Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl>[ClH:12].[C:16]1([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCC(CC)N1CCNCC1
Reactant: O=C(Cl)Oc1cccc2ccccc12
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2cccc3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175 μl, 1.0 mmol) and dry DCM (10 ml) was added 1-napthalenyl chloroformate (225 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (85%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22]O)=[C:15]([CH3:24])[CH:14]=1)=[N:7]2.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:27][CH2:22][CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[NH:5][C:4](=[O:25])[C:3]3[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[CH:14][C:15]=1[CH3:24]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one (1.14 g, 3.00 mmol) in anhydrous DMF (15 mL) was added carbon tetrabromide (1.10 g, 3.30 mmol). Then, triphenylphosphine (0.86 g, 3.30 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate (50 mL) and dried under vacuum to give 2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-one as a white solid. Yield: 0.46 g (35%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[C:14]([O:16]C)=[O:15].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([C:14]([OH:16])=[O:15])[CH:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: COC(=O)c1ccc2c(c1C)C(=O)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CN2CCOc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of methyl 6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylate (130e, 0.10 g, 0.45 mmol) in DMF (8 mL) was added NaH (54 mg, 1.36 mmol, 60% in oil) at 0° C. After stirring at 0° C. for 10 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 0.20 g, 0.77 mmol) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (30 mL). The mixture was extracted with EtOAc (2×20 mL). The aqueous layer was acidified with conc. HCl to pH 3 and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylic acid (130f, 0.17 g, 84.7%) as an off-white solid.
Reaction SMILES: [OH-].[Na+].CC([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:16]1[C:17]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:18]=2[S:19][C:20]=1[C:21]([O:23]CC)=[O:22])=[O:15])=O.C(O)(=O)C>CO.O>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:16]1[C:17]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:18]=2[S:19][C:20]=1[C:21]([OH:23])=[O:22])=[O:15]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)c1ccccc1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)c1ccccc1CO
Yield: 16.5 %

Procedure:
Sodium hydroxide (3 ml of 1M in water) was added to a suspension of ethyl 3-(2-[(methylcarbonyloxy)methyl]phenylsulfinyl)-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 35--500 mg, 0.98 mmol) in methanol (15 ml). The mixture was heated to reflux for 30 minutes. The resultant solution was cooled, diluted with water and acidified by dropwise addition of acetic acid. The precipitate was isolated by filtration and washing with water. The solid was recrystallised twice by dissolving in hot methanol, and cooling, to give the title compound as a colourless solid (71 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-bromobenzaldehyde, 1 (110 g, 0.59 mol), malonic acid (112.5 g, 1.189 mol), piperidine (11 mL) in pyridine (350 mL) was heated to 80° C. for 1 h, then refluxed for 3 h. Then the reaction mixture was cooled to room temperature, poured into a large beaker filled with cold water, and then acidified (pH<3) by slowly adding 25 mL of concentrated hydrochloric acid. The resulting precipitate was filtered and washed with cold water. The crude product was dissolved in aqueous sodium hydroxide, acidified (pH<3) (1:1 hydrochloric acid/water), filtered, and washed (cold water). The solid was dried in vacuo (60-70° C.) to give 2 (118.8 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1
Reactant: CI
Product: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to example 7 (91% yield). 1H NMR (CDCl3): 7.70-7.73 (m, 1H), 7.54 (ddd, J=8.7, 6.3 and 2.1 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.93-7.23 (m, 2H), 6.50-6.57 (m, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:9][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH3:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CO>[O:1]=[C:2]([NH:9][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCOc1ccc(CCc2ccc3cc(C(C)NC(=O)CC(=O)OCC)oc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(CCc2ccc3cc(C(C)NC(=O)CC(=O)O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 3-oxo-3-[(1-{6-[2-(4-propoxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)amino]propanoate (214 mg, 0.489 mmol) obtained in Example 34 in THF-methanol (5 mL-3 mL) was added 1N aqueous sodium hydroxide solution (0.750 mL, 0.750 mmol), and the mixture was stirred at room temperature for 15 min. The reaction mixture was acidified with 1N hydrochloric acid and extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with diethyl ether to give the title compound (158 mg, yield 79%) as a white solid.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.[CH:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>O1CCOCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: O=Cc1ccc2ccccc2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1nccn2c(C3CCN(Cc4ccc5ccccc5n4)CC3)nc(-c3cc4ccccc4[nH]3)c12

