Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Brc1ccccn1
Reactant: C1CNCCNC1
Solvent: O
Product: c1ccc(N2CCCNCC2)nc1
Temperature: 100 °C

Procedure:
A mixture of 2-bromopyridine and 12 g of homopiperazine is heated at 100° C. for 6 hours. 50 ml of water are added to the reaction mixture and the resulting mixture is extracted with EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 1.28 g of the expected product are obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[CH2:17]([C:16]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of 0-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.O=[C:12]([CH3:16])[C:13]([OH:15])=[O:14].C1N2CCN(CC2)C1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:12]([C:13]([OH:15])=[O:14])=[CH:16]2)#[N:7]
Reactant: N#Cc1ccc(N)c(I)c1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A suspension of 4-amino-3-iodobenzonitrile (2.44 g), 2-oxopropanoic acid (2.64 g), DABCO (3.36 g), and Pd(OAc)2 in DMF (30 mL) was heated to 105° C. and stirred at that temperature for 1 hour. The solvent was evaporated. EtOAc (200 mL) was added and the resulting solution was washed with water (100 mL) and aqueous NaOH solution (20 mL). The combined aqueous solution was extracted with EtOAc (3×150 mL). The organic fractions were combined. The combined solution was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was triturated to afford 5-cyano-1H-indole-2-carboxylic acid (D20) (1.1 g) as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc([C@H](C)N2CCCS2(=O)=O)cc1

Procedure:
Using methyl (S)-4-(1-aminoethyl)benzoate (0.61 g) and 3-chloropropane-1-sulfonyl chloride (0.54 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (0.90 g) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].C1COCC1.[OH-].[Na+]>O>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a mixture comprising [1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (11.8 g, 26.8 mmol) in water (100 ml) and THF (250 ml) is added dropwise NaOH (53.6 ml of a 1M aqueous solution) at room temperature and the two phase suspension is allowed to stir overnight. The solvent is removed in vacuo and the crude is triturated with diethyl ether, DCM and ethyl acetate. The resulting solid is dissolved in hot water (150 ml) and adjusted to pH 3-4 using 6M HCl. The suspension that forms is filtered and is further purified by dissolving in hot IPA (250 ml) and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the titled product is recrystallised from water/IPA as a white/pale green crystals. (MH+ 427)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.N1C=CC(COC2C=CC(C=O)=CC=2)=C[CH:17]=1>>[N:1]1[CH:2]=[CH:17][C:4]([CH2:3][O:7][C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCc2ccncc2)cc1
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Product: C(#Cc1ccccc1)OCc1ccncc1

Procedure:
Prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-(pyridine-4-ylmethoxy)benzaldehyde.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[N:13]1[CH:16]([O:17][C:18](=[O:20])[CH3:19])[CH:15]([C:21](=[O:23])[CH3:22])[C:14]1=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1>C(O)(C)C.O>[CH2:25]([CH:12]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[N:13]1[CH:16]([O:17][C:18](=[O:20])[CH3:19])[CH:15]([CH:21]([OH:23])[CH3:22])[C:14]1=[O:24])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)=O)C2OC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)O)C2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium borohydride (38 mg) and 1-(di-p-anisylmethyl)-3-acetyl-4-acetoxy-2-azetidinone (397 mg) in isopropanol (6 ml) was stirred for 0.5 hour at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-2-azetidinone (the product was a mixture of two stereoisomers (about 1:1) of hydroxyethyl group).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:9]=2
Reactant: CN(C)c1ccc(C=O)c(N)c1
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2ccc(N(C)C)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-dimethylaminobenzaldehyde and 3-(2-methoxyphenyl)propionitrile. The reaction was performed thermally (45 min, 70-80° C.).
Reaction SMILES: ClC1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1>ClCCl>[CH2:5]([C:4]1([CH3:3])[C:8](=[O:9])[O:10][CH2:4][C:8](=[O:9])[O:10]1)[CH3:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC1(C)OC(=O)COC1=O
Yield: 75 %

