Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
A yellow solution of 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (step 1) (1.0 g, 3.04 mmol) and ethyl 7-bromoheptanoate (1.440 g, 6.07 mmol) in DMF (20 ml), under a nitrogen atmosphere, was treated with potassium carbonate (2.098 g, 15.18 mmol) and the resultant suspension was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water (×2) and brine, dried (MgSO4) and evaporated under vacuum to a brown oil. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound as a pale solid;
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9](P(=O)(CC)CC)[CH3:10].[CH:17]#[CH:18]>>[CH:17]([N:7]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:10]=[CH:9]1)=[CH2:18]
Reactant: ON=C1CCCCC1
Reactant: C#C
Reactant: CCP(=O)(CC)CC
Product: C=Cn1ccc2c1CCCC2
Temperature: 70 °C
Yield: 24 %

Procedure:
5 g of cyclohexanone oxime, 0.05 g of potassium tert.butylate and 0.5 g of triethylphosphine oxide are placed into a one-liter rotary autoclave which is filled with acetylene under the pressure of 12 atm and heated at the temperature of 70° C for 3 hours. After cooling, the autoclave is again filled with acetylene under the same pressure and again heated at 70° C for 3 hours. The resulting cooled mixture is extracted with dibutyl ether and the extract is distilled to give 1.4 g (yield of 24%) of 1-vinyl-4,5,6,7-tetrahydroindole.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]1[C:15](=[O:16])[C:14](=[O:19])[C:13]=1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: Nc1ccc(F)cc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(F)cc2)c(=O)c1=O

Procedure:
A solution of 4-fluoroaniline and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]2[C:17](=[CH:18][CH:19]=1)[C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][NH:11]2.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:42])([F:41])[CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.[BH4-].[Na+]>CCO>[F:7][C:8]1[CH:9]=[C:10]2[C:17]([C:13]([CH2:14][CH2:15][NH:16][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH2:31][C:30]([F:29])([F:41])[F:42])[CH:34]=3)=[CH:12][NH:11]2)=[CH:18][CH:19]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c2c1
Reaction time: 1 h

Procedure:
Combine 6-fluorotryptamine oxalate (350 mg, 1.3 mmol), N,N-diisopropylethylamine(506 mg, 3.9 mmol), 3-(2,2,2-trifluoroethoxy)benzaldehyde (266 mg, 1.3 mmol), and 4 Å molecular sieves (4 g) in EtOH (30 mL) and reflux for 7 hours. Decant the liquid into a separate flask and treat with NaBH4 (148 mg, 3.9 mmol). Stir 1 hour, concentrate the mixture in vacuo to give a residue. Partition the residue between 25 mL 5N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 mL dichloromethane, combine the organic layers, dry over MgSO4, and concentrate to approximately a 20 mL volume. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 mixed with conc. NH4OH to give the title compound. Combine an EtOAc solution of the title compound with an EtOAc solution of one equivalent of oxalic acid to give a solid, filter, and dry under vacuum to give the oxalate salt of the title compound: ISMS 367 (M+1); Analysis for C19H19ClF4N2O: calcd: C, 55.27; H, 4.42; N, 6.14; found: C, 55.17; H, 4.38; N, 6.09.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O>>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][N:1]([CH2:31][C:27]1[NH:26][CH:30]=[CH:29][N:28]=1)[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1
Reactant: O=Cc1ncc[nH]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and 1H-imidazole-2-carbaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 507 (MH)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C([O:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH:17]=1)C.Cl>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:18]2[CH2:19][CH2:20][CH2:21][C:16](=[O:15])[CH:17]=2)[CH:8]=1
Reactant: Brc1cccnc1
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1C=C(c2cccnc2)CCC1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
To a solution of n-BuLi (1.54 M in Hexane, 145 mL. 224 mmol) in Et2O (600 ml) was added dropwise 3-Bromopyridine (22.0 mL, 224 mmol) at −75˜−68° C., and stirred for 20 min. To a reaction mixture was added dropwise 3-ethoxy-2-cyclohexenone (25.0 mL, 187 mmol) at −75˜−69° C., and stirred at room temperature for 1 h. The reaction mixture was acidified with 2M HCl (300 mL), and aqueous layer was washed with AcOEt. The aqueous layer was basified with 1M NaOH aq., and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/2) to yield 3-(3-pyridyl)-2-cyclohexen-1-one (21.5 g, 66%) as yellow powder.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>C(Cl)(=O)C(Cl)=O.ClCCl.C1COCC1>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
3-Carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (128 mg, 0.44 mmol) was dissolved in a mixture of oxalyl chloride (0.6 mL) and dichloromethane (3.4 mL). The reaction mixture was stirred for 30 min at ambient temperature and the solvent was evaporated. The residue was dissolved in a mixture of dichloromethane (2.5 mL) and anhydrous TBF (2.5 mL) and added to a mixture of 3-chloro4-fluoro-aniline (17 mg, 0.12 mmol) and N,N-(diisopropyl)aminomethylpolystyrene resin (140 mg, Argonaut Technologies, Inc) in anhydrous THF (3 mL). The mixture was shaken overnight. The resin was filtered off, the solvents were evaporated and the crude product was purified on a preparative LC/MS (XTerra Cs column 19×100mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled fractions were lyophilized to afford 7.2 mg (20%) of the title compound. Calculated for C15H11ClFN3O m/z: 303.7, found 304.7 [M+H]+. 1H NMR (400 M, MeOD) δ ppm 5.2 (s, 2H), 7.2 (t, J=9.1 Hz, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.5 (d, J=7.1 Hz, 1H), 7.7 (d, J=7.1 Hz, 1H), 7.8 (dd, J=6.6, 2.5 Hz, 1H), 8.2 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:39]>>[CH3:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Cc1cccc(C)c1CBr
Product: Cc1cccc(C)c1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-1,3-dimethylbenzene following the procedure of Example 478: MS (ES) m/z 511.5.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH:16]1([NH:22][C:13]([C:10]2[N:11]=[CH:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ncn(Cc2ccccc2)n1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ncn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid (1.54 g, 7.6 mmol), cyclohexylamine (0.87 mL, 7.6 mmol) and N,N-diisopropylethylamine (2.65 mL, 15.1 mmol) in DMF (30 mL) was added HBTU (3.45 g, 9.1 mmol). The solution was then stirred at room temperature overnight. Aqueous hydrochloric acid was added and the solution was filtered to yield 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid cyclohexylamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Yield: 66 %

