Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:10]1[C:9]2([CH2:14][CH2:15][CH:6]([CH:4]=[O:3])[CH2:7][CH2:8]2)[O:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=CC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (5.4 g, 25.2 mmol, prepared as in STEP A above) in anhydrous toluene (25 mL) was cooled to −78° C. under an argon atmosphere. To the resulting solution was added a solution of DIBAL-H (26 mL, 1N DIBAL-H in toluene, 26 mmol) in toluene while ensuring the inside temperature was kept between −60 to −70° C. Methanol (25 mL) was added slowly and the resulting mixture was allowed to warm to room temperature, then treated with aqueous sodium chloride (20 mL). The resulting mixture was passed through a silica gel plug (100 g) using ethyl acetate. The resulting eluent was concentrated to yield 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[O:13][C:14](=O)[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:3]1.[NH3:25]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:25][C:14](=[O:13])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:3]1
Reactant: Cc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c1
Reactant: N
Solvent: CN(C)C=O
Product: Cc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Temperature: 150 °C

Procedure:
0.30 g of 3-(1-methyl-3-indolyl)-4-(3-methylphenyl) furan-2,5-dione was treated with 8 ml of DMF and 60 ml of 33% aqueous ammonia and heated at 150° C. for 5 hours and then allowed to cool. The formed precipitate was filtered off, washed with water and dried to give 162 mg of 3-(1-methyl-3-indolyl)-4-(3-methylphenyl)-1H-pyrrole-2,5-dione, m.p. 243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH3:25])[C:16]=1[CH3:39])=[O:14].CO.[ClH:42]>>[ClH:42].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[CH3:25])[C:16]=1[CH3:39])=[O:14]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)-tert-butyl 4-(1-(3-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-2-methyl-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (Compound 327) (1.850 g, 3.45 mmol), MeOH (13.79 ml, 3.45 mmol), and HCl (2.59 ml, 10.34 mmol) (4 N in dioxane). The reaction was allowed to stir at rt for 6 h before being conc, in vacuo to afford the title compound (1.65 g, 3.14 mmol, 91% yield). LCMS 437 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].[OH-].[Na+]>C1(C)C=CC=CC=1.O.CO>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31 g, 775 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 242 mmol) and dimethyl methylsuccinate (58 g, 362 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. A 2.0 N aqueous NaOH solution (300 mL) was added slowly at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 242 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28 g, 24% overall). MS calcd. for C12H12FO4 [(M+H)+] 239, obsd. 239.2.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:26](C(Cl)=O)=[CH:25][CH:24]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH2:43])[CH3:39]>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13]([C:35]2[CH:34]=[CH:33][C:32]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:37][CH:36]=2)=[O:15])[C@H:10]([C:20]([NH:43][CH2:42][CH2:41][N:40]([CH2:44][CH3:45])[CH2:38][CH3:39])=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=Cc2ccccc2)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90% purity by LC/MS. MS(ESI+): m/z=482.4.
Reaction SMILES: [C:1]1([N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[O:31])=[CH:25][CH:24]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:43](O)=[O:44])=[O:40]>>[CH3:37][O:38][C:39]([NH:41][C@H:42]([C:43]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:43](=[O:44])[C@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[NH:41][C:39]([O:38][CH3:37])=[O:40])=[CH:13][CH:14]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:28][CH:27]=1)=[O:31])=[O:44])[C:46]([CH3:47])([CH3:48])[CH3:49])=[O:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(Nc1ccc(CN(Cc2ccc(/C=C/[C@@H]3CCCN3)cc2)c2ccccc2)cc1)[C@@H]1CCCN1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)C(C)(C)C
Yield: 45.8 %

Procedure:
The product from Example 149H (35 mg, 0.73 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (33.1 mg, 0.175 mmol) were processed using the method described in Example 43 to afford 33 mg (55%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.98 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.17 (m, 4H), 7.06 (m, 3H), 6.63 (m, 2H), 6.55 (t, J=7.3 Hz, 1H), 6.37 (d, J=15.7 Hz, 1H), 6.22 (m, 1H), 6.17 (dd, J=16.0, 6.3 Hz, 1H), 4.63 (m, 1H), 4.61 (s, 2H), 4.58 (s, 2H), 4.42 (m, 1H), 4.19 (m, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.63 (m, 2H), 3.52 (s, 6H), 2.16 (m, 2H), 1.96 (m, 2H), 1.84 (m, 4H), 0.95 (s, 9H), 0.93 (s, 9H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O1CCO[CH2:46][CH2:45]1>>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:37]([CH2:45][CH3:46])[CH2:36][CH3:35])[CH2:39][CH2:40]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN1CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C1COCCO1
Product: CCC(CC)N1CCN(c2nccc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc(Cl)cc5)c4s3)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added 1-(3-propyl)-piperazine (60.5 mg, 0.387 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 20 min, then 40° C. for 1 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C34H43ClN5O3S (M+H+): 636.3; Found: 636.2 (M+H+).
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)O.C1C=[N+]([C@@H]2[O:23][C@H:22](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[K+].[C:63](#N)C>>[CH3:22][O:23][C:7]1([O:8][CH3:63])[CH2:5][CH2:3][O:12][CH2:11][C@@H:9]1[OH:10]
Reactant: CC#N
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Cl-]
Agent: [K+]
Product: COC1(OC)CCOC[C@@H]1O
Temperature: 30 °C
Reaction time: 17 h