Procedure:
A solution of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30 mg, 0.09 mmol), 2-formylquinoline (17 mg, 0.11 mmol) and triethylamine (0.019 mL, 0.14 mmol) in 1,4-dioxane (1 mL) was treated with sodium cyanoborohydride (5.7 mg, 0.090 mmol) and microwaved at 300 watts, 120° C. for 20 min. The mixture was concentrated in vacuo, the residue was dissolved in methanol loaded onto an SCX ion exchange cartridge, and then eluted with 1M NH4OH in methanol. The semi-pure material thus obtained was then subjected to semi-preparative HPLC to afford desired product. 1H NMR (400 MHz, MeOD) δ ppm 2.13-2.33 (m, 4H), 2.90 (t, J=10.86, 9.60 Hz, 2 H), 3.47 (d, J=10.11 Hz, 2 H), 4.29 (s, 2 H), 6.74 (s, 1 H), 7.02-7.11 (m, 2 H), 7.19 (t,J=8.08, 7.07 Hz, 1 H), 7.47 (d, J=9.09 Hz, 1 H), 7.58-7.65 (m, 3 H), 7.69 (d, J=8.59 Hz, 1 H), 7.80 (t, J=8.34, 6.82 Hz, 1 H), 7.96 (d, J=7.33 Hz, 1 H), 8.08 (d, J=834 Hz, 1 H) and 8.39 (d, J=8.59 Hz, 1 H). MS (ES+): m/z 474.23 [MH+].
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]=[S:3].[NH3:16]>ClCCl>[CH3:14][C:7]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([NH:1][C:2]([NH2:16])=[S:3])[S:5][C:6]=1[CH3:15]
Reactant: CCOC(=O)c1c(N=C=S)sc(C)c1C
Reactant: N
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a solution of ethyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (Example 50b) (1.21 g, 5.27 mmol) in dichloromethane (10 mL) was added ammonia (7 M in MeOH, 1.12 mL, 7.91 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 3 h, quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The dark orange residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (37.1 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ1.32 (t, 3H, J=7.1 Hz), 2.18 (s, 3H), 2.19 (s, 3H), 4.30 (q, 2H, J=7.1 Hz), 8.43 (s, 2H), 11.38 (s, 1H). MS 259 (MH+).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[C:7]([CH2:13][C:14]([O:16]C)=[O:15])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:4].CC(C)=O.[ClH:23].O>C(Cl)Cl>[Cl:23][CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: Cl
Reactant: COC(=O)Cc1cc(C(=O)C(C)Br)ccc1OC
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)C(C)Cl)cc1CC(=O)O
Yield: 64 %

Procedure:
To a 250 mL round bottom flask containing 11.4 grams (36.3 mmole) of methyl ester 8 was added 70 mL of acetone and the mixture sonicated until solution was complete. To the solution was then added 15 mL of concentrated HCl, 20 mL of H2O and the resulting solution refluxed for 6 hours. At the end of 6 hours the volatile components of the reaction mixture were removed under reduced pressure to give an oil/water mixture which was then dissolved in 100 mL of CH2Cl2. The organic/aqueous mixture was then extracted with 150 mL of saturated NaHCO3. The aqueous layer was then removed and acidified with concentrated hydrochloric acid to a pH equal to 1. The aqueous mixture was then quickly extracted with 100 mL of CH2Cl2. The organic layer was then dried over MgSO4, filtered and the volatile components removed under reduced pressure to give an oil which crystallized to give 6.0 grams (64% yield) of 9 as a white solid.
Reaction SMILES: [OH-:1].[Na+].[NH2:3]O.Cl.[C:6]([O:15]C)(=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9]>O>[OH:1][NH:3][C:6](=[O:15])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9]
Reactant: NO
Reactant: COC(=O)c1ccccc1N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccccc1C(=O)NO
Reaction time: 72 h
Yield: 85 %

Procedure:
48 parts of NaOH are introduced into 300 parts of water. 41.6 parts of NH2OH.HCl are added in portions, with cooling, followed by 45.2 parts of methyl anthranilate. After the mixture has been left to stand at room temperature for 3 days, the solution is concentrated and concentrated hydrochloric acid is added to the residue thus obtained until the pH is 6. After the mixture has been filtered and the filtrate has been washed with ethanol, anthranilic acid hydroxylamide is obtained as colourless crystals of melting point 140°-142° C. with a yield of 85%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[NH:4]1.C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[CH3:28]I>CS(C)=O>[OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[N:4]1[C:25]([S:27][CH3:28])=[S:26]
Reactant: OC[C@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Reactant: S=C=S
Reactant: CI
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CSC(=S)N1[C@@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1CO

