Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])([O:7][CH2:8]C)([O:4][CH2:5]C)[CH2:2][CH3:3].[CH2:13]([C:15](CO)(CO)CC)O.COCCOCCOC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:2]([C:1]12[O:4][CH2:5][C:12]([CH2:13][CH3:15])([CH2:8][O:7]1)[CH2:11][O:10]2)[CH3:3]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: COCCOCCOC
Product: CCC12COC(CC)(OC1)OC2

Procedure:
Into a flask as specified in Example 1 were charged 529 g of triethyl orthopropionate, 402 g of trimethylol propane, 330 g of diethylene glycol dimethyl ether, and 0.9 g of PTSA. The mixture was heated for 0.5 hour at 140° C., with 402 g of ethanol being distilled off. The temperature was lowered to 100° C., and the remaining diethylene glycol dimethyl ether was distilled off under reduced pressure. The residue was subjected to vacuum distillation. The fraction having a boiling temperature of 54° C. at a pressure of 0.5 mbar yielded 370 g of clear, low-viscous liquid having a boiling point of 223° C. at atmospheric pressure and with the following structure
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([F:31])[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@H:17]([O:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=4)[C:16]3=[O:30])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.O.O[C:34]1[C:42]2[N:41]=NNC=2C=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.N1CCCC1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([F:31])[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@H:17]([O:20][C:21]4[CH:26]=[N:25][C:24]([C:27]([N:41]5[CH2:36][CH2:35][CH2:34][CH2:42]5)=[O:29])=[CH:23][CH:22]=4)[C:16]3=[O:30])[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
(S)-5-(1-(1-(5-Chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinic acid hydrochloride (0.027 g, 0.062 mmol), hydroxybenzotriazole hydrate (0.013 g, 0.084 mmol), EDCI (0.016 g, 0.084 mmol), and DIEA (0.016 mL, 0.093 mmol) were stirred in CH2Cl2 (0.5 mL) for five minutes. Pyrrolidine (0.010 mL, 0.12 mmol) was added and the solution was stirred overnight at ambient temperature. The mixture was partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (40 mL). The organic phase was washed successively with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organics were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with 1:24 MeOH/EtOAc) to afford (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(6-(pyrrolidine-1-carbonyl)pyridin-3-yloxy)pyrrolidin-2-one (24 mg, 0.049 mmol, 79%) as a colorless solid. Mass spectrum (apci) m/z=488 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3([CH3:24])[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:25]1[CH2:28][C:27](=O)[CH2:26]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:27]4[CH2:28][O:25][CH2:26]4)[CH2:19][C:18]3([CH3:24])[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3(C)C)cn2)c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A mixture of 125d (900 mg, 2.3 mmol), oxetan-3-one (497 mg, 6.9 mmol), NaBH3CN (435 mg, 6.9 mmol), and zinc chloride (311 mg, 2.3 mmol) in methanol (30 mL) was stirred at 50° C. for 4 hours. It was then concentrated under reduced pressure. water (10 mL) was added to the residue and the mixture was extracted with CHCl3 3×50 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column-chromatography eluting with 50:1 dichloromethane/methanol to afford 125e (800 mg, 78%). LCMS: [M+H]+ 448.1. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.0 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.85 (s, 1H), 7.37-7.34 (m, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 4.69-4.61 (m, 4H), 3.60 (s, 3H), 3.50-3.14 (m, 3H), 2.43-2.17 (m, 4H), 1.06 (s, 6H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (3 ml) was added an excess of 2,6-lutidine (45 μl) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (64 μl) was added by syringe. After 15 minutes the reaction mixture was diluted with ethyl acetate, extracted from saturated bicarbonate, washed with brine and the organic phase dried over magnesium sulfate. Removal of solvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:18])[C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl[Sn]Cl.[OH-].[Na+]>O1CCOCC1.Cl>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([N:11]([CH3:18])[C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:3]=1
Reactant: CN(c1cncnc1)c1cc(F)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(c1cncnc1)c1cc(N)cc(F)c1
Yield: 113.8 %

Procedure:
Compound 31 (224 mg, 0.902 mmol, 1.00 eq) was dissolved in dioxane (4.5 mL) and SnCl2 (856 mg, 4.51 mmol, 5.00 eq) dissolved in conc HCl (1.5 mL) was added dropwise over 15 min. After determination of completion by LCMS, the reaction was neutralized with 1N NaOH, filtered, diluted with water and extracted with CH2Cl2 (2×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give 224 mg (63%) of a tan solid that was used subsequently without purification. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.44 (s, 2H), 6.11-6.10 (m, 1H), 6.09-6.07 (m, 1H), 6.07-6.04 (m, 1H), 5.46 (s, 2H), 3.23 (s, 3H); ES-MS [M+1]+: 219.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][CH:3]=1>N.CO.O.[Ni]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][NH2:12])[NH:4][CH:3]=1
Reactant: N#Cc1cccc2[nH]cc(Cl)c12
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCc1cccc2[nH]cc(Cl)c12
Yield: 98.2 %

