Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[CH:14]([OH:19])[C:15](OC)=[O:16])[CH2:2][CH3:3].[NH2:34][C:35](N)=[O:36].C[O-].[Na+]>>[CH2:1]([C:4]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:14]2[O:19][C:35](=[O:36])[NH:34][C:15]2=[O:16])[CH:20]=[CH:21][CH:22]=1)[CH2:2][CH3:3]
Reactant: NC(N)=O
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(C(O)C(=O)OC)c1
Agent: C[O-]
Agent: [Na+]
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(C2OC(=O)NC2=O)c1

Procedure:
A solution of methyl 3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)mandelate (194 mg), urea (39 mg) and sodium methoxide (0.90 mL, 0.5 M) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil, which was chromatographed over silica gel with 3% of methanol in methylenechloride to afford the title compound.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([O:17][CH:18]([C:26]#[N:27])[C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][O:21][CH2:20]1)(=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[CH2:11]([C:10]12[O:16][CH2:20][C:19]([CH2:23][CH2:24][CH3:25])([CH2:22][O:21]1)[CH:18]([C:26]#[N:27])[O:17]2)[CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCC(=O)OC(C#N)C1(CCC)COC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCC12OCC(CCC)(CO1)C(C#N)O2
Temperature: 25 °C

Procedure:
Boron trifluoride etherate (0.25 ml) was added to a solution of 1-cyano-1-(3-propyloxetan-3-yl)methyl hex-5-ynoate (0.5 g) in dry dichloromethane (10 ml) stirred at -70° under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature overnight. Triethylamine (0.38 ml.) was added and the solvent was removed under vacuum. The residue was partitioned between water and diethyl ether. The organic phase was separated and washed with water and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. The residue was purified by column chromatography on alumina eluting with 1:4 dichloromethane:hexane saturated with ammonia. 1-(Pent-4-ynyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile was obtained as an oil (0.25 g). Gas-liquid chromatography (g.l.c): OV-17 at 175° produced one peak.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[C:53]1[N:57]([CH3:58])[N:56]=[CH:55][CH:54]=1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[C:53]2[N:57]([CH3:58])[N:56]=[CH:55][CH:54]=2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: OO.[NH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[CH:5][C:6]([NH2:8])=[S:7]>CO>[F:17][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[C:6]([NH2:8])[S:7][N:3]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(N)=CC(N)=S)cc1F
Agent: OO
Solvent: CO
Product: COc1ccc(-c2cc(N)sn2)cc1F
Temperature: 25 °C
Yield: 3.5 %

Procedure:
Add hydrogen peroxide (30% in water, 8.73 g, 257 mmol) to 3-amino-3-(3-fluoro-4-methoxyphenyl)-thioacrylamide (29.0 g, 128 mmol) in methanol (1,283 mL) and stir the reaction mixture at room temperature. Quench the reaction with Na2S2O3 (20% in water) and concentrate to dryness. Dilute with EtOAc (900 mL) and water (900 mL), collect the organic phase, and evaporate. Crystallize from EtOAc/hexanes to afford 3-(3-fluoro-4-methoxyphenyl)isothiazol-5-ylamine (1 g). Chromatography of the mother liquor (25 g) over silica gel, eluting with 25-50% EtOAc in hexane, affords additional product. [In one instance, a column loading accident led to loss of ½ of the material; but additional clean material was recovered from the chromatography (1 g).] Yield: 12.2%. ES-MS: m/e 225.0 (m+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[CH3:3][C:2]1([CH2:3][C:2]([CH3:1])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:1])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:2]([CH3:7])([C:1]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH2:3]1
Reactant: C=C(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CC1(C)CC(C)(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Yield: 46.6 %

Procedure:
To a four-necked 2000 ml-volume flask equipped with a stirring machine, a dropping funnel, a Dimroth condenser and a thermometer, there was added a solution of 300.4 g of α-methylstyrene in 1200 g of toluene, followed by setting the temperature thereof to 0° C. by dipping the flask in ice-water and gradual dropwise addition of 300 ml of a toluene solution containing a catalyst, i.e., 1.02 g AlCl3 -2.5 ml CH3NO3 to the contents of the flask with stirring. The reaction solution at the completion of the reaction-was colored pale yellow. After the completion of the reaction, water was gently dropwise added to the reaction system to thus decompose the catalyst. Then the organic phase was washed with water, dried and concentrated. Further the organic phase was subjected to vacuum distillation under a degree of vacuum of 670 Pa and at a temperature ranging from 218 to 221° C. to give 140.0 g of 1,3-dimethyl-3-phenyl-1-(2-methyl-2-phenylpropyl) indane (MPI).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Na].O[CH:30]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][O:31]1>CS(C)=O>[OH:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1/[CH:39]=[CH:30]/[CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: OC1Cc2ccccc2CO1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Product: O=C(O)CCCC/C=C/c1ccccc1CO
Reaction time: 1 h

