 4.117 mmol) in dioxane (20 ml), methanol (10 ml) and water (10 ml) at room temperature was added lithium hydroxide monohydrate (3.455 g, 82.341 mmol). After stirring at 50° C. for 2 days the solution was acidified to pH 6 with 2M HCl and the resulting white precipitate was extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over sodium sulphate and concentrated to dryness, to give the acid as a white solid (1.460 g, 100%). LC-MS (LCT) m/z 376 [M+Na+], Rt 7.62 min.