Procedure:
To a solution of 3-chloro-1H-indole-4-carbonitrile (630.0 mg, 3.57 mmol) in ammonia in MeOH (2M, 45 mL) was added Raney Ni (3.05 g) in water (2 mL). The reaction mixture was then hydrogenated under H2 balloon at 1 atm for 20 h. The reaction mixture was filtered through a pad of Celite®, and the pad was washed alternatively with MeOH (10 mL×3) and water (10 mL×3). Volatile solvents were removed from the filtrate. The remaining crude was extracted with EtOAc (3×75 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization from ether/heptane afforded (3-chloro-1H-indol-4-yl)methanamine (133) as a white solid (633 mg, 98.2%). 1H NMR (400 MHz, DMSO) δ 11.33 (br s, 1H), 7.44 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.11-7.01 (m, 2H), 4.18 (s, 2H), 1.73 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
A solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.60 g) in methanol (72 ml) was cooled at 0° C., and sodium borohydride (0.2271 g) was added bit by bit thereto under cooling with stirring. The mixture was stirred at the same temperature for 15 minutes. The reaction mixture was adjusted to about pH 6 with 50% acetic acid and the methanol was distilled off under reduced pressure below 30° C. The residual solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and then evaporated to dryness. The residual oil (3.70 g) was crystallized by triturating with diisopropyl ether to give crude crystals (2.74 g), which were recrystallized in first from methanol (8 ml) and then from ethyl acetate (10 ml) to give pure crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (770 mg), mp 164.5° to 165° C. The whole mother liquor of above recrystallizations were combined together and concentrated. The crystalline residue was collected by filtration and washed with methanol (5 ml) to give additional crystals (1.72 g), which were recrystallized from ethyl acetate to give additional pure specimen of the same product obtained above, (840 mg) m.p. 164.5° to 165° C. Total yield, 1.61 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[CH:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[CH:2]
Reactant: C1COCCN1
Reactant: C#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a mixture of 3-ethynylbenzaldehyde (650 mg, 5 mmol) and morpholine (0.87 mL, 10 mmol) in DCE (15 mL) was added NaBH(OAc)3 (1.325 g, 6.25 mmol), followed by AcOH (0.2 mL). The resulting mixture was stirred for 2 h at rt. Aqueous workup followed by extraction with EtOAc gave crude 4-(3-ethynylbenzyl)morpholine (0.98 g) as a light brown oil. The title compound (1.75 g, quantitative yield over 2 steps) was obtained as a light brown oil using the method (PhCH3=12 mL, 1 mol % HRuCl(CO)(PPh3)3, 50° C., 2 h) for the preparation of Example A42A. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.46-7.37 (m, 2H), 7.35-7.27 (m, 2H), 6.19 (d, J=18.4 Hz, 1H), 3.78-3.68 (m, 4H), 3.52 (s, 2H), 2.52-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28](=[O:36])[N:29]([CH3:35])[C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)[CH2:11]2)=CC=1.[N+:39]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][O:47][C:48]([NH:50][CH:51]=N)=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28](=[O:36])[N:29]([CH3:35])[C@H:30]2[CH2:34][CH2:33][N:32]([CH:51]=[N:50][C:48]([O:47][CH2:46][C:45]3[CH:53]=[CH:54][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[O:49])[CH2:31]2)[CH2:11]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN(C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 57 %

Procedure:
Following a procedure similar to that described in Preparations 23(iii) and 23(iv), but using 1.00 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamoyl]pyrrolidine hydrochloride and 405 mg of N-(4-nitrobenzyloxycarbonyl)formamidine, 620 mg of the title compound were obtained as a powder.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH2:10])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.7 %

Procedure:
6.5 g of 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione was suspended in ethanol (140 ml), and hydrazine hydrate (3.0 ml) was added to the resulting suspension. The mixture was stirred for 3.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. 13 ml of 5N sodium hydroxide aqueous solution was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 4.03 g of oily red orange 3-(4-fluoro-2-nitrophenoxy)propylamine (yield: 100%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: N=C(OCC=Cc1ccc(F)cc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-fluorocinnamyl trichloroacetimidate (112 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 20 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (33 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.[N+]([NH:13][C:14](N)=[O:15])([O-])=O>>[NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:14]([NH2:13])=[O:15])[CH2:6]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: NCCOC1CCNC1
Product: NCCOC1CCN(C(N)=O)C1