Procedure:
To a solution of 60.2 g. of 4-carboxybutyltriphenylphosphonium bromide in 200 ml. of dimethylsulfoxide is added a solution of the sodium salt of dimethylsulfoxide. The solution is stirred for one hour and 6.8 g. of 3-hydroxyisochromane in 25 ml. of dimethylsulfoxide is added. The solution is stirred at room temperature for 40 hours and then poured into 1200 ml. of ice water and filtered. The filtrate is washed with ether-ethyl acetate (1:1) and acidified to pH2 with oxalic acid. The mixture is again filtered and the filtrate is extracted with ether-pentane (2:1). The extract is washed with brine, dried, concentrated, and the solid recrystallized from toluene to yield 7-(2-hydroxymethylphenyl)trans-6-heptenoic acid as white crystals having a melting point of 92°-94.5° C.
Reaction SMILES: CON(C)[C:4](=[O:39])[CH:5]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)=[CH:11][C:10]=1[Cl:30].[CH3:41][Mg+].[Br-].O>C1COCC1>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH:5]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:4](=[O:39])[CH3:41])=[C:10]([Cl:30])[CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The compound of Example 130-1 (570 mg) was dissolved in THF (15 mL). To this solution, a THF solution (2 mL) of 3 mol/L MeMgBr was added at 0° C. and the mixture was stirred for 3 hours. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product as a colorless oil (200 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCOCC1>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[CH:12][CH:13]=1
Reactant: CNc1ccc(C#CCCCN(C)C)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1COCCO1
Product: CN(C)CCCC#Cc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 173 mg (0.8 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine in 2 ml dioxane was treated with 0.15 ml (0.88 mmol) Huinigsbase and 247 mg (1 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction mixture was stirred over night at room temperature and extracted with aqueous 10% KHSO4/EtOAc (3×). The aqueous phase was treated with NaHCO3 (pH 7-8) and extracted with CH2Cl2 (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (9:1) yielded 223 mg (65%) of N-[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 425 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:12]1[CH:11]=[C:10]([CH:6]2[O:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CCCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 55 h
Yield: 38.9 %

