Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])C.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([NH:8][CH2:7][CH2:6][C:5]([OH:4])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)CCNCc1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Ten grams of β-alanine ethyl ester hydrochloride and 9 g of benzaldehyde were added to 100 mL of toluene and heated and refluxed using a Dean-Stark trap. After heating and stirring for three hours, the product was cooled in air, and the reaction system was concentrated under reduced pressure. 200 mL of ethanol were added to the resulting residue, and 5 g of sodium borohydride were added while stirring under freezing conditions. After stirring over a period of one night, hydrochloric acid was added and the pH was brought to 2 or less. After filtering, the product was concentrated under reduced pressure, the resulting residue was dissolved in 200 mL THF-water, and 2 g of sodium hydroxide were added. After stirring for six hours at room temperature, the product was neutralized with Amberlite IR120B[H] and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized to obtain 8.2 g f the desired product (yield of 70%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOP(=O)(NC1CNCCC1C)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1C)OCC
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of diethyl 4-methylpiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes) to yield diethyl 4-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 52% yield. LCMS (m/z): 373.0 (MH+), Rt=1.93 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][OH:34])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][OH:34])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCO)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 4.3 %

Procedure:
With 750 mg of the compound obtained in Step 141-4 and 491 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 49 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2. [α]D25=−113° (c=0.150, CHCl3)
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.N1C=CC=CC=1.CN(C)[CH:18]=[O:19].C(OC(=O)C)=O>O>[CH:18]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: Nc1nc(CCl)cs1
Agent: CC(=O)OC=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=CNc1nc(CCl)cs1

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (2 g), anhydrous pyridine (3.2 g) and anhydrous N,N-dimethylformamide (10 ml) was slowly added acetic formic anhydride (1.7 g) with stirring at 0° to 5° C. After one hour of stirring, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and aqueous sodium chloride solution successively and dried over magnesium sulfate. The solvent was then distilled off and the residue was collected and dried to give 2-formylamino-4-chloromethylthiazole (0.94 g).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>C1C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]([OH:19])[CH2:18][NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccccc1C1CO1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC
Yield: 36.2 %

Procedure:
Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene oxide (10.1 g, 0.0753 mole) were stirred at 100° under argon for 16 hours and then diluted with benzene and hexane and cooled in ice. The solid which precipitated was filtered and recrystallized from benzene-hexane to give 8.6 g (36%) of 2-methyl-α-[N-(3,4-dimethoxyphenethyl)aminomethyl]benzyl alcohol, mp 91°-94°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH3:15])=[CH:4][N:3]=1
Reactant: COC(=O)C(C)Br
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cnc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 0.17 g of 2-chloro-5-hydroxypyrimidine, 0.22 g of methyl 2-bromopropionate, 0.20 g of anhydrous potassium carbonate and 2.6 ml of N,N-dimethylformamide was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, then, poured into water, and extracted with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[NH:13][CH:12]=1)=O.O.NN.[OH-].[K+].O>C(O)COCCO>[F:1][C:2]1[C:3]([CH2:9][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3cccs3)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Oc1cccc(Cc2c[nH]c3ncc(-c4cccs4)cc23)c1F

Procedure:
To (2-fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0521, 50.0 mg, 0.15 mmol) in diethylene glycol (5.0 mL) were added hydrazine hydrate (1.0 mL, 0.020 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated in a CEM Discovery microwave instrument at 180° C. for 20 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0052, 10 mg, 20%). MS (ESI) [M+H+]+=325.2.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[C:16]([CH2:21]Cl)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O>CS(C)=O>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:21][C:1]#[N:2])[C:15]=3[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nccc3c(CC#N)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Sodium cyanide (1.89 g) was dissolved in 100 ml of dimethylsulfoxide, and 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline was added. At room temperature, the mixture was stirred for 1 hour. After the reaction, the reaction mixture was poured into water, extracted with ether, washed in water, and dried. The solvent was distilled off. The residue was recrystallized from ether to afford 7 g of 1-(4-methylphenyl)isoquinoline-5-acetonitrile as prisms having a melting point of 101.7° to 102.1° C.
Reaction SMILES: Br.Br.[CH2:3]([N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][NH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.N12CCCN=C1CCCCC2>C(#N)C>[CH2:3]([N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][N:13]2[C:23]1[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:18]=1[F:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Yield: 96.7 %