Procedure:
In the same manner as described in Example 13 by using (1RS, 3SR)-trans-1,3-dihydroxymethyl-1,2,3,4-tetrahydro-β-carboline (0.65 g), triethylamine (0.79 ml), CS2 (0.34 ml), methyl iodide (0.35 ml) and dimethylsulfoxide (6 ml), there is prepared the title compound (350 mg, 39%) as colorless needles, m.p. 179°-180° C. (recrystallized from water-ethanol). NMR (CDCl3 -DMSO-d6, δ): 2.66 (s, 3H, CSSCH3), Mass m/e: 304 (M+ --H2O), 274 (M+ --CH3SH).
Reaction SMILES: CN(/C=[C:5]1\[CH2:6][CH2:7][C:8]2[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([CH3:15])[NH:11][C:12]=2[C:13]\1=O)C.[C:21]([O-])(=O)C.[K+].S(O)(O)(=O)=O.[CH3:31][NH:32][C:33](=[NH:35])[SH:34]>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:10]1[NH:11][C:12]2[C:13]3[N:35]=[C:33]([S:34][CH3:21])[N:32]=[CH:31][C:5]=3[CH2:6][CH2:7][C:8]=2[C:9]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(C)[nH]c2c1CC/C(=C\N(C)C)C2=O
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)[nH]c2c1CCc1cnc(SC)nc1-2
Temperature: 100 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
To a solution of ethyl (6E)-6-[(dimethylamino)methylidene]-2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate 2 g (7.22 mmol) in 20 mL of anhydrous DMF, 1.41 g (14.4 mmol) of anhydrous potassium acetate and 4.0 g (14.4 mmol) of methylisothiourea sulfate were added. The reaction was stirred at 100° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and evaporated. The crude was purified by silica gel chromagraphy (ethyl acetate: hexane 4:6) to give as major compound 0.8 g of ethyl 8-methyl-2-(methylsulfanyl)-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-7-carboxylate (40%)
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=[O:3].O[C:9](C(F)(F)F)=O.[NH2:15][C:16]1[C:21]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:31])[CH:23]=2)=[CH:20][C:19]([C@H:32]2[CH2:36][C@@H](C(OC)=O)[NH:34][CH2:33]2)=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@@H:75]([C:78]1[CH:83]=[CH:82][CH:81]=[C:80]([Cl:84])[CH:79]=1)[CH2:76][OH:77]>CN(C=O)C>[NH2:15][C:16]1[N:17]=[CH:18][C:19]([C@@H:32]2[CH2:33][NH:34][C@H:4]([C:2]([O:1][CH3:9])=[O:3])[CH2:36]2)=[CH:20][C:21]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:27])[NH:74][C@@H:75]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([Cl:84])[CH:79]=2)[CH2:76][OH:77])=[C:24]([F:31])[CH:23]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@H](c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)c2)CN1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CN1
Yield: 13.6 %

Procedure:
A mixture of 4-(2-amino-5-((3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl)pyridin-3-yl)-2-fluorobenzoic acid-2TFA (35 mg, 0.060 mmol), HATU (34 mg, 0.089 mmol), and DIEA (0.104 mL, 0.596 mmol) in DMF (2 mL) was treated with (S)-2-amino-2-(3-chlorophenyl)ethanol (51 mg, 0.348 mmol). At completion, the reaction was washed with water and brine, then dried over MgSO4 and concentrated. The crude material was purified by reverse phase prep HPLC to provide (2S,4R)-methyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-2-carboxylate (4.2 mg, 9%). LCMS (m/z): 513.2, 515.2 (MH+), 0.58 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.97-7.86 (m, 3H), 7.49-7.40 (m, 3H), 7.39-7.34 (m, 2H), 7.33-7.26 (m, 1H), 5.19 (t, J=5.87 Hz, 1H), 4.62 (dd, J=7.63, 10.76 Hz, 1H), 3.93-3.77 (m, 6H), 3.74-3.61 (m, 1H), 2.87 (td, J=6.90, 13.21 Hz, 1H), 2.33-2.21 (m, 1H).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[CH2:27][N:2]1[C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C=O
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c(C)[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-2-methyl-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 537.01 (M+H).
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][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[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][CH2:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 38.5 %

Procedure:
tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy}propanoate (1.70 g, 4.0 mmol) was dissolved in trifluoroacetic acid (15 ml) under ice cooling, and the mixture was stirred at 0° C. for 5 hrs. The reaction mixture was combined with isopropylether (50 ml) and stirred for 30 minutes. The precipitated crystals were collected by filtration. The crystals were recrystallized from ethanol-hexane to give the titled compound (0.57 g, 39%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 21 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H) 8.3 (d, 1H) 8.0 (s, 1H) 7.9 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.5 (, 2H) 2.8 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].O.C(OCC)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:19][CH2:18][CH2:16][OH:17])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Cl)c2cnc(S(C)(=O)=O)nc21
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1nc(Cl)c2cnc(NCCO)nc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 3-chloro-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (131 mg, 0.5 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added ethanolamine (150 mg, 2.5 mmol, 5 eq) and the reaction mixture was heated to 50° C. After 1 hour, water (20 mL) was added, followed by ethyl acetate (20 mL). The layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The resulting yellow residue was purified by column chromatography (50% ethyl acetate-hexane) to give 2-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (100 mg, 87% yield); LC/MS (m/e)=228.2 (MH+), Rt=1.44 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[ClH:18].[ClH:18].[O:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][C:8]=2[CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:21][CH2:22]1
Reactant: ClCN1CCOCC1
Reactant: c1ccc2cc(CN3CCCCC3)ccc2c1
Product: Cl
Product: c1ccc2c(CN3CCOCC3)c(CN3CCCCC3)ccc2c1

Procedure:
1-Morpholinomethyl-2-piperidinomethylnaphthalene dihydrochloride, m.p. 243°-244° was prepared in a manner similar to Example 40 from 2-piperidinomethylnaphthalene and chloromethylmorpholine.