Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:42](=[O:43])[CH2:41][CH2:40][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc4c(c3)C(=O)OC(C)(C)O4)C(=O)CCC3CCCC3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using 6-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a colorless oil (72%). 1H NMR (CDCl3, 300 MHz) δ 7.74 (m, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 7.35-7.21 (m, 1H), 7.20-6.85 (m, 5H), 4.56 (m, 2H), 4.52-4.40 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.42 (m, 2H), 1.80-1.62 (m, 11H), 1.61-1.30 (m, 8H). 1.18-1.00 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). HPLC, Rt: 6.11 min (Purity; 98.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:26][N:25]([CH2:23][CH3:24])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Reactant: CCNN
Product: CCc1nn(CC)c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-1,3,5-triethyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and ethylhydrazine in analogy to Example 55 b): off-white solid; MS (ISP): 323.3 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[NH:8][CH2:7][CH2:6][C:5]2=1.CCN(CC)CC.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1COCC1>[C:29]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c([nH]c3ccc(C)cc23)C1c1cccc(O)c1
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and acetic anhydride (1.2 equiv). After one hour, the solution was purified by prep-HPLC to give 3-(2-acetyl-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 1.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[CH:17]=[N:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:28][CH3:29]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:28]([N:14]1[C:13](=[O:22])[N:12]2[C:20]3[N:19]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=4)=[CH:10][CH2:11]2)[N:18]=[CH:17][C:16]=3[C:15]1=[O:21])[CH3:29]
Reactant: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cnn3c2n(c1=O)CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5.0 g of 8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylene-3,5(4H)-dione (prepared as described in Example 14) in 50 ml of dry N,N-dimethylformamide, under nitrogen, is added 800 mg of 60 percent sodium hydride (dispersion in mineral oil). The mixture is stirred at room temperature for 2 hours, then 10 ml of iodoethane is added and stirring is continued for 48 hours. The reaction mixture is evaporated to dryness, then treated with water, and the gummy solid which is isolated is dissolved in chloroform and the extract dried over anhydrous sodium sulfate. Evaporation gives an oil which is triturated with diethyl ether-hexane to provide a yellow solid which is collected by filtration to give 2.0 g of the desired product as a white solid. The product is recrystallized from isopropyl alcohol, mp 161-163° C.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:60]2[CH2:59][CH2:58][CH:57]([N:54]3[CH2:53][CH2:52][N:51]([CH3:50])[CH2:56][CH2:55]3)[CH2:62][CH2:61]2)=[O:11])[CH:24]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (73.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (60.1 mg, 95%).
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][OH:21]>O>[OH:21][CH2:20][CH2:19][CH2:18][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Cc1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
1-(4-Hydroxyphenyl)propan-2-one ethylene ketal (3.88 g) was added to a solution of sodium hydroxide (1.5 g) in water (30 ml) and the mixture was stirred at room temperature for 30 minutes. 1-Bromo-3-hydroxypropane (2.98 g) was added and the mixture was boiled under reflux with stirring for 11/2 hours. After cooling water (50 ml) was added, the mixture was extracted with ether, the extracts dried (MgSO4) and evaporated to give the title compound (3.94 g) as its ethylene ketal.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.9 %

Procedure:
A solution of boron tribromide in dichloromethane (1N, 24.8 ml) was added to a solution of methyl 3′-methoxybiphenyl-4-carboxylate (2.00 g) in anhydrous dichloromethane (10 ml) at −70° C. The mixture was stirred at ambient temperature for 4 hours and a mixture of ice and water was added to the reaction mixture in an ice bath and then the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of hexane and diisopropyl ether to afford the title compound (1.82 g) as pale yellow crystals.
Reaction SMILES: [C:1]12([CH:9]3[CH2:10][CH2:11][CH:6]1[C:7](=[O:12])[CH2:8]3)[CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)(=[O:15])C>>[C:1]12([CH:6]3[CH2:11][CH2:10][CH:9]1[C:8](=[O:15])[C:7]3=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]2
Reactant: O=C1CC2CCC1C21CCCC1
Reactant: CC(=O)O
Product: O=C1C(=O)C2CCC1C21CCCC1
Temperature: 120 °C

Procedure:
As described in Example 1 Step B]: from spiro[bicyclo[2.2.1]heptane-7,1′-cyclopentan]-2-one, 1.05 g, SeO2 (1.56 g) in acetic acid (5 ml) on heating at 120° C. for 12 h, purification crude product by flash chromatography (heptane/AcOEt 100-90%, there was obtained spiro[bicyclo[2.2.1]heptane-7,1′-cyclopentane]-2,3-dione (0.88 g) as yellow solid. MS (ESI): 196.2 (M+NH4)+.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7]([O:11][C:12]([NH:14][CH:15](P(OC)(OC)=O)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([NH:14]/[C:15](=[CH:1]\[C:2]([CH3:5])([CH3:4])[CH3:3])/[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 96 h

