Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[C:10]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.O.O.[Rh](Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#CCc1ccncc1
Agent: Cl[Rh](Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C#N)c1ccncc1
Yield: 313.5 %

Procedure:
4-Pyridylacetonitrile (5.6 g, 47.46 mmol) dissolved in ethanol (70 ml) was heated under reflux with rhodium chloride trihydrate (624 mg, 2.37 mmol), triphenylphosphine (3.11 g, 11.87 mmol) and anhydrous sodium carbonate (5.534 g, 52.2 mmol) for 20 hours, filtered and concentrated. Elution from a column (4.5, 35 cm) of silica gel (Merck 7734) with CHCl3 afforded a pure fraction of 2-(4-pyridyl)butyronitrile (5.44 g, 78.5% yield). This was taken up in t-butanol (15 ml) and stirred with `Triton B` (0.2 ml) and acrylonitrile (2.5 ml, 58 mmol) for 2 hours. Excess solvent was evaporated and the residue was diluted with water (200 ml). Extraction from CHCl3 (2×100 ml) afforded impure 2-ethyl-2-(4-pyridyl)butyronitrile which was heated under reflux with a mixture of glacial acetic acid (30 ml) and concentrated sulphuric acid (6 ml) for 3 hours and poured onto ice water. Sodium hydrogen carbonate was added to neutralise the solution, to pH 7-7.5 and the solution was then extracted with CHCl3. Column chromatography (3×20 cm, silica gel, CHCl3 :MeOH 19:1 v/v) of the crude product afforded a pure fraction of the title compound, (3.29 g), in a 40.2% yield based on 2-(4-pyridyl)butyronitrile. The title compound was crystallised from toluene, m.p. 138-139° (corrected).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>O.[NH4+].[OH-].C1COCC1.S([O-])([O-])(=O)=O.[Fe+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[CH:12]\[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])/[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)/C(=C/c1ccccc1[N+](=O)[O-])c1ccc(Br)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1/C=C(/C(=O)O)c1ccc(Br)cc1

Procedure:
506 g (1.8 mol) of iron (II) sulfate are initially introduced in 475 ml of water and 1000 ml of 25% NH4OH solution and heated to the boil. 79.3 g (228 mmol) of (E)-2-(4-bromophenyl)-3-(2-nitrophenyl)acrylic acid in a mixture of 150 ml of 10% NH4OH solution and 200 ml of THF are added dropwise over the course of 30 min, and the mixture is heated at the boil for a further 30 min. The reaction mixture is filtered hot through Celite, washed with warm 10% NH4OH solution and neutralised using acetic acid, and the resultant solid is filtered off with suction, washed with water and MeOH and dried. Yield of yellow, felt-like crystals: 52 g (72.3%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:34](OC)=[O:35])[CH2:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:38][OH:39]>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:15][CH:16]([CH2:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:34]([NH:38][OH:39])=[O:35])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: NO
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCc1ccccc1)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.2 %

Procedure:
To a solution of the title compound of Example 16b (440 mg, 0.81 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added NH2OH (50% aqueous solution, 0.74 mL, 12 mmol). After stirring for 20 hours at room temperature, the solution was concentrated. Purification by flash chromatography (5:95 MeOH/CHCl3) yielded the title compound as a white solid (80 mg, 18%): Anal. Calcd. for C25H25N3O7S2.0.25 H2O: C, 54.78; H, 4.69; N, 7.67; S, 11.70. Found: C, 54.78; H, 4.72; N, 7.46; S, 11.53.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.C1(C)C=CC=CC=1.C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg) were added 4-fluorophenyl borate (272 mg), potassium carbonate (537 mg), water (1.5 ml), ethanol (1.5 ml) and toluene (15 ml). Under argon atmosphere, the mixture was stirred at room temperature for 1 hour, and to the mixture was added tetrakistriphenyl-phosphine palladium (61 mg, 3 mol %). Under argon atmosphere, the mixture was refluxed for 21 hours, and to the mixture was added ethyl acetate (100 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography to give methyl 7-(4-fluoro-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (310 mg, 59%) as pale yellow crystals.
Reaction SMILES: [C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2].[F:25][C:26]1[C:27](I)=[C:28]([NH2:32])[CH:29]=[N:30][CH:31]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:28]1[CH:29]=[N:30][CH:31]=[C:26]([F:25])[C:27]=1[C:2]#[C:1][C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Reactant: Nc1cncc(F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2c(N)cncc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 166.9 %

Procedure:
tert-Butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate (2.75 g, 7.73 mmol), 5-fluoro-4-iodopyridin-3-amine (1.84 g, 7.73 mmol), bis(triphenylphosphine)palladium(II) chloride (0.380 g, 0.541 mmol), triethylamine (32.3 mL, 232 mmol), and copper(I) iodide (0.147 g, 0.773 mmol) were heated at 70° C. for 2 hours. The reaction was quenched with saturated aqueous KH2PO4 and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (330 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (2.20 g, 12.9 mmol, 42% yield) as a viscous oil, MS (ESI): m/z=466.45 (MH+); 68% pure by LCMS, remainder is un-reacted 5-fluoro-4-iodopyridin-3-amine, taken onto next reaction as mixture.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:10].Cl.[CH2:12]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]1)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: SCCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCNC(O)=[SH]CCCN1CCN(CC=Cc2ccccc2)CC1
Yield: 64.2 %