Procedure:
The above organic solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one was extracted 3× with phosphate buffered water (0.55 L). To the combined aqueous extracts was added D-glucose (180 g, 100 mmol), and the solution was heated to 30° C. When the solution exceeded 27° C. upon heating B-NADP+ (1.60 g, 499 mmol), GDH-103 (1.60 g, 499 mmol), and KRED-130 (1.60 g, 499 mmol) were added and the mixture was stirred for 17 hours at 30° C. Potassium chloride (200 g, 2.68 mol) and acetonitrile (1.3 L) were added. After 30 minutes, the reaction mixture was transferred to 6 L separating funnel and additional MeCN (0.67 L) and toluene (0.87 L) were added. The aqueous layer was back extracted 1× with a mixture of acetonitrile (1.95 L) and toluene (0.65 L), and 1× with acetonitrile (1.5 L). The combined organic extracts were concentrated in vacuo to provide (3S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
2-Chloro-4-nitrobenzoic acid (50 g, 248 mmol) was subjected to esterification using methanol (500 mL) and H2SO4 (98%, 15 mL) according to the procedure described in the example 155 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])[CH2:27]P(OC)(OC)=O)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)C>[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])/[CH:27]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:13])[CH3:12]
Reactant: COC(=O)CC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)CC(CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
In 10 mL of isopropanol (water content: 9,500 ppm) were dissolved 457 mg (2.6 mmol.) of 2,4-dichlorobenzaldehyde and 1.0 g (2.6 mmol.) of methyl 3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate togive an alcoholic solution. To the alcoholic solution was added 362 mg (2.3mmol) of potassium carbonate, and the mixture was stirred for 3 hours at room temperature (22° C.). To the resulting reaction mixture was added 40 mL of ethyl acetate, and the mixture was stirred and washed with 20 mL of water. The washing was repeated twice. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered to give a filtrate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=95/5, volume ratio) to give 1.06 g (yield: 94%) of methyl (E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Cc1ccncc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: Cc1ccncc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 61.8 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 4-methylpyridine-3-boronic acid (150 mg, 0.96 mmol) were reacted. After purification the title compound (100 mg, 62% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.1 Hz, 1 H), 8.47 (s, 1H), 8.46 (bm, 1H), 7.99 (a dd, J=5.2, 9.2 Hz, 1H), 7.58 (t, J=8.7 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 2.96 (m, 1H), 2.11 (s, 3H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=338, HPLC 1.68 min.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[C:19]2[C:14](=[C:15]([CH3:24])[C:16]([O:20][CH2:21][O:22][CH3:23])=[CH:17][CH:18]=2)[O:13][C:12](=[S:25])[C:11]=1[CH3:26].O>CC(C)=O>[CH3:23][O:22][CH2:21][O:20][C:16]1[C:15]([CH3:24])=[C:14]2[C:19]([C:10](=[O:9])[C:11]([CH3:26])=[C:12]([S:25][CH3:1])[O:13]2)=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc2c(O)c(C)c(=S)oc2c1C
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COCOc1ccc2c(=O)c(C)c(SC)oc2c1C
Temperature: 25 °C
Yield: 79.7 %

