Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[CH2:10][C:11]([CH3:26])([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[O:12]2)=[CH:7][C:6]=1[OH:28])([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[O:12][C:11]([CH3:26])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:10][C:9]2=[O:27])(=[O:31])[CH3:30]
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(O)c(C(C)(C)C)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 1.7 g of 7-t-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one, 1 ml of acetic anhydride and 10 ml of pyridine was allowed to stand at room temperature for 1 day. The reaction mixture was then poured into ice-water and stirred for 2 hours, and the crude substance was extracted with benzene. The organic solution was washed successively with 3N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the crude product thus obtained was recrystallized from a 10:1 by volume mixture of benzene and ethyl acetate, to give the desired 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:31][CH2:32][CH2:33][NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>C(#N)C.C(N(CC)CC)C>[OH:31][CH2:32][CH2:33][N:34]([C:7]([C:5]1[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=1)=[O:9])[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(=O)N(CCO)C2CCN(C(=O)OC(C)(C)C)CC2)c[nH]1
Yield: 17.9 %

Procedure:
2-Methylimidazole-4-carboxylic acid (2.0 g) was suspended in acetonitrile (150 ml). HOBt (3.7 g) and WSC (4.6 g) were sequentially added thereto, and then mixed at room temperature for 20 minutes. To the reaction solution was added a solution of tert-butyl 4-(2-hydroxyethyl)amino-1-piperidinecarboxylate (4.7 g) obtained in Example 91a) and triethylamine (8.0 ml) in acetonitrile (50 ml), and mixed at room temperature for 15 hours. Acetonitrile was distilled off under reduced pressure, and then to the residue were added chloroform and water. The organic layer was collected by separation and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a colorless oil (1.0 g, 18%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([Cl:25])=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Product: O=C(Cl)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1

Procedure:
To a solution of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate (0.95 g, 3 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (0.76 g, yield 83%). LC-MS (ESI) m/z: 303 (M+1)+. 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (610 mg, 2 mmol) was added to thionyl chloride (10 mL), and the mixture was added at room temperature for 48 h. Then the solvent was removed under reduced pressure, dried in vacuum to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoyl chloride.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:17]([CH2:35][C:36]1([C@H:39]2[CH2:43][C:42](=[O:44])[N:41]([C@H:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH3:46])[CH2:40]2)[CH2:38][CH2:37]1)[Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:5]([O:4][C:2]([CH:43]1[C:42](=[O:44])[N:41]([C@H:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH3:46])[CH2:40][C@H:39]1[C:36]1([CH2:35][O:17][Si:18]([C:31]([CH3:32])([CH3:34])[CH3:33])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:37][CH2:38]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Ethyl chloroformate (0.059 mL, 0.617 mmol) and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.57 mL, 0.570 mmol) were sequentially added dropwise to a solution of (3R)-3-[1-(tert-butyldiphenylsiloxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine (258 mg, 0.518 mmol) in tetrahydrofuran (2 mL) at 0° C. over two minutes. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.57 mL, 0.570 mmol) was further added. The mixture was stirred at room temperature for 2.5 hours and then ice-cooled. The reaction was quenched with a 10% citric acid solution (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL) and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to give 227 mg (77%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:14][CH:13]1[CH2:32][OH:33])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:14][CH:13]1[CH:32]=[O:33])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C=O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
methylene chloride (50 ml) is added dropwise at -78° C. a solution of dimethyl sulfoxide (2.86 g) in methylene chloride (20 ml). The mixture is stirred for 10 minutes. To the resulting reaction mixture is added dropwise a solution of 1-tertbutoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (5.0 g) obtained in Reference Example 4 in methylene chloride (10 ml). The mixture is stirred for 20 minutes. To the mixture is added triethylamine (7.4 g), followed by raising the reaction temperature up to room temperature. The reaction mixture is poured into ice water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is recrystallized from ethyl acetate to give 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carbaldehyde as colorless prisms (4.1 g), m.p. 160-161° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]2)([CH3:13])[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]1([S:7]([C:10]([CH:14]2[CH2:19][CH2:18][C:17]3[C:27]4[C:26](=[CH:25][CH:24]=[C:23]([CH3:22])[CH:28]=4)[NH:29][C:16]=3[CH2:15]2)([CH3:13])[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C#N)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c3c(c2c1)CCC(C(C)(C#N)S(=O)(=O)c1ccccc1)C3
Yield: 29.5 %