Procedure:
To the phenol from example 29 (200 mg 0.9 mmol) in dichloromethane (5 ml) was added N-bromosuccinimide (161 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for 55 hours, before concentrating in vacuo. The crude product was purified by column chromatography on silica eluting with dichloromethane, methanol (95:5) to give the title compound as a white foam (117.5 mg, 0.35 mmol, 44%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.59 (q, 2H), 2.03 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d, 1H), 2.98 (d, 1H), 3.82 (t, 1H), 4.01 (d, 1H), 4.56 (d, 1H), 6.96 (d, 1H), 7.20 (d, 1H), 7.49 (s, 1H). LRMS: m/z 302 (M-H+, Br isotope).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:12]([O:11][CH3:10])=[O:22])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a 3-necked round-bottomed flask equipped with a magnetic stir bar were added anisole (31 mL, 30.8 g, 0.285 moL) and terephthalic acid monomethyl ester chloride (19.6 g, 0.099 moL). The flask was equipped with a powder addition funnel and nitrogen inlet. The powder addition funnel was charged with AlCl3 (40.2 g, 0.301 moL). The reaction mixture was cooled in an ice-water bath and the AlCl3 was added slowly, portionwise with stirring, under a nitrogen atmosphere. The ice-water bath was removed and the stirred reaction mixture was allowed to warm to room temperature for 3.5 h. The viscous reaction mixture was cooled in an ice-water bath and ice was added very slowly portionwise (Note: significant HCl was released upon addition of ice) followed by the slow addition of ice-water. The reaction mixture solidified upon quenching. The solid was filtered, washed with water, and allowed to stand overnight at RT. The solid was washed with water and triturated with hexanes (2×) to give a pink solid. The crude product was recrystallized from EtOAc to give a white solid. The solid was dried to give 16.0 g (60%) of compound 23 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3H), 3.88 (s, 3H), 7.08 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H).
Reaction SMILES: [F:1][C@H:2]1[CH2:12][N:5]2[C:6](=O)[CH2:7][NH:8][C:9](=O)[CH:4]2[CH2:3]1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[F:1][C@H:2]1[CH2:12][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3]1
Reactant: O=C1NCC(=O)N2C[C@H](F)CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: F[C@@H]1CC2CNCCN2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A pressure bottle was charged with (7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (200 mg, 1162 μmol) and 4.6 mL THF, and the bottle was purged with nitrogen and cooled to 0° C. Lithium aluminum hydride (2323 μl, 2323 μmol) was added. The mixture was allowed to warm to RT, and was then heated at reflux for 4 h. The reaction was cooled to 0° C. and 1 mL water was added carefully, followed by 1 mL 6N NaOH. The mixture was stirred for 15 min, and was filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated and a sample was analyzed by H-NMR and GC/MS: [M+H]=145.
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:19][C@@H:20]([CH:74]([CH3:76])[CH3:75])[C:21]([NH:23][C@@H:24]([CH3:73])[C:25]([NH:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH2:32][C@H:33]2[CH:39]=[N:38][C:37]3[CH:40]=[C:41]([O:46][CH2:47][CH2:48][CH2:49][O:50][C:51]4[C:52]([O:69][CH3:70])=[CH:53][C:54]5[C:60](=[O:61])[N:59]6[CH:62]=[C:63](/[CH:65]=[CH:66]/[CH3:67])[CH2:64][C@H:58]6[CH:57]=[N:56][C:55]=5[CH:68]=4)[C:42]([O:44][CH3:45])=[CH:43][C:36]=3[C:35](=[O:71])[N:34]2[CH:72]=1)=[O:26])=[O:22].[I:77][CH2:78][C:79](=[O:98])[NH:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][O:86][CH2:87][CH2:88][O:89][CH2:90][CH2:91][O:92][CH2:93][CH2:94][C:95](O)=[O:96]>ClCCl>[I:77][CH2:78][C:79]([NH:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][O:86][CH2:87][CH2:88][O:89][CH2:90][CH2:91][O:92][CH2:93][CH2:94][C:95]([NH:19][C@@H:20]([CH:74]([CH3:76])[CH3:75])[C:21]([NH:23][C@@H:24]([CH3:73])[C:25]([NH:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH2:32][C@H:33]2[CH:39]=[N:38][C:37]3[CH:40]=[C:41]([O:46][CH2:47][CH2:48][CH2:49][O:50][C:51]4[C:52]([O:69][CH3:70])=[CH:53][C:54]5[C:60](=[O:61])[N:59]6[CH:62]=[C:63](/[CH:65]=[CH:66]/[CH3:67])[CH2:64][C@H:58]6[CH:57]=[N:56][C:55]=5[CH:68]=4)[C:42]([O:44][CH3:45])=[CH:43][C:36]=3[C:35](=[O:71])[N:34]2[CH:72]=1)=[O:26])=[O:22])=[O:96])=[O:98]
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Reactant: O=C(O)CCOCCOCCOCCOCCNC(=O)CI
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCOCCOCCOCCOCCNC(=O)CI)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Reaction time: 18 h
Yield: 12.3 %

Procedure:
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.007 g, 0.0290 mmol, 1.0 eq) was added to a solution of amine 20c (assumed 100%, 0.023 g, 0.0290 mmol, 1.0 eq) and 1-iodo-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-oic acid (I5)(0.0126 g, 0.0290 mmol, 1.0 eq) in dry dichloromethane (2 mL). The reaction mixture was stirred for 18 hours, then diluted with DCM (6 mL) and washed with water (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (silica gel; 40:1 v/v DCM/MeOH to 5:1 v/v DCM/MeOH) to afford the product as a pale yellow oil (0.0043 g, 29%). LC/MS (2.380 min (ES+)), m/z: 605.0 ½[M+2H]+.
Reaction SMILES: [NH2:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH2:4][C:3]3[C:2](=[C:22]([F:23])[CH:21]=[CH:20][CH:19]=3)[NH:1][C:24]2=[O:25])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-amino-3-fluorobenzyl)-1-benzylpiperidin-4-amine (36.3 g, 116 mmol) in tetrahydrofuran (600 mL) at room temperature was added carbonyl diimidazole (20.7 g, 1.10 equiv.) in one portion. The reaction was stirred at room temperature for 3 h, heated at reflux for 30 min, and concentrated. The resulting solid was dissolved in 1:1 diethyl ether/ethyl acetate, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give the crude product as a wet, yellow solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.68 (m, 2H), 1.86 (dddd, J=11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J=11.6, 10.1, 2H), 2.98 (d, J=11.6, 2H), 3.51 (s, 2H), 4.34–4.44 (m, 3H), 6.71 (bs, 1H), 6.79–6.89 (m, 2H), 6.94 (dd, J=9.2, 9.2, 1H), 7.21–7.34 (m, 5H). Mass spec.: 340.30 (MH)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.[CH3:47][S:48][CH2:49][CH2:50]O.[CH:52]1([CH2:55][C:56]2[C:61]3[S:62][C:63]([CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[CH:68]=4)=[C:64]([OH:65])[C:60]=3[C:59](=[O:77])[N:58]([CH3:78])[N:57]=2)[CH2:54][CH2:53]1>O1CCCC1>[CH:52]1([CH2:55][C:56]2[C:61]3[S:62][C:63]([CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[CH:68]=4)=[C:64]([O:65][CH2:50][CH2:49][S:48][CH3:47])[C:60]=3[C:59](=[O:77])[N:58]([CH3:78])[N:57]=2)[CH2:53][CH2:54]1
Reactant: CSCCO
Reactant: Cn1nc(CC2CC2)c2sc(Cc3cccc(C(F)(F)F)c3)c(O)c2c1=O
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1c(Cc2cccc(C(F)(F)F)c2)sc2c(CC3CC3)nn(C)c(=O)c12
Reaction time: 18 h