Procedure:
Potassium carbonate (995 mg, 7.20 mmol) and methyl iodide (1.50 mL, 24.0 mmol) were added to a solution of 4-hydroxy-7-(methoxymethoxy)-3,8-dimethyl-2H-chromene-2-thione (1.60 g, 6.00 mmol) obtained in Example 37-1 in acetone (16 mL), and the mixture was refluxed for 45 minutes. After cooling to room temperature, water (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=95/5→60/40) to obtain 1.34 g of the title compound (yield: 80%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1C(Cl)=O)([O-:29])=[O:28].Cl>CCCCCC.O1CCCC1.C(OCC)C>[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])([O-:29])=[O:28]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The starting material is prepared as follows: The solution of 39.6 g of monoethyl malonate, 50 mg of 2,2-bipyridyl (indicator) and 650 ml of tetrahydrofuran is cooled to -70°, whereupon 305 ml of 1.97 M n-butyl lithium in hexane are added slowly under nitrogen while stirring. The temperature is allowed to rise to about -5° near the end of addition, after the pink color of the indicator persists. The mixture is recooled to -65°, and the solution of 31.7 g of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added dropwise within 10 minutes. The resultant mixture is stirred at room temperature for 1 hour and then poured onto a mixture of 650 ml of 1 N hydrochloric acid and 1100 ml of diethyl ether. The organic layer is separated, washed successively with 350 ml of saturated aqueous sodium bicarbonate, 400 ml of water and 200 ml of brine, dried and evaporated, to yield the ethyl 2-(o-nitrobenzoyl)-acetate, as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].[CH:23](N(CC)C(C)C)([CH3:25])[CH3:24].C(Br)C=C>C(Cl)Cl>[CH2:25]([N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]2=[O:22])=[CH:8][CH:9]=1)(=[O:14])=[O:15])[CH:23]=[CH2:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.6 %

Procedure:
Synthesized according to General Procedure 23. To a stirring suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 0.59 mmol) in CH2Cl2 (0.50 mL), under N2, at 0° C., was added N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide (51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for 19 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Cl[CH2:25][C:26]([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:27].[I-].[Na+]>CN(C)C=O.O.C(OCC)C>[NH3:5].[CH:29]1([NH:28][C:26](=[O:27])[CH2:25][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([CH3:1])[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=3)[CH2:4]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CC(=O)NC3CCCCC3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol), 2-chloro-N-cyclohexylacetamide (36 mg, 0.2 mmol) and sodium iodide (catalytic) and the reaction was heated at 50° C. for 20 h. After cooling diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (22 mg, 28%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:28]=[CH:27][C:10]3[C:11]4[N:15]([CH2:16][CH2:17][O:18][C:9]=3[CH:8]=2)[CH:14]=[C:13]([C:19]2[N:20]([CH:24]([CH3:26])[CH3:25])[N:21]=[CH:22][N:23]=2)[N:12]=4)[CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH:24]([N:20]1[C:19]([C:13]2[N:12]=[C:11]3[C:10]4[CH:27]=[CH:28][C:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][C:9]=4[O:18][CH2:17][CH2:16][N:15]3[CH:14]=2)=[N:23][CH:22]=[N:21]1)([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCOCC3)cc1OCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCOCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.7 %

Procedure:
A mixture of 8-(3,6-dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (73 mg, 0.19 mmol), 20% palladium hydroxide on carbon (50 mg) and ethyl acetate (10 mL) was degassed then stirred at RT for 72 h under an atmosphere of hydrogen. The reaction mixture was filtered, the filtrate concentrated in vacuo and the residue triturated in cyclohexane to give 294 as a white solid (51 mg, 71%). LCMS: RT=4.30 min, [M+H]+=380 1H NMR 400 MHz (DMSO-d) δ: 8.34 (1 H, d, J=8.29 Hz), 7.91 (2 H, d, J=1.36 Hz), 7.08 (1 H, dd, J=8.34, 1.79 Hz), 6.92 (1 H, d, J=1.73 Hz), 5.90-5.89 (1 H, m), 4.50 (4 H, q, J=5.58 Hz), 3.96-3.95 (2 H, m), 3.44 (2 H, td, J=11.21, 3.01 Hz), 2.77-2.76 (1 H, m), 1.73-1.66 (4 H, m), 1.49 (6 H, d, J=6.60 Hz)
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][NH:44][C:21]([NH:12][C:2]34[CH2:9][CH:8]5[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]5)[CH2:3]3)[CH2:11]4)=[O:22])[CH2:39][CH2:40]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1CCN(c2cccc(Cl)c2)CC1)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-adamantanamine hydrochloride (1.0 gm, 0.0053 mol) and triethylamine (2.2 gm, 0.021 mol) in 25 ml of dry methylene chloride under a dry nitrogen atmosphere was added, dropwise, trichloromethyl chloroformate (1.15 gm, 0.0027 mol). The resulting suspension was refluxed for three hours, and then a solution of 3-[4-(3-chlorophenyl)-1-piperazinyl]propylamine (1.35 gm, 0.0053 mol) in 15 ml of dry methylene chloride was added. The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted to 200 ml with methylene chloride, washed with 3% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The title compound (TLC on silica gel using a 20% methanol in ethyl acetate solvent system, Rf=0.42) was isolated by gravity chromatography on silica gel and recrystallized from methylene chloride/hexane (1.52 gm, 61% of theory), mp.=174°-175° C.