Procedure:
To 322 mg (1.10 mmol) of 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile in 10 mL of glacial acetic acid, 193 mg (1.21 mmol, 1.1 eq) of (4-methyl-phenyl)-hydrazine hydrochloride were added and stirring was continued at RT over night. An aqueous solution of NaHCO3 was added until pH=7, and the product was extracted with EtOAc, the organic phase was dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with AcOEt/heptane 1:4, and triturated with Et2O. 158 mg (38%) of (RR,SS)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile and 123 mg (29%) of (RS,SR)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile were isolated as light yellow solids, MS: 379 (MH+).
Reaction SMILES: C(C1C=CC(C2[O:15]N=C3C4C(CCC=23)=CC(C=O)=CC=4)=CC=1C(F)(F)F)C(C)C.[CH3:30][N:31]1[C:39]2[C:38]3[CH:40]=[CH:41][C:42]([CH:44]=C)=[CH:43][C:37]=3[CH2:36][CH2:35][C:34]=2[C:33]([C:46]2[C:50]([C:51]([F:54])([F:53])[F:52])=[C:49]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:48][N:47]=2)=[N:32]1>>[CH3:30][N:31]1[C:39]2[C:38]3[CH:40]=[CH:41][C:42]([CH:44]=[O:15])=[CH:43][C:37]=3[CH2:36][CH2:35][C:34]=2[C:33]([C:46]2[C:50]([C:51]([F:53])([F:52])[F:54])=[C:49]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:48][N:47]=2)=[N:32]1
Reactant: C=Cc1ccc2c(c1)CCc1c(-c3noc(-c4ccccc4)c3C(F)(F)F)nn(C)c1-2
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Product: Cn1nc(-c2noc(-c3ccccc3)c2C(F)(F)F)c2c1-c1ccc(C=O)cc1CC2

Procedure:
This compound was prepared according to the general procedure described for Preparation 23D, employing 50 mgs of 3-(1-methyl-7-vinyl-4,5-dihydro-1H-benzo[g]indazol-3-yl)-5-phenyl-4-(trifluoromethyl)isoxazole (78B). Yield: 48 mgs (96%); LC/MS M+1=424.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: COc1c(Cl)ccc(Br)c1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1c(Cl)ccc(C=O)c1F
Temperature: -78 °C
Yield: 61 %

Procedure:
1-Bromo-4-chloro-2-fluoro-3-methoxybenzene (23.7 g, 99 mmol, see U.S. Pat. No. 7,300,907 for preparation) was dissolved in dry diethyl ether and cooled to −78° C. 2.5M n-Butyllithium in hexanes (44 mL, 110 mmol) was added in portions, keeping the temperature below −70° C. during the addition. DMF (15.5 mL, 200 mmol) was then added in portions, keeping the temperature below −60° C. The reaction mixture was then allowed to warm to ambient temperature and quenched with water. The organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound in sufficient purity for subsequent reactions (11.4 g, 61% yield): 1H NMR (CDCl3) δ 10.32 (s, 1H), 7.55 (m, 1H), 7.3 (m, 1H), 4.05 (d, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C1COCC1>[C:4]1([C:1]([OH:3])([CH2:12][CH:11]=[CH2:10])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of acetophenone (30 g, 0.25 mol) in dry THF (250 mL) at −78° C. was added dropwise 1M allylmagnesium bromide (1.25 L, 1.25 mol). After addition was complete, the mixture was allowed to stir at rt for 3 h. The reaction was quenched with satd aq NH4Cl solution (30 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give 2-phenylpent-4-en-2-ol (40.2 g), which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH:16]=2)=[O:11])=[C:6]([CH3:29])[N:5]=[C:4]([NH:30]C(=O)OC(C)(C)C)[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C:4]1[N:5]=[C:6]([CH3:29])[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH:16]=2)=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(N)nc4C)nn3)ccc2n1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4,6-dimethyl-5-((1-((2-methylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)pyridin-2-yl)carbamate (131.9 mg, 0.263 mmol) in DCM (1.2 ml) was added TFA (0.405 ml, 5.26 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was evaporated to afford the crude material, which was purified by preparative HPLC (Sunfire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% TFA and B=ACN+0.1% TFA, gradient from 5% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined and acetonitrile was evaporated. Residual aqueous layer was frozen and lyophilized to afford the product as a TFA salt, which was dissolved in acetonitrile/methanol and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE). The eluted solution was evaporated, and the residue was triturated in Et2O and filtered to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.70 (s, 1H), 8.62 (broad s, 1H), 8.24 (d, 1H), 7.91 (d, 1H), 7.86 (s, 1H), 7.66 (d, 1H), 7.43 (d, 1H), 6.37 (broad s, 1H), 5.82 (s, 2H), 4.33 (d, 2H), 2.64 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H); HPLC (Method G) Rt=0.932 min; MS (Method F) [M+H]+=402.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.11, 6.96, 5.66, 4.52, 2.95–2.62, 2.55, 2.38, 2.05, 1.97, 1.79, 1.26, 1.20, 1.07; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1224.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([OH:12])[CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+]>CC(O)(C)C>[O:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]([OH:12])[CH2:9][CH2:10]1
Reactant: OCCC(O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: OC1CCOc2ncccc21
Temperature: 80 °C