Procedure:
To 5 ml of dry tetrahydrofuran was added 0.64 ml of 1M triphenylphosphine in tetrahydrofuran followed by 0.64 ml of 1M diethyl diazodicarboxylate in tetrahydrofuran and then by 0.64 ml of 1M 2,6-di-t-butylphenol in tetrahydrofuran. This mixture was mixed for 5 minutes and then 1.28 ml of 0.5M 2-(methylthio)ethanol in tetrahydrofuran was added. The solution was then mixed for 5 minutes. 7-Cyclopropylmethyl-3-hydroxy-5-methyl-2-[(3-trifluoromethylphenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one (248 mg in 1 ml tetrahydrofuran) was added and the solution was mixed periodically over 24 hours. The solution was opened to the air for 18 hours and then purified by chromatography, eluting with an isohexane ethyl acetate gradient, to give the title compound (77 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[C:39]([O:38][CH2:37][C@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)COC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](COC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 45.4 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-3-tert-butoxy-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-24) 65 mg (0.15 mmol) to obtain the title compound 20 mg (22%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:19][CH2:20][CH2:21][NH:22][C:23]2[C:24](=[O:40])[N:25]([C:36]([CH3:39])([CH3:38])[CH3:37])[S:26](=[O:35])(=[O:34])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=O)=O)=CC=1>CCOC(C)=O>[C:36]([N:25]1[C:24](=[O:40])[C:23]([NH:22][CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:34])=[O:35])([CH3:37])([CH3:38])[CH3:39]
Reactant: Oc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccncc2)=C(c2ccccc2)S1(=O)=O
Yield: 35 %

Procedure:
The title compound was prepared as described for Example 12 from 4-hydroxypyridine and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. EtOAc was added to the reaction mixture and the mixture was washed with water, brine and evaporated. The residue was purified twice by silica gel column chromatography (Horizons Biotage) using 50-80% EtOAc in hexane then 50% EtOAc in DCM as eluent to give the title compound (0.035 g, 35%). 1H NMR (500 MHz CDCl3): δ 8.44 (d, 2H), 7.54-7.48 (m, 2H), 7.48-7.41 (m, 3H), 6.75 (d, 2H), 5.64 (t, 1H), 3.91 (t, 2H), 3.114-3.08 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 164.5, 159.8, 151.4, 135.2, 131.8, 129.9, 128.9, 125.2, 110.3, 107.6, 65.7, 61.8, 41.9, 28.8, 27.9; Mass Spectrum: M+H+ 416.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:31](C)=[O:32])=[C:23]3[C:13](=[CH:14][C:15]([CH:21]=[CH:22]3)=[N+:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[O:12][C:10]=2[CH:11]=1)[CH2:4][CH3:5].C(N(CC)C1C=C([OH:43])C=CC=1)C.C1(=O)OC(=O)C2=CC=CC=C12.C(=O)=O.[OH-].[Na+]>O>[CH3:5][CH2:4][N:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:24]3([O:32][C:31](=[O:43])[C:30]4[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3[CH:22]=[CH:21][C:15]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]=3[O:12][C:10]=2[CH:11]=1)[CH2:2][CH3:1]
Reactant: CCN(CC)c1ccc2c(-c3ccccc3C(C)=O)c3ccc(=[N+](CC)CC)cc-3oc2c1
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C1OC(=O)c2ccccc21
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc2c(c1)Oc1cc(N(CC)CC)ccc1C21OC(=O)c2ccccc21
Temperature: 40 °C
Reaction time: 6.5 h
Yield: 90 %

Procedure:
The Rhodamine dye of formula (II), Rhodamine B free base (Colour Index 45170:1), a well-known pigment, can be prepared by heating a stirred mixture of 10 parts by weight of m-diethylaminophenol and 12 parts by weight of phthalic anhydride to 175° C. under a blanket of carbon dioxide. The reaction mixture is stirred at 170°-175° C. for a period of 6-7 hours, then cooled to 40° C. and discharged into water. The pH of the resulting slurry is adjusted to 12 by adding caustic soda, and the insoluble material is recovered by filtration. The filter cake is then rinsed with water and dried to obtain Rhodamine B Base in a yield about 90% of theoretical.