Procedure:
Generally speaking, the reaction of a 3-aminoethoxypyrrolidine II with nitrourea to give a 3-aminoethoxypyrrolidine-1-carboxamide I is run in a lower alkanol solvent, e.g., ethanol, usually at or below reflux temperature for a period of time of from about 4 hours to about 18 hours. The reaction of a 3-aminoethoxypyrrolidine II with an isocyanate to give an N-substituted-3-aminoethoxypyrrolidine-1-carboxamide I is run in a dry aprotic solvent such as benzene at room temperature for a period of time up to about 18 hours. The reaction of a 3-aminoethoxypyrrolidine II with a compound having an active halide radical is generally run in a solvent such as dimethylformamide or a lower alkanol at a temperature of from about 70°-90° C. in the presence of an inorganic acid acceptor such as sodium carbonate for a period of from about 8 to 18 hours. The products of Formula I are isolated by methods known to the art such as concentration of the reaction mixture under reduced pressure followed by crystallization of the product from a suitable solvent, distillation of the product in vacuo, or acid base extraction of the reaction mixture.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([N:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([N:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)=[CH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B(O)O)cc1)Cc1ccccc1
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of methyl 4-chloro-2-nitrobenzoate (3.81 g) and [4-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-phenyl]boronic acid (6.91 g) in 1,4-dioxane (76 ml) were added cesium carbonate (8.64 g), potassium fluoride (3.08 g), tri-tert-butylphosphine (1.1 ml) and tris(dibenzylideneacetone)dipalladium(0) (1.62 g) under nitrogen at room temperature and then stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, filtrated through silica gel pad and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-3-nitro-4-biphenylcarboxylate (3.41 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[Li]C.C([Li])CCC.C([O:32]B(OC(C)C)OC(C)C)(C)C.[OH-].[Na+].OO>C1COCC1.CO>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([OH:32])=[CH:3][C:4]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(Nc2ncc(O)cc2Oc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
N-(5-Bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (2.66 mmol) is dissolved in THF (30 mL) and cooled to −78° C. MeLi (2.07 mL, 3.32 mmol) is slowly added and the reaction mixture is stirred for 10 minutes. n-Butyllithium (1.33 mL, 3.32 mmol) is added and the reaction mixture is stirred for 15 minutes. Triisopropylborate (0.613 mL, 2.66 mmol) is added and the reaction mixture is stirred for 30 minutes. The reaction mixture is warmed to 0° C., and methanol (5 mL), 10% aqueous NaOH (5.1 mL, 12.8 mmol), and 30% aqueous H2O2 (1.27 mL, 13.3 mmol) are added. The reaction mixture is stirred at 0° C. for 1 hour, then purified by silica gel chromatography (10-20% EtOAc in hexanes) to afford 6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Compound 13A (645 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5 ml) was added with LiOH.H2O (3 equiv., 297 mg) and the reaction was stirred at rt 3 hours. The reaction was concentrated under vacuum. Water was added and 10% HCl till precipitation of the acid. The acid was extracted with ethyl acetate and the organic phase was washed with Brine, dried over sodium sulfate and concentrated under vacuum to give 600 mg of 15C as a white solid. Yield=98%. 1HNMR (DMSO, 200 MHz) δ 1.38 (2H, m), 1.35 (2H, bs), 7.42 (2H, m), 7.80 (2H, m), 8.80 (1H, bs), 12.46 (1H, bs)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][NH2:20]>C1(C)C=CC=CC=1>[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19]/[N:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1]
Reactant: CN(C)CCNc1c(F)cccc1C=O
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CN(C)CCNc1c(F)cccc1/C=N/CCC(C)(C)C

Procedure:
2-(2-(Dimethylamino)ethylamino)-3-fluorobenzaldehyde (157 mg, 0.7467 mmol) and 3,3-dimethylbutan-1-amine (150 μL, 1.115 mmol) were stirred at RT in toluene (5 mL) with 4 Å MS overnight. The suspension was filtered and volatiles removed on a rotary evaporator at 40° C. 1H-NMR was consistent with 2-((E)-(3,3-dimethylbutylimino)methyl)-N-(2-(dimethylamino)ethyl)-6-fluorobenzenamine (175 mg). The crude product was carried on to next reaction.