Procedure:
A mixture of 1-(2-chloropyridin-3-yl)propane-1,3-diol (62.9 mmol) and KOtBu (189 mmol) in 240 mL tBuOH (dried over 3 Å molsieves) was heated to 80° C. for 2.5 h. The reaction mixture was then concentrated to about ¼ of its volume, diluted with water and extracted 5 times with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using MeOH/DCM (99/1 to 95/5) gives the desired compound as orange oil.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1)#[N:23]>C(N(CC)CC)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[NH:31][CH2:32][CH2:33][N:34]([C:2]3[C:3]([F:21])=[CH:4][C:5]4[C:6]([CH:20]=3)=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=4)[CH2:35]2)=[CH:28][CH:29]=1)#[N:23]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: N#Cc1ccc(C2CNCCN2)cc1
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(C#N)cc5)C4)cc3nc21
Yield: 41.9 %

Procedure:
(RS)-8-[3-(4-Cyanophenyl)-1-piperazinyl]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11, but starting with 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.84 g), (RS)-2-(4-cyanophenyl)piperazine (5.61 g) and triethylamine (1.7 cc). (RS)-8-[3-(4-Cyanophenyl)-1-piperazinyl]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.15 g) is obtained in the form of a yellow solid, decomposing at 332° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:47]C2CCCCO2)[CH2:21][N:22]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][N:22]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c([C@H](CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 47.4 %

Procedure:
A solution of 8-(benzyloxy)-5-[(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one (80 mg) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at 80° C. for 17 h prior to concentration in vacuo. The residue was purified by chromatography (Hexane-EtOAc 2:1, biotage) to give the title compound (33.5 mg).
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@@H:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]([O:19]C(C)=O)[C@@H:8]([O:23]C(C)=O)[C@@H:7]1[O:27]C(C)=O)=O.CO.C[O-].[Na+]>C(O)(=O)C>[CH:16]1[CH:15]=[CH:14][C:13]([O:12][C@@H:10]2[O:11][C@H:6]([CH2:5][OH:4])[C@@H:7]([OH:27])[C@H:8]([OH:23])[C@H:9]2[OH:19])=[CH:18][CH:17]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To phenyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (21.2 g) were added methanol (120 ml) and 28% sodium methylate (0.28 ml) and the mixture was refluxed with stirring for 5 hours. After the reaction solution was cooled, acetic acid (0.1 ml) was added and the mixture was stirred for 30 minutes. Concentration of the reaction solution and crystallization with ethanol (180 ml) gave 10.0 g (yield 78%) of phenyl-β-D-glucopyranoside. Melting point: 177.0° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28][NH:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[CH:13][CH:12]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccc(Cl)cc32)cc1
Yield: 45.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (911 mg, 1.3 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (617 mg, 3.16 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (577 mg, 46%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[N:3]=[C:4]([S:19][CH3:20])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(Nc2c(F)cccc2F)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2,6-difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ0.31 (s, 3H), 6.98-7.20 (m, 3H), 7.26 (m, 2H), 7.38-7.42 (m, 2H), 9.79 (s, 1H), 10.39 (br s, 1H). LC MS (m/e)=376 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[CH2:25][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[O:36]1[CH2:24][CH:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[C:12]([C:9]3[C:8]([CH2:25][CH2:26][CH3:27])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(-c2noc(-c3noc(-c4ccccc4)c3CCC)n2)cc1
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(C4CO4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(5-phenyl-4-propylisoxazol-3-yl)-3-(4-vinylphenyl)-1,2,4-oxadiazole (4.64 g, 12.97 mmol) in DCM (500 mL) was added m-CPBA (9 g, 52.2 mmol). The reaction mixture was stirred overnight at room temperature. Next, the reaction mixture was washed with 1N NaOH. The organic layer was dried with MgSO4, filtered, and concentrated to yield Preparation 1B. MS (m+1)=374. HPLC Peak RT=4.36 minutes (Analytical Method A).