Procedure:
The procedure described in Example 2 was followed, using 0.4 g of n-hexyl isocyanate, 1.0 g of 3-(4-cinnamylpiperazin-1-yl)propanethiol dihydrochloride, 0.6 g of triethylamine and 50 ml of methylene chloride, to give 0.44 g (31% of theory) of N-(n-hexyl)-S-[3-(4-cinnamylpiperazin-1-yl)propyl]thiocarbamate dihydrochloride as a white crystalline solid, M.p. 251°-253° C.
Reaction SMILES: [CH:1]#[C:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC[C@@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (R)-(+)-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (R)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 91 mg, 62%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:18]=[C:13]3[CH2:14][O:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:19]2[C:24]([CH:25]=[O:26])=[C:23]([N:27]3[CH2:38][CH2:37][N:36]4[C:29](=[CH:30][C:31]5[CH2:32][C:33]([CH3:40])([CH3:39])[CH2:34][C:35]=54)[C:28]3=[O:41])[N:22]=[CH:21][CH:20]=2)=[CH:3]1.[BH4-].[Na+]>CO>[N:11]1[N:12]2[C:13]([CH2:14][O:15][CH2:16][CH2:17]2)=[CH:18][C:10]=1[NH:9][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][N:22]=[C:23]([N:27]3[CH2:38][CH2:37][N:36]4[C:35]5[CH2:34][C:33]([CH3:40])([CH3:39])[CH2:32][C:31]=5[CH:30]=[C:29]4[C:28]3=[O:41])[C:24]=2[CH2:25][OH:26])[CH:5]=1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2cc3n(n2)CCOC3)c1=O
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
To a suspension of 168b (200 mg, 0.36 mmol) at 0° C. in methanol (10 mL) was added sodium borohydride (42 mg, 1.1 mmol). The reaction mixture was stirred for 30 minutes and quenched with water (2 mL). It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 168 (53 mg, 21%) as a yellow solid. MS-ESI: [M+H]+ 556.6. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=5.2 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.33 (d, J=5.2 Hz, 1H), 6.83 (s, 1H), 5.71 (s, 1H), 5.04-5.01 (m, 1H), 4.78 (s, 2H), 4.64-4.62 (m, 1H), 4.49 (d, J=2.8 Hz, 1H), 4.32-4.28 (m, 1H), 4.14 (d, J=4.4 Hz, 2H), 4.09-4.08 (m, 4H), 3.87-3.83 (m, 1H), 3.70 (s, 3H), 2.56 (d, J=2.8 Hz, 2H), 2.50 (s, 2H), 1.26 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38](Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH3:46]>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: COc1ccccc1N=C(Cl)c1ccccc1OC
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3OC)n(-c3ccccc3OC)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-methoxyphenyl)-2-methoxy-benzimidoyl chloride (1.2 g, 4.1%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12.C(N(CC)CC)C.NC(N)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>CC(C)=O>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12)=[O:44]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Agent: NC(N)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g. of p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 30 ml. of acetone containing 364 mg. (0.5 ml., 3.6 mmole) of triethylamine was added 962 mg. of urea. With stirring at room temperature, a solution of 730 mg. (4.4 mmole) of 2-thiophene acetyl chloride in 20 ml. of acetone was added dropwise to the mixture. After 2.5 hours the reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and the solution was washed successively with water, a 5% solution of sodium bicarbonate, 5% hydrochloric acid, and a saturated solution of sodium chloride. The washed solution was dried and then was concentrated by evaporation in vacuo to yield 1.2 g. of the reaction product as a crystalline residue. The product was recrystallized from ethyl acetate to yield pure p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate having the following spectral properties.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]3[C:17]=1[C:16](C(O)=O)=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]3=[C:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)[C:27]=2[CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]3[C:17]=1[CH:16]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]3=[C:26]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:35]=1)[C:27]=2[CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(=O)O)c2c(OCc3ccccc3)ccc3c(CC)c(-c4ccc(OCc5ccccc5)cc4)c1n32
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)c1cc2c(OCc3ccccc3)ccc3c(CC)c(-c4ccc(OCc5ccccc5)cc4)c1n23
Temperature: 170 °C

