Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0 mmol, 1.0 equiv), 3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv; commercially available) and acetic acid (11.4 mL, 12.01 g, 200.0 mmol, 4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (6.27 g, 100.0 mmol, 2.0 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 5 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate to yield 9.71 g (53%) of the title compound as a white solid. MS (ISP): 365.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1.Cl.[CH3:23][C@@H:24]1[CH2:29][O:28][CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:21][N:3]1[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=[C:2]1[N:25]1[CH2:26][CH2:27][O:28][CH2:29][C@H:24]1[CH3:23]
Reactant: C[C@@H]1COCCN1
Reactant: Cn1c(Cl)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(-c2ccnc(-c3ccccc3)n2)cc(=O)n1C
Yield: 89.2 %

Procedure:
A solution of 2-chloro-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (149 mg, 0.50 mmol), (3R)-3-Methyl-morpholine hydrochloride (83 mg, 0.82 mmol), and diisopropylethylamine (0.313 ml, 1.8 mmol) in N,N-dimethylformamide (2.0 ml) was stirred at 80° C. Water was added to the solution and the precipitate was filtered, washed with water and diethyl ether, and dried to afford 1-methyl-2-((3R)-3-methyl-morpholin-4-yl)-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (162 mg, quant.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][NH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][NH:26][CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c[nH]nc3C)cc12
Temperature: 100 °C

Procedure:
A mixture of 5-Bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (12 mg, 0.031 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (13.0 mg, 0.0626 mmol), potassium carbonate (0.0130 g, 0.0938 mmol) and 4:1 Dioxane:water (4:1,1,4-Dioxane:H2O, 0.31 mL, 3.1 mmol) were added to a microwave vessel and the vessel was degassed 3×. The reaction was heated in the microwave at 100° C. for 30 min. Reaction mixture was concentrated in vacuo and purified by HPLC to afford the title compound. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 2.23 (s, 3H), 3.66 (br. s., 3H), 5.12 (d, J=6.8 Hz, 1H), 6.91 (dd, J=9.0, 4.2 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 7.62 (br. s., 1H), 8.18 (d, J=1.8 Hz, 1H). MS (ES+): m/z=384.96/386.94 (100/65) [MH+]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].[OH-].[Li+]>>[C:17]([O:16][C:14]([N:6]1[CH2:7][C@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1C[C@H](S(C)(=O)=O)C[C@H]1C(=O)O

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-methanesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=294.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:18][CH3:19])([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](O)/[CH:21]=C\CO>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([C:3]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:2][CH2:1][CH:21]=[CH:20][CH2:19][O:18]1)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC/C=C\CO
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(c1ccccc1)C1(c2ccccc2)OCC=CCO1
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
1 g of p-toluene sulphonic acid was added to a suspension of 77 g (0.3 mols) of benzil dimethyl ketal in 160 g (~1.8 mols) of cis-2-butene-1,4-diol, and heated to from 50° to 60° C. under a pressure of from 10 to 15 torr. After 45 minutes, a clear solution was obtained, the temperature of which rose to from 65° to 70° C. After a further 45 minutes, the reaction mixture had solidified into a crystal mass. After a total of 4 hours, the material was recrystallized from isopropanol, and 80 g (96%) of 2-benzoyl-2-phenyl-4,7-dihydro-1,3-dioxepin were obtained as colourless crystals having a melting point of from 118° to 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:27][CH:28]=[CH2:29])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C=CCN
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.004 mole), potassium iodide (0.67 g., 0.004 mole), allylamine (0.84 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and then concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate-Skellysolve B hexanes to give 8-chloro-1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 39 8-Chloro-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]C(OC)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:16][Mg]I.[Cl-].[NH4+].Cl.CC[O:24][CH2:25][CH3:26]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:25]([CH3:26])([CH3:16])[OH:24])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCC1CCN(C(C)=O)CC1
Reactant: CCOCC
Reactant: C[Mg]I
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N1CCC(CCC(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude methyl 3-(1-acetyl-piperid-4-yl)propionate (13 g) in dry ether (80 ml) was added dropwise, at 0°-10°, to methyl magnesium iodide [prepared from Mg (8 g) and methyliodide (40 g)] in dry ether (150 ml). The mixture was then stirred at room temperature (20°) overnight, after which time the resulting complex was decomposed by the addition of saturated, aqueous ammonium chloride (50 ml). Dilute hydrochloric acid was added until all the solids dissolved (pH 7-8) and then the ether layer was separated. The aqueous layer was extracted with ether (200 ml) and chloroform (200 ml) and the combined organic extracts were washed with 2 N hydrochloric acid (100 ml) and then with brine (50 ml). After drying (Na2CO3), the organic solvents were removed in vacuo to give 3-(1-acetyl-piperid-4-yl)-1,1-dimethyl propanol as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:39][O:40][CH2:41][C:42]1[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][CH2:41][C:42]2[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Reaction time: 0.33 h