Procedure:
To 250 mg of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofaran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 210 mg (66%) of 4-(3-chloro-4-fluoro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 131-132° C.; mass spectrum (m/e): M+H 386.0.
Reaction SMILES: C1COCC1.Br[C:7]1[C:15]2[O:14][C:13]([F:17])([F:16])[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[N:18]1[O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1>[F:16][C:13]1([F:17])[O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C@:22]34[CH2:23][O:24][CH2:25][CH2:26][C@H:21]3[CH2:20][O:19][NH:18]4)[C:15]=2[O:14]1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Reactant: C1CC2CON=C2CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC1(F)Oc2cccc([C@]34COCC[C@H]3CON4)c2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.Cl[C:28](Cl)([O:30][C:31](=O)[O:32]C(Cl)(Cl)Cl)Cl.CO>ClCCl>[CH3:28][O:30][C:31](=[O:32])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Solvent: ClCCl
Solvent: CO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OC)cc3)nc21

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (150 mg, 0.43 mmol) in dichloromethane (5 mL) was treated with triphosgene (64 mg, 0.21 mmol). After the passage of 5 minutes, an excess of methanol was added to the mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide methyl{4-[1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate. MS (ES+): 409.0 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.C[N+]1([O-])CCOCC1>C1COCC1.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g of tert-butyl 4-hydroxy-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 40 ml of THF-CH3CN (1:1) ar rt were added 2.0 g of MS 4A, 435 mg of NMO, and 88 mg of TPAP, and the reaction mixture was stirred at rt overnight. The mixture was filtered through a Celite pad, washed with CHCl3 and CHCl3-MeOH (9:1), and the filtrate was concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane-AcOEt (100/0-0/100) as eluent to give the intended compound as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[N:15]1([C:18]2[CH:19]=[CH:20][C:21]([NH:22][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
A suspension of 4-formylbenzoic acid (2.53 g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3 g; 16.8 mmol; 1 eq) and Bu2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction, was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25 g (99%). LRMS: calc 312.37. found: 313.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=C(C(O)=O)[CH:9]=[CH:10][C:11]=1[C:12]2=[O:17].CN(C([O:28]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]([N:48]([CH:51]([CH3:53])C)[CH2:49][CH3:50])([CH3:47])C.C(NCC)C>CN(C=O)C>[CH2:51]([N:48]([CH2:49][CH3:50])[C:45]([C:47]1[CH:9]=[CH:10][C:11]2[C:12](=[O:17])[C:13]3[C:4]([O:5][C:6]=2[CH:7]=1)=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][CH:14]=3)=[O:28])[CH3:53]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cccc2c(=O)c3ccc(C(=O)O)cc3oc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc2c(=O)c3cccc(OC)c3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a solution of 5-methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 3c (6.8 g, 25.2 mmol) in DMF (70 mL), were added HBTU (10 g, 26.4 mmol) and N,N-diisopropyl-N-ethylamine (5.27 mL, 30.2 mmol). The mixture was stirred for 15 min at rt. N,N-Diethylamine (3.12 mL, 30.2 mmol) was added, and the mixture was stirred for 4 h at rt. The mixture was poured into ice-water (300 mL), and a solid precipitated. The solid was separated via filtration, washed with H2O, and air-dried. The solid was purified via flash column chromatography (eluent gradient: 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) to yield 7.93 g (96.7%) of title compound 5-methoxy-9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 4c. MS m/z=326.0 (MH+).