Procedure:
Pivalaldehyde (303.2 g, 3.41 mol, 10 eq.) and methyl {[(tert-butoxy)carbonyl]amino}-(dimethoxyphosphoryl)acetate (101.5 g, 0.341 mol, 1.0 eq.) are dissolved in THF (800 ml) and cooled to −70° C. At −70° C., TMG (78.7 g, 0.683 mmol, 6.95 ml, 2.0 eq.) is slowly added dropwise and the mixture is then stirred at −70° C. for 4 h and subsequently at RT for 4 days. The reaction mixture is concentrated and then extracted by shaking with ethyl acetate (twice 500 ml) and water, and the combined org. phases are washed with a sat. sodium chloride solution (100 ml) and dried over sodium sulfate. After concentration the crude product is chromatographed (1.5 kg of silica gel, eluent: cyclohexane/ethyl acetate 5:1). 67 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([O:18][C:19]([O:21]C2C=CC=CC=2)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].C(O)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:33][C:19](=[O:21])[O:18][C:9]=2[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(F)cc1

Procedure:
A mixture of ethyl 6-(4-fluorophenyl)-6-oxo-5-phenoxycarbonyloxyhexanoate (18.0 g), ammonium acetate (17.8 g) and acetic acid (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (200 ml×2), and the extract was washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 4-[4-(4-fluorophenyl)-2-oxo-4-oxazolin-5-yl]butanoate was obtained as an oil (7.67 g, 56%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[CH:7]=1.OS(O)(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[C:7]=1[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=2)[NH:23][CH:22]=1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: COc1ccc2[nH]ccc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(C3=C(Cl)C(=O)C=C(Cl)C3=O)c2c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of 2,5-dichloro-1,4-benzoquinone (0.242 g, 1.37 mmol) in THF (3 mL) was added H2SO4 (35 μL, 0.68 mmol) at room temperature. To this mixture was added 5-methoxyindole (0.100 g, 0.68 mmol). After the reaction mixture was stirred for 1 hour at room temperature under nitrogen protection, DDQ (0.232 g, 1.02 mmol) was added. After stirring for 2 hours, the mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford 2,5-dichloro-3-(5-methoxy-1H-indole-3-yl)-[1,4]benzoquinone (0.211 g, 96%) as blue needles from benzene/hexane. Melting Point 195–196° C. 1H NMR (CDCl3): 6.78 (1H, d, J=2.4 Hz), 6.93 (1H, dd, J=2.1, 8.4 Hz), 7.23 (1H, s), 7.34 (1H, d, J=9.0 Hz), 7.54 (1H, d, J=3.0 Hz), 8.62 (1H, br s). 13C NMR (d6-acetone): 55.2, 103.8, 106.7, 112.4, 112.8, 126.5, 130.9, 131.0, 131.4, 133.4, 139.8, 143.7, 154.8, 177.8, 178.0. IR (KBr): 3328, 3043, 2924, 2855, 1675, 1638, 1543, 1484, 1260, 1227 cm−1. Anal. Calcd. for C15H9Cl2NO3: C, 55.93; H, 2.82; N, 4.35. Found: C, 55.72; H, 2.99; N, 4.24.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:26][CH3:25])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CN
Product: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and methylamine (2M in THF).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)=[O:29])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(SCC2COC(c3ccccc3)=N2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CC1COC(c2ccccc2)=N1)c1ccc(O)cc1

Procedure:
To a solution of 2.85 q (10.0 mm) of the sulfide prepared in Example 1 in 50 ml methylenechloride at 25° C. was added 2.1 g (12 mm) of 90% MCPBA. Small portions of MCPBA were added until conversion was completed as indicated by thin layer chromatography. The soution was poured into 50 ml methylenechloride, washed with 100 ml NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give crude title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:13]2[C:8](=[N:9][C:10]([N:24](C(OC(C)(C)C)=O)[NH:25][C:26](OC(C)(C)C)=O)=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:40]C(O)=O>>[CH3:40][C:26]1[N:9]2[C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:14]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:16])=[O:17])[C:13]=3[CH:12]=[CH:11][C:10]2=[N:24][N:25]=1
Reactant: CCOC(=O)c1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Product: CCOC(=O)c1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 180 °C
Yield: 74 %

Procedure:
A solution of di-tert-butyl 1-[2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (2.5 g, 4.4 mmol, from Step 2) in AcOH (40 mL) was split into 5 batches and each was heated in the microwave to a temperature of 180° C. for 3 minutes. The reaction contents were pooled and AcOH was removed in vacuo. The residue was dissolved in EtOAc and washed with sat′d NaHCO3 solution, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-100% EtOAc in hexanes, followed by 10% MeOH in DCM as mobile phase afforded solid product (1.27 g, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[ClH:24]>O1CCOCC1>[ClH:24].[NH:15]1[CH2:16][CH:13]([CH2:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(CS(=O)(=O)c2ccc(C#N)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(S(=O)(=O)CC2CNC2)cc1
Reaction time: 0.17 h