Procedure:
A mixture of (1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptane dihydrobromide [Henry et al. J. Med. Chem. (1974), 17, 481] (1.05 g, 3 mmol), 3,4-difluoronitrobenzene (0.48 g, 3 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.38 g, 9 mmol) in acetonitrile (10 ml) was stirred and heated at reflux for 2 hours. Solvent was evaporated and the residue was partitioned between EtOAc and water. The organic layer was filtered (1PS paper) and the filtrate evaporated to give 4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene (0.95 g, 97%) as a solid. MS: 328 (M+); NMR(CDCl3); 1.82-2.07 (2H, dd); 2.77-2.98 (2H, dd); 3.59 (2H+1H, s); 3.72 (2H, s); 3.91 (1H, m); 4.58 (1H, s); 6.6 (1H, t); 7.2-7.34 (5H+CHCl3);
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1C
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1C

Procedure:
Step 4—Synthesis of compound vh: (S)-1-ethyl-3-(2-methyl-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.043 g, 0.10 mmol) and 2-Chloropyrimidine (0.0121 g, 0.106 mmol) were combined, nitrogen purged three times, added N,N-Dimethylformamide (1.50 mL, 19.4 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.7, 2H), 8.12-7.99 (m, 3H), 7.72 (s, 1H), 6.67 (dt, J=10.9, 5.0, 2H), 4.90 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.14 (dd, J=17.9, 5.1, 2H), 3.93-3.77 (m, 2H), 3.71 (dd, J=11.2, 2.5, 1H), 3.61 (d, J=12.1, 3H), 3.43 (dd, J=18.5, 7.5, 1H), 3.18-3.06 (m, 2H), 2.74 (s, 2H), 2.26 (s, 3H), 1.25 (d, J=6.6, 3H), 1.08 (t, J=7.2, 3H). LC/MS-m/z+489.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[N:16]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:21]=[CH:20][C:5]([O:6][C:7]3[C:12]4=[N:13][CH:14]=[C:15]([N:17]([CH3:18])[CH3:19])[N:16]=[C:11]4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:22])=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: CN(C)c1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-N,N-dimethylpyrido[3,2-b]pyrazin-3-amine and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to give the product as a light yellow solid. Yield: 65 mg (90%).
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]2[F:14])[N:6]=1)(=[O:4])=[O:3].C(O)C(O)C.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>O>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]2[F:14])[N:6]=1)(=[O:4])=[O:3]
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1ccccc1F
Solvent: O
Solvent: CC(O)CO
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3ccccc3F)nn12
Temperature: 5 °C

Procedure:
A mixture of 12.5 g (46.9 mmol) of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine and 25 mL of 1,2-propanediol was placed in a round bottom flask and cooled to 5° C. under nitrogen. 2-Fluoroaniline (13.7 g, 123 mmol) was added with stirring and cooling over a 10-min period. There was an exotherm. The mixture was allowed to warm to ambient temperature with stirring overnight and was then diluted with 30 mL of water. The mixture was stirred for 30 min and the solids present were then collected by filtration, washed with 2×25 mL of water and 2×25 mL of 2-propanol. The resulting solid was recrystallized from about 175 mL of 2-propanol and dried under reduced pressure at 45° C. to obtain 13.2 g (82.5 percent of theory) of the title compound as a white solid of 99 percent purity. The structure of this compound was confirmed by its proton nuclear magnetic resonance spectrum (300 MegaHertz, D-6 acetone): 9.70(s, 1H), 8.17(d, 1H, J=1.9 Hertz), 7.58(m, 1H), 7.24(m, 1H), 7.16(m, 2H), 4.29(s, 3H) and its C-13 carbon nuclear magnetic resonance spectrum (75 MegaHertz, D-6 acetone): 165.6, 156.8(d, J=244.8 Hertz), 149.1(d, J=26.1), 147.8, 145.7(d, J=252.9), 130.2(d, J=21.8), 128.5(d, J=4.1), 125(m), 116.7(d, J=19.7), 57.6.
Reaction SMILES: C([O:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])C.[Se](=O)=O.[O:16]1CCO[CH2:18][CH2:17]1>O.C(OCC)(=O)C>[CH2:17]([O:16][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:5]([CH:4]=[O:3])=[O:6])[CH3:18]
Reactant: C1COCCO1
Reactant: CCOCC(=O)c1ccccc1
Agent: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccccc1C(=O)C=O