Procedure:
A solution of 0.5 g of cyclic keto-ester (3.5 mmol) and 1.21 g of metachloroperbenzoic acid (2 eq.) in 10 ml of dichloromethane is heated under reflux for 48 hours. After returning to ambient temperature, the solvent is eliminated under vacuum. NMR 1H analysis reveals the complete conversion of the ring with 5 members and the formation of mostly 3-ethyl-3-methyl-2,5-dioxane-1,4-dione (spectroscopic yield: 75%). NMR 1H characteristics [4.97 (s, 2H), 1.95 (q, 2H, 3JHH=7.5 Hz), 1.67 (s, 3H), 1.03 (t, 3H, 3JHH=7.5 Hz)].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>S(=O)(=O)(O)O>[OH:20][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Concentrated sulfuric acid (two drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide (2.6 g) in acetic anydride (8 ml). The mixture was stirred at 110° C. for 4 hours, which was then concentrated. The residue was dissolved in methanol (20 ml), to which was added sodium hydroxide (1.2 g) dissolved in water (5 ml). The mixture was stirred at room temperature for 30 minutes, which was concentrated. To the residue was added water, and the mixture was subjected to extraction with ethyl acetate. The extract was dried on magnesium sulfate, followed by removal of the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from isopropyl ether to yield 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine as yellow crystals, m.p. 67°-68° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:15])[NH:13][OH:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:15])[NH:13][O:14][C:16](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: N=C(NO)C1(COCCCl)CCOCC1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)C=C(ONC(=N)C1(COCCCl)CCOCC1)C(=O)OCC
Yield: 84 %

Procedure:
Reaction of 4-((2-chloroethoxy)methyl)-N-hydroxytetrahydro-2H-pyran-4-carboximidamide (10.50 g, 44.36 mmol) with diethyl acetylenedicarboxylate gave 15.25 g (84% yield) of title material as light yellow oil after chromatography. 1HNMR 400 MHz (CDCl3) δ (ppm): (mixture of E/Z isomers ratio˜3:2) 1.25-1.4 (6H, quartet of triplets), 1.6 (2H, m), 2.05 (2H, m), 3.52 (1H, s), 3.54 (1H, s), 3.65-3.85 (8H, m), 4.16-4.23 (2H, m), 4.28-4.41 (2H, m), 5.33 (1H, broad s), 5.59 (1H, broad s), 5.64 (1H, s), 5.78 (1H, s). MS (ESI+) m/e 407 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[N:14]([CH3:25])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[N:14]([CH3:25])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N(C)C(C)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N(C)C(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methyl-(1-methyl-3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[O:22].O>CC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([O:1][CH2:20][C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])=[C:3]2[C:7]=1[CH2:6][CH2:5][CH2:4]2
Reactant: O=C(CBr)c1cccs1
Reactant: COc1ccc(O)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(OCC(=O)c2cccs2)c2c1CCC2
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
To the clear solution of 4-Hydroxy-7-methoxy indane (2.0 gm, 0.0121 mole) in Acetone (20 ml), Potassium carbonate (2.52 gm, 0.0182 mole) was added at room temperature and stirred for 1.5 hours. A solution of 2-Bromo-1-thiophene-2-yl-ethanone (3.75 gm, 0.0181 mole) in Acetone (10 ml) was added at 0° C. and stirred for 8 hours at room temperature. The reaction mixture was poured into the water (50 ml) and extracted with Ethyl acetate (2×100 ml). The Ethyl acetate layer was dried over Sodium sulphate and evaporated to give a crude product which was purified by column chromatography using 2% Ethyl acetate in hexane as a mobile phase The collected eluent was evaporated to yield desire product (2.1 gm) as an viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.ClCCl.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1cc(Br)cc2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylate (9 g, 25 mmol) was dissolved in trifluoroacetic acid (6 mL) and stirred at room temperature for 16 hours. Dichloromethane and sodium hydroxide solution (2 M) were added and the organic layer washed twice with sodium hydroxide solution until the aqueous layer pH>7. The organic layer was then concentrated in vacuo to give 6.5 g (100%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[C:16](=O)[C:15]3[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][CH:4]=[N:3]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[C:16]3=[N:30][NH:31][C:18](=[O:20])[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=43)[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][CH:4]=[N:3]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a solution of ethyl 3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (400 mg, 1.06 mmol) in methanol (8 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was then stirred at 25° C. for 10 hr. The mixture was filtered to obtain a white solid (110 mg, yield 30%). LC-MS (ESI) m/z: 345 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.77 (s, 3H), 4.48-4.49 (d, J=6.4 Hz, 1H), 5.16-5.19 (d, J=6.4 Hz, 1H), 7.40-7.42 (m, 2H), 7.54-7.58 (t, 1H), 7.74 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.CC(O)=O.CNC>CC(O)C>[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CNC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccc(Cl)cc1Cl)C(C)=O
Temperature: 40 °C

