Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].C1(C)C(C)=CC=CC=1.Cl[C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1>C(O)(=O)C>[CH2:1]([O:15][C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Reaction time: 2 h

Procedure:
A mixture of 21.4 g (0.100 mole) of 1-tetradecanol, 5.9 g (0.146 mole) of sodium hydride (59.5% in oil) and 300 ml of dried xylene is heated to reflux with stirring for 2 hours then allowed to cool after which 7.5 g (0.046 mole ) of 5-chloro-2-thiophenecarboxylic acid is added. The mixture is refluxed for 64 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with acetic acid, and extracted with the addition of ether. The ether is evaporated and aqueous layer extracted 5 times with water: strong ammonia solution (1:1). The combined aqueous extract is acidified with acetic acid. The solid obtained is crystallized twice from hexane to give 5-(tetradecyloxy)-2-thiophene carboxylic acid, M.P. 95°-96° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C1C=CC=CC=1>CN(C)C=O>[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)Cl
Reaction time: 3 h

Procedure:
Thionyl chloride (7.24 g, 0.0608 mole) was added to a stirred solution of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-2-fluorophenoxy)propanoic acid (21.0 g, 0.0553 mole), benzene (150 ml), and dimethyl formamide (0.3 g). Refluxing was effected for three hours. The benzene and residual thionyl chloride were removed by distillation under vacuum. The resulting amber colored oil (21 g) was shown to be the desired acid chloride by NMR and IR spectroscopy. This material was used directly in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[CH2:10][C@H:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:45][C:46]1[N:50]2[C:51](=[O:60])[N:52]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH2:53][C:49]2=[CH:48][N:47]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[CH2:10][C@H:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([N:57]2[CH2:56][CH2:55][CH:54]([N:52]3[CH2:53][C:49]4=[CH:48][N:47]=[C:46]([CH3:45])[N:50]4[C:51]3=[O:60])[CH2:59][CH2:58]2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(C[C@@H](C(=O)O)C1CCCCC1)Nc1ccc(Cl)cc1
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@H](CC(=O)Nc3ccc(Cl)cc3)C3CCCCC3)CC1)C2
Yield: 29.1 %

Procedure:
To a solution of (2R)-4-((4-chlorophenyl)amino)-2-cyclohexyl-4-oxobutanoic acid (0.27 g) obtained in Example 5b) and HOBt (0.20 g) in acetonitrile (10 ml) was added WSC (0.25 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.26 g), DBU (0.27 g) and triethylamine (0.27 g) were added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=10/1), and the product was washed with ethyl acetate-hexane to obtain the title compound as colorless powder (0.13 g, 29%).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48])[CH3:38].CN(C)CCCN=C=NCC>ClCCl>[CH3:50][N:35]([CH3:34])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:24]1[CH2:25][C@H:26]2[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH2:20][S@@:21](=[O:27])[C@H:22]2[CH2:23]1)=[O:48])[CH3:38]
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: CC(CN(C)C)Oc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(CN(C)C)Oc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)[S@](=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to 0° C., of 1.06 g of (1R*, 4aR*, 7aR*) -(-) -4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.81 g of 2-[(3-dimethylamino-2-propoxy)phenyl]acetic acid in 60 cm3 of dry dichloromethane, followed by 0.77 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring for 2 hours at 0° C. and 20 hours at 20° C., the reaction mixture is washed with 20 cm3 of water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 35 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 50 cm3. Fractions 8 to 19 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide, dried over magnesium sulphate and then concentrated to dryness. The solid obtained is recrystallized from an ethyl acetate and ethyl ether mixture, the crystals are washed with diisopropyl oxide, drained and dried. 0.99 g of (1R*,4aR*,7aR*)-(-)-6-{2-[(3-dimethylamino2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 120° C. [α]D20 =-323° ; (c=0.5; acetic acid).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(N(CC)CC)C.[C:59](OC(=O)C)(=[O:61])[CH3:60]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:59]([CH3:60])=[O:61])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
Erythromycin A (50.0 g, 68.1 mmol) (commercially available from Abbott Laboratories) was dissolved in 600 mL of methylene chloride (CH2Cl2) at ambient temperature. Triethylamine (20 mL) and 10 mL (10.82 g, 106 mmol) of acetic anhydride were added to this solution. The reaction mixture was heated to reflux and 100 mL of CH2Cl2 was distilled from the reaction mixture to remove any traces of water. The reaction mixture was heated at reflux temperature for an additional five hours. After six hours, when the reaction was complete, according to TLC analysis, the reaction mixture was cooled to ambient temperature and transferred to a separatory funnel. The CH2Cl2 solution was washed with 300 mL of ammonium hydroxide/sodium bicarbonate solution containing 2.9% ammonia and 1.8% sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The CH2Cl2 was removed using a rotary evaporator with a water bath temperature of 30°-40° C. The residue was crystallized from 200 mL of acetonitrile (CH3CN) by first dissolving it in hot CH3CN and allowing the solution to stand overnight at ambient temperature, then cooling it to -25° C. and maintaining this temperature for 24 hours. The product was isolated as white crystals which were washed with cold (-25° C.) CH3CN and dried in a vacuum oven at 50° C. for approximately 64 hours. The 2'-O-acetylerythromycin A was obtained in 83% yield (43.91 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 74.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[Cl:5][CH:6]([CH2:11][CH3:12])[C:7](=O)[CH2:8][CH3:9].C(OCC)(=O)C>C(O)C>[ClH:5].[CH2:11]([C:6]1[N:1]=[CH:2][S:3][C:7]=1[CH2:8][CH3:9])[CH3:12]
Reactant: NC(N)=S
Reactant: CCC(=O)C(Cl)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ncsc1CC
Product: Cl
Yield: 67.1 %