Procedure:
0.230 g (0.4 mmol) of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido) -3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid was dissolved in 3.5 ml of dimethylacetamide. Within 6 hours 0.11 g (0.7 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 0.133 g (0.7 mmol) of p-toluenesulfonic acid hydrate were added. After further stirring for 18 hours the dimethylacetamide was evaporated off at strongly reduced pressure, and the residue was taken up in water and stirred for 20 minutes in order to completely precipitate the product. The product was filtered off, washed well with water and dried under strongly reduced pressure at room temperature. (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro -5-hydroxy-4-oxo-2-pyrimidinyl) methoxy]imino]-acetamido]-3-[[(2-carbamoyl -5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as a beige powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:4]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)c(OCCOC)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CO)c(OCCOC)c1

Procedure:
This compound was hydrogenated in the manner of Step (c) of Example 1, using 7.5 grams (0.036 mole) of 4-ethyl-2-(2-methoxyethoxy)benzaldehyde in 200 mL of ethanol in the presence of 10% palladium on carbon. The yield of the subject compound was 1.8 grams, following purification by column chromatography on silica gel. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: I[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]=1[N+:18]([O-:20])=[O:19]>N1C=CC=CC=1>[N+:18]([C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[C:6](=[O:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]=1)([O-:20])=[O:19]
Reactant: O=c1c2ccccc2c(I)c([N+](=O)[O-])c2ccccc12
Solvent: c1ccncc1
Product: O=c1c2ccccc2cc([N+](=O)[O-])c2ccccc12

Procedure:
Initially 10-iodo-11-nitro-5H-dibenzo[a,d]cyclohepten-5-one is contacted with pyridine to form 10-nitro-5H-dibenzo[a,d]cyclohepten-5-one. This compound is reduced to 10,11-dihydro-10-hydroximino-5H-dibenzo[a,d]cyclohepten-5-one employing a solution of stannous chloride in concentrated hydrochloric acid and tetrahydrofuran generally at 0°-50° C. for 2-16 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.[BrH:29]>O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.[BrH:29].[BrH:29].[BrH:29].[NH:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)CC1
Agent: Br
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Product: c1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
A mixture of 30 parts of ethyl 4-[[1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate and 300 parts of a hydrobromic acid solution 48% in water was stirred and heated for 3 hours at 80° C. The reaction mixture was evaporated and the residue was crystallized from methanol, yielding 41 parts (93.2%) of N-(4-piperidinyl)-1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-amine trihydrobromide; mp. 295.9° C. (66).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[CH3:8]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Cc1ncc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 50.1 %

Procedure:
5-bromo-2-methylpyridin-3-amine (224.9 mg, 1.202 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (413.7 mg, 1.300 mmol), potassium carbonate (549.4 mg, 3.975 mmol), and Pd(dppf)Cl2*DCM complex (108.7 mg, 0.133 mmol) were suspended in DME (5.0 ml) and water (1.25 ml), and the flask was fit with a reflux condensor and argon was bubbled through for about 15 seconds. Then, the flask was placed in a preheated oil bath (100° C.) and stirred under argon for 80 minutes. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated, treated with MeOH, and filtered. Solid washed with MeOH, water, MeOH, and Et2O. Solid then collected and dried under high vacuum to afford N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (179.7 mg, 50% yield). MS (ESI pos. ion) m/z: 299. Calculated exact mass for C15H14N4OS: 298.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.Cl[C:15]1[C:16]2[CH2:26][CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:17]=2[N:18]=[C:19]([NH2:21])[N:20]=1>COCCO.[OH-].[Na+]>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:15]2[C:16]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:17]=3[N:18]=[C:19]([NH2:21])[N:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCc2ccccc2-3)n1
Temperature: 130 °C

Procedure:
The product of Example 1E (155 mg, 0.686 mmol) and the product of Example 1C (140 mg, 0.571 mmol) were combined in 2-methoxyethanol (0.8 mL) and heated to 130° C. for three hours. The mixture was diluted with 1 N aqueous sodium hydroxide and extracted twice with methylene chloride. The organic layers were combined and dried over sodium sulfate and the mixture was absorbed on silica gel and purified using silica gel chromatography, eluting with a gradient of 7 N ammonia in methanol in methylene chloride (5-15%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.62 (d, J=4.41 Hz, 1H) 7.50-7.56 (m, 1H) 7.26-7.34 (m, 2H) 7.19-7.26 (m, 1H) 6.67-6.75 (m, 1H) 5.85 (s, 2H) 5.70-5.81 (m, 4H) 3.37-3.52 (m, 4H) 2.44 (t, J=6.78 Hz, 2H) 2.08-2.18 (m, J=6.78, 6.78 Hz, 2H) 1.92-2.04 (m, 2H); MS (ESI+) m/z 363.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:10]([NH:18][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CNCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 4-hydroxybenzaldehyde (1.00 g, 8.12 mmol) in methanol (40.6 mL). Add 3 Å molecular sieves and phenethylamine (1.02 mL, 8.12 mmol). Stir at room temperature for 17 hours. Add NaBH4 (0.341 g, 9.01 mmol). After five hours, filter and concentrate. Purify by 10 g SCX column washing with methanol and eluting with 2.0 M NH3 in methanol to give the title compound as an off white solid: HRMS calcd for C15H18NO 228.1388 (M+H)+, found 228.1387, time 0.74 min, MS TOF ES+ 228.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.4 min, 100% purity.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Temperature: 0 °C