Procedure:
7-Benzyloxy-3-(4-benzyloxyphenyl)-2-ethoxycarbonyl-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid (21.63 g, 38 mmol) was dissolved in 220 ml of quinoline under a nitrogen atmosphere. Copper powder (3.35 g, 50 mmol) was added and the mixture was heated to 170° C. for 21/2 hour. The reaction mixture was filtered when hot, and the filtrate was flash chromatographed over silica gel 60, using toluene: petroleum ether (1:1) as the eluent. Fractions containing the product were combined and added 300 ml of water was added and the pH was adjusted to 2 with 6N hydrochloric acid. The organic material was extracted into 3×300 ml of dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using toluene:petroleum ether (1:1) as the eluent. The crude product was crystallised from hot toluene and petroleum ether. This gave 15.90 g (79%) of ethyl 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-2-carboxylate as yellow crystals. M.p. 114-116° C. MS(SP): m/z 529 (M+). 1H-NMR (DMSO-d6, 300 MHz) δ: 0.92 (t, 3H); 1.28 (t, 3H); 2.93 (q, 2H); 4.00 (q, 2H); 5.19 (s, 2H); 5.61 (s, 2H); 7.12 (d, 2H); 7.32-7.53 (m, 11H); 7.59 (d, 2H); 7.74 (s, 1H); 8.16 (d, 1H).
Reaction SMILES: [NH3:1].[C:2]([O:6][CH3:7])(=[O:5])[CH:3]=[CH2:4]>>[CH3:7][O:6][C:2]([CH2:3][CH2:4][N:1]([CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5])[CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5])=[O:5]
Reactant: C=CC(=O)OC
Reactant: N
Product: COC(=O)CCN(CCC(=O)OC)CCC(=O)OC
Temperature: 0 °C
Yield: 76 %

Procedure:
While vigorously stirring at 0° C., 5.00 g of 28% aqueous ammonia was added to 21.2 g of methyl acrylate. The resulting mixture was heated gradually to 25° C. over 20 hours. After concentration under reduced pressure, the residue was purified by distillation under reduced pressure, whereby tris(2-methoxycarbonylethyl)amine was obtained (boiling point: 143° C./70 Pa, yield: 76%),
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:31])[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:19]3[CH:18]=[C:17]([CH3:31])[CH:22]=[CH:21][CH:20]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][NH:13][CH3:14]>O1CCCC1>[CH3:12][N:13]([CH3:14])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:10]
Reactant: CC(=O)c1ccc(C(=O)Cl)o1
Reactant: CNC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)N(C)C)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 9.1 g. (0.053 mole) of 5-acetylfuran-2-carbonyl chloride in 150 ml. of tetrahydrofuran at ca -30° C. was added, dropwise, 7.0 ml. (0.106 mole) of dimethylamine. Stirring was continued, and the reaction mixture was allowed to warm to room temperature and then stirred overnight. The tetrahydrofuran was removed by evaporation in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 1:20 methanol-chloroform, to give 7.33 g. of the title compound as a solid, mp 101°-104° C. A small sample was recrystallized from cyclohexane to give a pale yellow solid, mp. 104°-106° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CS(C)=O.CCOC(C)=O>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.68 g, 7.63 mmol) in dimethylsulfoxide (25 mL) under argon was added cesium carbonate (2.73 g, 8.39 mmol), followed by 4-aminophenol (0.874 g, 8.01 mmol). The reaction was stirred at 80° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with water; the aqueous layer was back-extracted with EtOAc (1×). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 50% EtOAc/Hexanes) afforded 1-(4-(2-(4-aminophenoxy)-pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a tan solid. MS (ESI, pos. ion) m/z: 310.0 (M+1).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[S:15].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[NH2:16][C:14]1[S:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[N:13]=1
Reactant: NC(=S)Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1nc2c(Cl)cccc2s1
Temperature: 20 °C

Procedure:
210 Parts of sulfuryl chloride were added within about 2 hours at a temperature of 35°-40° C. to a stirred mixture of 186.5 parts of 2-chlorophenylthiourea, 500 parts of toluene, 300 parts of chlorobenzene and 11 parts of sodium carbonate. The gas development being terminated, 250 parts of water were added, the solvent mixture was distilled off with steam, and the remaining aqueous phase was combined with 500 parts of 30% hydrochloric acid. Filtration from the undissolved matter was carried out at about 90° C., the filtrate was cooled to about 20° C., and the free amine was precipitated from the 2-amino-4-chlorobenzothiazole dissolved as hydrochloride by adding excess sodium hydroxide solution until a final pH of 8.5-9.0 was adjusted. The product was suction-filtered, washed to neutral with water, and dried. 170 Parts of 2-amino-4-chlorobenzothiazole having a melting point of 199°-200° C. (92.4% of th.) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[O:28][N:27]=[C:26]([C:29]([O:31]CC)=[O:30])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[O:28][N:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: CCOC(=O)c1cc(-c2ccc3nnc(CNc4ccnc5cc(OC)cnc45)n3n2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C(=O)O)no5)nn34)ccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate (0.045 g, 0.10 mmol) in methanol (1 mL) and water (0.5 mL) was added sodium hydroxide (6M, 0.050 ml, 0.30 mmol). The mixture was stirred at 50° C. for two hours, then was concentrated and diluted with water (2 mL). 2M HCL was added dropwise until precipitation was observed, the tan solid was collected by filtration. The solid was taken up in isopropanol and heated to 100° C. The resulting suspension was cooled to room temperature and filtered to yield the product as a tan solid. MS m/z=418.6 [M+1]+. Calc'd for C19H14N8O4: 418.1.