Procedure:
Thiourea (21.8 g., 0.286 mole), 4-chloro-3-hexanone (34.4 g., 0.26 mole) and 200 ml. of ethanol were combined and heated to reflux for 19 hours. The reaction mixture was cooled and stripped of solvent to yield the crude product as a white solid. White crystals of 4,5-diethylthiazole hydrochloride (31 g., m.p. 154°-156° C.) were obtained by recrystallization from a mixture of ethyl acetate and ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:15]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Yield: 44.7 %

Procedure:
A mixture of N -(tert-butoxycarbonyl)-L-glutamine (4.92 g, 20 mmol) and carbonyl diimidazole (3.24 g, 20 mmol) in THF (100 mL) was refluxed for 16 h. Thereafter, solvent was removed and the crude product was recrystallized from hot EtOAc to give compound 203 (2.04 g, 45%) as white crystals: mp 214-215° C.; 1H NMR (DMSO-d6) δ 4.22 (dd, J=6.2 Hz, J=11.0 Hz, 1H), 2.77-2.65 (m, 1H), 2.45 (m, 1H), 1.96-1.87 (m, 2H), 1.40 (s, 9H); MS (CI/CH4) m/z 227 [M−1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[NH3:14]>CO>[CH3:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([C:8]([NH2:14])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1cc(=O)[nH]c(C)n1
Reactant: N
Solvent: CO
Product: Cc1nc(C(N)=O)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
Dissolve ethyl 2-methyl-6-oxo-1H-pyrimidine-4-carboxylate (7.26 g, 39.9 mmol) in a solution of ammonia in MeOH (70 mL, 7 N) and stir the mixture for 17 hours at ambient temperature. Remove the solvents under reduced pressure to provide the title compound as a black solid (5.7 g, 93.4%). MS (m/z): 154 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ncc(I)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(I)cnc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-iodopyrimidin-2-one (556 mg) and α-bromoacetophenone (533 mg) in triethylamine (0.5 ml) and ethanol (50 ml) was stirred at ambient temperature for 71/2 hours. The resulting solution was evaporated and the residue triturated with water. This product was purified by preparative thin-layer chromatography on silica before crystallisation from ethyl acetate to give the title pyrimidinone: yield 253 mg: m.p. 155°-157°: λmaxEtOH 238.5 nm (ε 23070), 340 nm (ε 2400), λinf 250 nm (ε 17160), 275 nm (ε 1780).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[I:18]N1C(=O)CCC1=O.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([I:18])=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: O=c1[nH]cnc2cc(-c3ccccc3Cl)nn12
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cnc2c(I)c(-c3ccccc3Cl)nn12
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a suspension of 7-(2-chlorophenyl)-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one (I-3A-9c; 2.59 g, 10.5 mmol) in chloroform (115 ml) cooled in an ice bath was added N-iodosuccinimide (2.36 g, 10.5 mmol), portionwise, over 15 minutes. After stirring for 3 hours, the reaction was added to stirring water and methylene chloride. A solution of saturated aqueous Na2S2O4 was added until the color remained light yellow. The solid precipitate that was dispersed in the aqueous phase was collected by vacuum filtration and then dried, in vacuo, to afford intermediate I-3A-9d as a solid (3.78 g, 97%): +APcI MS (M+1) 372.9; 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.55-7.40 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([NH2:14])=O)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[C:12]([CH:11]([CH3:15])[CH2:10][N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:22])([F:24])[F:23])[CH:5]=1)#[N:14]
Reactant: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(C#N)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 87 °C
Yield: 52.2 %