Procedure:
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (0.5 g, 1.687 mmol) was dissolved in methanol (10 ml). The mixture was cooled to 0° C. and sodium hydroxide 2 M solution (1.687 ml) was added. The reaction mixture was allowed to warm to RT with stirring. Stirring was two days during which more sodium hydroxide 2 M solution (3.4 ml in total) was added. The last hour was stirred at 40° C. Methanol was evaporated and water was added. The pH was adjusted to 1 with 1M HCl, which precipitated the product out of the solution. The mixture was filtered, precipitate washed with water and dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): δ, 5.82 (s, 2H), 7.17-7.38 (m, 6H), 8.17 (d, 1H), 9.39 (s, 1H), 14.35 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].Br[C:17]1[CH:18]=[C:19]2C(=[CH:25][CH:26]=1)C(=C(CC)CC)CCC2(C)C>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[C:17]([CH2:18][CH3:19])[CH2:26][CH3:25])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCC(CC)=C1CCC(C)(C)c2cc(Br)ccc21
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=C(CC)CC

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 530 mg (1.66 mmol) of 6-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound Q) was converted into the title compound using 1.63 g (16.6 mmol) of trimethylsilylacetylene, 20 mg (0.08 mmol) of cuprous iodide, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and 40 mg (0.3 mmol) of potassium carbonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]#[N:13])[S:11][C:7]=2[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[SH2:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12](=[S:27])[NH2:13])[S:11][C:7]=2[C:6]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C#N)nc12
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(N)=S)nc12
Yield: 87 %

Procedure:
0.50 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile and 5.46 ml triethylamine in 13 ml pyridine were stirred for 4 hours with about 5 ml hydrogen sulfide at room temperature. Solvent and excess hydrogen sulfide were removed and the residue chromatographed on siligagel with ethylacetate/heptane 1:1 to yield 0.49 g (87%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbothioic acid amide; M.p.: 238° C.; MS (ISP): m/e=310 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[NH2:20][C:21]1[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[C:25]=2[C:32]=1[CH3:33]>C1COCC1.O>[NH2:20][C:21]1[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]2[O:28][C:27]([CH3:29])([CH3:30])[C:26]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)([OH:31])[C:25]=2[C:32]=1[CH3:33]
Reactant: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C2(O)c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 4-bromotoluene (2.73 g, 16.0 mmol) in THF (30 mL) was added dropwise a solution of n-butyllithium in hexane (1.60 M, 10.0 mL, 16.0 mmol) under argon atmosphere at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction solution was added dropwise a solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained in Reference Example 57 (1.0 g, 4.56 mmol) in THF (10 mL) at the same temperature, and the reaction solution was stirred at room temperature for 1 hour, followed by addition of water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to obtain 921 mg (yield 65%) of the title compound. Melting point: 165-166° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.CCN(CC)CC.CC(OC(C)=O)=O>C(Cl)Cl>[C:2]([N:33]1[CH2:34][CH2:35][C:30]([CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([C:10]3[C:11]4[C:16]([OH:17])=[C:15]([C:18]#[N:19])[C:14](=[O:20])[NH:13][C:12]=4[S:21][C:9]=3[Cl:8])=[CH:27][CH:26]=2)([OH:36])[CH2:31][CH2:32]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(O)(COc2ccc(-c3c(Cl)sc4[nH]c(=O)c(C#N)c(O)c34)cc2)CC1

Procedure:
An ambient solution of 2-chloro-4-hydroxy-3-{4-[(4-hydroxypiperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (40 mg, 0.073 mmol), Et3N (0.015 mL, 0.11 mmol), and Ac2O (0.007 mL, 0.073 mmol) in DCM (0.5 mL) was stirred for 18 h. The reaction was then quenched by the addition of saturated NaHCO3 (1 mL) and EtOAc (1 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RPLC to give the title compound. MS (ESI) m/e 474 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.01 (s, 3H), 2.94 (m, 2H), 3.4 (m, 2H), 3.81 (s, 2H), 6.95 (d, J=8.81 Hz, 2H), 7.22 (d, J=8.48 Hz, 2H).