Procedure:
2 g of 2-ethoxyacetophenone are dissolved in 20 ml of dioxane, and a solution of 2 g of selenium dioxide in one ml of water is added thereto. The solution is refluxed for 10 hours. After the reaction, insoluble materials are removed by filtration, and the filtrate is concentrated. The residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and then with an aqueous sodium bicarbonate solution and water. Then, said solution is dried and evaporated to remove solvent. 2.1 g of 2-ethoxyphenylglyoxal are obtained as a crude oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[C:23]1([C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:33][CH2:32]1)(=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: O=C(c1ccccc1)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with phenyl(piperazin-1-yl)methanone (1.2 equiv) to give 194 (M+1 486.0)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17]CC=C)=[CH:9][CH:8]=1)[CH3:2].C(O[C:28](=O)[CH:29](OCC)[CH2:30]C1C2C(=CC=CC=2)C(O)=CC=1)C.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:30][CH:29]=[CH2:28])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Reactant: C=CCOc1ccc(CC(OCC)C(=O)OCC)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Temperature: 160 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
0.87 g (2.65 mmol) [rac]-3-(4-allyloxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester [prepared from [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester (example 150 a] and allylbromide, potassium carbonate in acetone at 60° C.] was stirred for 2 hours at 160° C. without any solvent. The dark residue was purified by flash chromatography (silica gel, hexane/AcOEt=4:1) to yield 0.82 g (94%) of [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [OH:1][C:2]1([C:7]#[CH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25](I)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25]([C:8]#[C:7][C:2]2([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]2)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCNC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCNC4)c32)c1

Procedure:
Using Method C above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P)4Pd (15 mg) and CuI (3.0 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 5 h. (Yield 10 mg, 21%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][OH:8])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][O:8][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of the compound of Example 47 (900 mg, 2.28 mmol) and triethylamine (322 mg, 3.18 mmol) in DCM (20 mL) is cooled to 0° C. before methanesulfonyl chloride (313 mg, 2.73 mmol) is added. The mixture is stirred at rt for 90 min. The mixture is diluted with DCM and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (1.10 g) as a white solid; LC-MS: tR=1.16 min, [M+H]+=474.02.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH2:11])=[O:10])[C:5]=1[N+:12]([O-])=O)([CH3:3])[CH3:2].CO>[Ni].O>[NH2:12][C:5]1[C:6]([C:9]([NH2:11])=[O:10])=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)c1[nH]nc(C(N)=O)c1N
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of 5-isopropyl-4-nitropyrazol-3-carboxamide (2.57 g; 12.97 mmol), methanol (20 mL) and water (5 mL) was added 0.7 g Raney Ni (W5). The mixture was stirred under hydrogen atmosphere (760 torr) for four hours. The reaction mixture was filtered, the filtrate was concentrated to dryness in vacuo and the residue was recrystallized from ethyl acetate to yield 1.94 g (89%) of the product. The product was purified by chromatography on silica gel, the mixture of chloroform/methanol (97/3) was used as mobile phase. Yield 95%; mp=178-179° C.; MS (ES+): 169.1 (100%, M+H+). 1H NMR (CD3OD; 400 MHz): 1.31 d (6H; J=7.5 Hz), 3.06 sept (1H; J=7.5 Hz), 4.83 s (2H).
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][C:2](=[N:7][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3])[CH3:6]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(C)=NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
First, 15.5 g of ethyl acetimidate hydrochloride, 150 mL of toluene, and 31.9 g of triethylamine (Et3N) were put into a 500-mL three-neck flask and stirred at room temperature for 10 minutes. With a 50-mL dropping funnel, a mixed solution of 17.7 g of benzoyl chloride and 30 mL of toluene were added dropwise to this mixture, and the mixture was stirred at room temperature for 24 hours. After a predetermined time elapsed, the reaction mixture was suction-filtered, and the solid was washed with toluene. The obtained filtrate was concentrated to give N-(1-ethoxyethylidene)benzamide (a red oily substance, 82% yield). A scheme of the synthesis of Step 1 is shown below.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(=O)(O)[O-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
This ester was added in portions to a stirred mixture of 1500 mL of 1 N aqueous sodium bicarbonate and 500 mL of dichloromethane at 0-5° C., then 80 mL (97 g, 0.69 mol) of benzoyl chloride was added dropwise at 0-5° C., and the mixture was stirred at room temperature overnight. The phases were separated and the aqueous phase was extracted with dichloromethane (twice with 250 mL). The organic phases were combined, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with toluene to afford 112.98 g (90.7% from cis4-hydroxy-D-proline) of N-benzoyl-cis-4-hydroxy-D-proline methyl ester as a white powder.