Procedure:
A mixture of 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanamide (0.044 mg, 0.12 mmol), CCl4 (1.5 mL), DCE (1.5 mL) and polymer-supported triphenyl phosphine (3 mmol/g, 0.089 g, 0.27 mmol) was heated at 87° C. for 2 h. Upon cooling, the resin was filtered off, washed thoroughly with CHCl3 and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% EtOAc-hexane gradient) and the product crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.021 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 4.31-4.10 (m, 2H), 3.79-3.68 (m, 2H), 3.10-3.01 (m, 1H), 1.41 (d, J=7.2 Hz, 3H); MS (ES) m/z 336 (M+1).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[NH2:12][C:13]([NH2:15])=[O:14].[CH2:16](OC(OCC)OCC)C>CO.CS(O)(=O)=O>[N:12]1[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH2:1][C:11]=2[CH:16]=[N:15][C:13]=1[OH:14]
Reactant: NC(N)=O
Reactant: CCOC(OCC)OCC
Reactant: O=C1CCCc2ccccc21
Agent: CS(=O)(=O)O
Solvent: CO
Product: Oc1ncc2c(n1)-c1ccccc1CC2
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A mixture of alpha-tetralone (60 g, 0.41 M), urea (27 g, 0.45 M), triethylorthoformate (68 ml, 0.41 M), in methanol (80 ml) to which was then added methanesulfonic acid (100 drops) was heated at 100° C. for 30 min. then at 130° C. for 1 hr while allowing some solvent to distill off. The resulting thick suspension was cooled slurried with acetone (100 ml) and the solids isolated via filtration washing with acetone (2×80 ml). The solid was dried under reduced pressure overnight to afford 1 as a yellow solid (42.1 g as a 1:1 urea complex, 35.6% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[C:10]([S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:11]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), 3-chloro-benzyl bromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.55 g, 1.1 mmoles).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](Br)=[CH:19][C:18]=1[C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:19][C:18]=1[C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
Potassium phosphate (0.1 g, 0.5 mmol) was added to a solution of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (0.14 g, 0.25 mmol) and phenyl boronic acid (0.095 g, 0.75 mmol) in 1 dioxan (4 ml) under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (cat.) was added and the suspension heated, 80° C. for ˜18 hrs. The suspension was allowed to cool and ethyl acetate (25 ml) added. The mixture was washed with water (3×25 ml) and saturated aqueous sodium chloride solution (25 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with hexane gave 5-(4,6-bis-benzyloxy-biphenyl-3-yl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole as an off-white solid, dried in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (96.2 mg, 0.706 mmol) and 3-chloro-4-methoxy-5-nitro-benzoyl chloride (194 mg, 0.777 mmol) were dissolved in dichloromethane (3 ml). Triethylamine (0.15 ml, 1.059 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:n-hexane=1:1. The fractions containing the product were collected and evaporated to obtain yellow solid (206 mg, 83.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[Cl-].[CH:21]([NH:24]C(C)C)([CH3:23])[CH3:22]>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 34A (1.0 g, 3.86 mmol) in CH2Cl2 (15 mL) was treated with one drop of DMF. Oxaly chloride (2.2 mL, 2M in CH2Cl2, 4.4 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 hour, and then concentrated to dryness. The crude acid chloride was dissolved in CH2Cl2 and cooled to 0° C. Diisopropylamine (600 mg, 10 mmol) in CH2Cl2 (2 mL) was added slowly and the resulting mixture was stirred for one hour at room temperature. The reaction was concentrated and partitioned between EtOAc (20 mL) and 1M HCl (20 mL). The organic layer was washed with 1 M HCl (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to a brown solid. The crude amide was recrystallized from EtOAc/heptane to afford 34B (740 mg, 64%).