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 6.5 g. (33.0 mmoles) of 1-adamantane carboxylic acid chloride, 4.0 g. (33.0 mmoles) of p-anisidine and 10.0 ml. of triethylamine to the process of Example 11 and crystallize the residue obtained thereby from chloroform to yield the title product, m.p. 181°-184° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([OH:27])[C:19]=1[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>ClCCl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]2[CH:14]=[C:13]([NH:12][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:33]=[CH:32][CH:31]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:20]=1[OH:27])(=[O:26])[CH3:25]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Add a solution of 3-cyanobenzoyl chloride (553 mg, 3.34 mmol) in dichloromethane (10 mL) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) in dichloromethane (10 mL), and triethyl amine (1.4 mL) at 0° C. Stir to room temperature for one hour. Partition the mixture between dichloromethane (20 mL) and 2N hydrochloric acid (30 mL). Wash the organic layer with 2N hydrochloric acid (20 mL), saturated sodium bicarbonate, brine, dry, filter, and concentrate to afford the title compound as a light yellow powder (1.33 g, 93%): 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.59 (sextet, 2H), 2.55 (s, 3H), 2.72 (t, 2H), 5.19 (s, 2H), 6.47 (d, 1H), 7.26 (d, 1H), 7.42 (t, 1H), 7.54-7.59 (m, 2H), 7.65 (t, 1H), 7.77 (s, 1H), 7.84 (d, 1H), 7.88 (s, 1H), 8.11 (d, 1H), 8.17 (s, 1H), 12.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:8](=O)[C:7]=2[CH:29]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH2:8][C:7]=2[CH:29]=1
Reactant: COc1cc2c(=O)n(CCN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1cnc3cc4c(cc3c1N(CCN(C)C)C2)OCO4
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one (160 mg, 0.38 mmol) in THF (650 mL) was added LiAlH4 (75 mg, 2.0 mmol), and the mixture was stirred under nitrogen at reflux. After 2 h, an additional 2.0 mmol of LiAlH4 was again added. The reaction was refluxed for an additional 3 h, then allowed to cool to room temperature. The reaction was quenched by the sequential addition of water (5 drops), 10% NaOH (5 drops), and water (5 drops). The mixture was filtered through Celite and evaporated, and the crude mixture was chromatographed on silica in 98:2 chloroform-methanol, to give 132 mg of the reduced product, in 85% yield; mp 271-273° C. (dec.); 1H NMR (CDCl3) δ 2.24 (s, 6H), 2.58 (t, 2H, J=6.8), 3.12 (t, 2H, J=6.8), 3.97 (s, 3H), 4.02 (s, 3H), 4.27 (s, 2H), 6.13 (s, 2H), 6.79 (s, 1H), 7.38 (s, 2H), 7.61 (s, 1H), 9.05 (s, 1H); 13C NMR (CDCl3) δ 46.0, 50.6, 51.2, 56.2, 26.3, 58.4, 99.6, 101.7, 105.7, 106.6, 110.0, 120.7, 123.1, 124.8, 131.1, 144.1, 146.9, 148.0, 149.0, 149.4, 149.8, 150.2; HRMS calcd for C23H25N3O4: 407.1845; found 407.1848.
Reaction SMILES: O[CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Cl:57])C(=O)C1>CN(C=O)C.C(Cl)(Cl)(Cl)Cl.O>[Cl:57][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[C:17]4[CH:30]=[CH:29][S:28][C:18]=4[C:19](=[O:27])[NH:20][C:21]=3[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CCl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a mixture of N-(1-hydroxypropan-2-yl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (140 mg, 0.30 mmol) and triphenylphosphine (160 mg, 0.62 mmol) in DMF/CCl4 (1 mL/3 mL) was added NCS (41 mg, 0.31 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (ca. 20 mL), and extracted with DCM (1×50 mL). The extract was washed with water (2×20 mL), brine (1×10 mL), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by flash chromatography to afford the desired product (100 mg, 74%) as light yellow solid; ESI MS m/z 464 [C21H19ClN2O4S+H]+