Procedure:
The foregoing tert-butyl 3-{[(4-cyanophenyl)sulfonyl]methyl}azetidine-1-carboxylate (200 mg, 0.59 mmol) was treated with 4N HCl in 1,4-dioxane and stirred for 10 minutes. The reaction was evaporated without heat to give the title compound crude as a white solid (100 mg). 1H NMR (500 MHz, CDCl3) δ 2.99–3.05 (1H, m), 3.78 (2H, t, J=7.8 Hz), 3.86–3.94 (4H, m), 8.08 (2H, d, J=8.6 Hz), 8.20 (2H, d, J=8.6 Hz), 8.95 (2H, br s).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]=[C:15]([CH2:21][CH3:22])[C:14]=1[C:23](OC)=[O:24].[Na]>C(O)C>[CH2:21]([C:15]1[N:16]=[C:17]([CH2:19][CH3:20])[CH:18]=[C:13]2[C:14]=1[C:23]([OH:24])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:3](=[O:5])[NH:12]2)[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCc1cc(N)c(C(=O)OC)c(CC)n1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Temperature: 150 °C

Procedure:
Diethyl malonate (14.5 ml) and methyl 4-amino-2,6-diethylpyridine-3-carboxylate (21.3 g) was added to a solution of sodium (2.33 g) in ethanol (60 ml) and the resulting mixture was heated at 150° C. for 20 hours in an autoclave. The mixture was allowed to cool and then volatile material was removed by evaporation and the resultant semi-crystalline solid was triturated with ether. The solid was collected by filtration and dissolved in a minimum of water. The solution as acidified with 2M hydrochloric acid and the resulting precipitate was collected by filtration and washed with water. The solid was dried under vacuum to give ethyl 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate (B) (12.72 g); m.p. 240-242° C.; NMR (CDCl3): 1.34(dt, 6H), 1.52(t, 3H), 2.84(q, 2H), 3.36(q, 2H), 4.52(q, 2H), 6.87(s, 1H), 7.26(s, 1H), 11.41(broad, 1H); mass spectrum (CI, ammonia): 291 (M+H)+ ; microanalysis, found: C, 62.1; H, 6.2; N, 9.7%; C15H18N2O4 requires: C, 62.1; H, 6.3; N, 9.7%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[O:6]=[C:7]1[C:16](=[O:17])[NH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=2)[NH:8]1.C(O)(=O)C>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:6])[C:16](=[O:17])[NH:15]2)(=[O:19])=[O:20]
Reactant: COCCN
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: COCCNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 7.51 g (0.1 mole) of 2-methoxyethylamine in 20 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added in small portions, under stirring, and the mixture is stirred at room temperature for 16 hours. It is allowed to stand further for 2 days, and then 15 ml of acetic acid and 10 ml of water are added to it. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.80 g (63%) of 1,2,3,4-tetra-hydro-N-(2-methoxy-ethyl)-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 264-267° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:54])[C:35]([CH3:53])([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[C:39]([O:44][CH3:45])[CH:38]=1)C>C(O)C>[CH3:45][O:44][C:39]1[CH:38]=[C:37]([CH2:36][C:35]([CH3:53])([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:34]([OH:54])=[O:33])[CH:42]=[CH:41][C:40]=1[O:20][CH2:19][CH2:18][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3cccs3)cc2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.132 mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester(see Ex. 7, Part D) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to provide analytically pure material. MS (EI) 570.4 (M+H)+.
Reaction SMILES: [Li]C.C[Si](C)(C)[O:5][C:6]([CH3:8])=[CH2:7].[CH2:11]([Si:14]1(Cl)[O:18][C@@H:17]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[C@H:16]([C:24]([CH3:28])([O:26][CH3:27])[CH3:25])[O:15]1)[CH:12]=[CH2:13]>CCCCC>[CH2:11]([Si:14]1([O:5][C:6]([CH3:8])=[CH2:7])[O:18][C@@H:17]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[C@H:16]([C:24]([CH3:28])([O:26][CH3:27])[CH3:25])[O:15]1)[CH:12]=[CH2:13]
Reactant: C=C(C)O[Si](C)(C)C
Reactant: C=CC[Si]1(Cl)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Agent: [Li]C
Solvent: CCCCC
Product: C=CC[Si]1(OC(=C)C)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a cooled (0° C.) solution of MeLi (13.0 mL; 21 mmol; 1.6 M in Et2O) was added 2-(trimethylsilyloxy)propene (2.8 g; 21 mmol). The solution was stirred 30 minutes at 0° C., and then warmed to room temperature and was stirred for 1 hour. The mixture was recooled to 0° C., and (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane (6.6 g; 21 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours. The solution was diluted with pentane (20 mL), and the mixture was then filtered through a pad of celite. The filtrate was concentrated, and the residue was distilled under reduced pressure to give 3.0 g (43%) of (4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane as a clear, colorless liquid.