Procedure:
To a stirred solution of methyl acetoacetate (345 mg, 2.97 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) in 2-propanol (5 mL) was added AcOH (7 mg, 0.11 mmol) and dimethylamine (0.06 mL, 2M in THF, 0.11 mmol). The reaction was heated to 40° C. for 4 hrs followed by cooling to ambient temperature for 15 hrs. The reaction was concentrated and purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate as a mixture of two isomers (colorless oil, 610 mg, 78%).
Reaction SMILES: [N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10]24OCCO[C:9]2(OCC[O:23]4)[CH2:8]3)[CH2:5]1)=[O:2].CC1C=CC(S(O)(=O)=[O:40])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][C:19](=[O:40])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH2:5]1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)CC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate (2.50 g) and pTSA.H2O (6.05 g) in acetone (150 mL) was stirred at room temperature for 1.5 h. The solution was neutralized by addition of 5% aqueous NaHCO3, and acetone was evaporated. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/acetone/CH2Cl2 70/15/15) to give the title compound II-aa as a white solid (1.66 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.09 (ddd, 1H), 2.60-0.95 (m, 17H), 1.25 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[CH:8]=1)=[O:6].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[CH:16]=[CH:15]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(Oc3ncnc4cc(OC)c(OC)cc34)ccc2c1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a stirred mixture of NaH (200 mg, 60% in mineral oil, 5.0 mmol, Aldrich) in 10 mL of DMF at RT was added 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (Step a, 675 mg, 3.34 mmol). After 20 min, 4-chloro-6,7-dimethoxy-quinazoline (750 mg, 3.34 mmol, Oakwood) was added and the reaction was heated to 60° C. for 20 min. The reaction was cooled to RT, quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with CHCl3 (30 mL). The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (30% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 390.9 (M+1). Mass Calc'd for C22H18N2O5: 390.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([NH:19][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (150 mg), pyridine (84 μL) and dichloromethane (3 mL) was added benzoyl chloride (72 μL) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained residue was solidified from a mixed solvent of hexane and ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}benzamide (166 mg) as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:26][CH:27]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(c1ccc(C(=O)OC(C)(C)C)cc1)c1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(c1ccc(C(=O)O)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[1-(1,3-benzoxazol-2-yl)-2-methoxy-2-oxoethyl]benzoate (90 mg, 0.25 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (0.5 mL) and the solution was stirred at ambient temperature for 1 hour. The reaction was evaporated to dryness to give the title compound as a clear oil. ESIMS calcd 312.1 (M++H), found 312.0 (M++M).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+].Cl>O1CCCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCCC[C@@H]2O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
10.0 g of (±)-2-[4-(2-oxocyclohexylmethyl)phenyl]propionic acid were dissolved in 150 ml of tetrahydrofuran. The solution was cooled to -78° C. and, whilst maintaining the solution at this temperature and under a stream of nitrogen, 200 ml of K-Selectride (as a 0.5 molar tetrahydrofuran solution) were added dropwise. When the whole of the K-Selectride had been added, the reaction mixture was stirred for 1 hour at 0° C., after which it was cooled to -10° C. and 400 ml of a 0.5N solution of hydrochloric acid was added through a dropping funnel. The reaction mixture was stirred for 1 hour, after which it was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off, giving 10.5 g of the title compound in the form of crystals. These were recrystallised from a mixture of diethyl ether and hexane, giving the title compound as pure crystals melting at 130°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), Cul (0.02eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.