Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[CH2:5][CH2:6][O:7]CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][N:4]([CH2:5][CH2:6][OH:7])[C:3]2=[O:2]
Reactant: CCOCCN(CCc1ccccc1Br)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2cccc(Br)c2CCN1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
1.5 g of methyl[2-(2-bromophenyl)ethyl](2-ethoxyethyl)carbamate are dissolved under an inert atmosphere in 140 cm3 of dichloromethane at a temperature close to 20° C. 1.6 g of 4-dimethylaminopyridine are added to the reaction mixture, which is cooled to a temperature in the vicinity of 0° C. 3.7 cm3 of trifluoromethanesulfonic anhydride in solution in 15 cm3 of dichloromethane are poured in to the reaction mixture over 30 min. The suspension is kept stirring for 1 h at 0° C., then for 48 h at a temperature close to 20° C. 100 cm3 of a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction medium. Stirring is continued for 1 h at a temperature close to 20° C. After decanting, the organic phase is washed with 100 cm3 of a 20% aqueous solution of acetic acid then with 150 cm3 of a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by filtration through a bed of silica of 20 g. The latter is washed with 100 cm3 of ethyl acetate. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 0.8 g of 5-bromo-2-(2-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one is obtained in the form of a beige oil.
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.IC1C=CC=CC=1O.[H][H]>[Ta]>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: Oc1ccccc1I
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 95 %

Procedure:
131 parts of a tetrachloroaniline/pentachloroaniline mixture, 200 parts of phenol and 10 parts of 2-iodophenol are reacted in the presence of 12.5 parts of ruthenium-on-charcoal catalyst (5%) in a tantalum autoclave with hydrogen under a pressure of from 29 to 50 bars at a maximum temperature of 165° C., during the course of 8 hours, whilst stirring. 87.5 parts of 3,5-dichloroaniline are obtained after working up the reaction mixture. Yield: 95% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:15][N:16]=[C:17]=[S:18]>ClCCl>[CH3:15][NH:16][C:17]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[S:18]
Reactant: CN=C=S
Reactant: Cc1ccc(N2CCOCC2)c(N)c1
Solvent: ClCCl
Product: CNC(=S)Nc1cc(C)ccc1N1CCOCC1
Reaction time: 144 h

Procedure:
A solution of 4-(2-amino-4-methylphenyl)morpholine (5.7 g) in dichloromethane (30 ml) was treated with methylisothiocyanate (2.8 g) and the reaction mixture kept at room temperature for 6 days to yield 1-methyl-3-(5-methyl-2-morpholinophenyl)thiourea as a colourless solid (m.p. 107° C.).
Reaction SMILES: [C:1]1([CH:7]([CH3:14])[CH2:8][O:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH3:14])[CH2:8][O:9][CH2:10][C:11]([NH2:22])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CC(COCC(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(COCC(N)=O)c1ccccc1

Procedure:
The subtitle compound (4.39 g) was prepared according to the procedure in example 5 part b using 2-(2-phenyl-1-propoxy)acetic acid (5.0 g), oxalyl chloride 4.5 ml), concentrated ammonium hydroxide (20 ml), and toluene (30 ml).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10](Br)=[N:9][C:8]([Br:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3].C([O-])=O.[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:12][C:8]1[N:9]=[C:10]2[C:2]([CH3:3])=[CH:1][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: C=CCNc1ncc(Br)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncc(Br)nc12
Temperature: 50 °C
Yield: 11 %

Procedure:
The mixture of allyl-(3,5-dibromo-pyrazin-2-yl)-amine (3.51 g, 12.0 mmol), TEA (4 mL, 28.8 mmol), sodium formate (204 mg, 3.00 mmol), Bu4NH4Br (580 mg, 1.80 mmol), and Pd(OAc)2 (269 mg, 1.20 mmol) in 24 mL of DMF was heated at 50° C. overnight then cooled to RT. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried (MgSO4), concentrated, and purified by SiO2 chromatography (120 g SiO2, hexanes/EtOAc 0-70% EtOAc) to give 0.279 g of 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (11% yield).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:15]([C:19](=[O:30])[NH:20][C@H:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][OH:23])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12](O)=[O:13])[CH:11]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:15]([C:19]([NH:20][C@H:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][OH:23])=[O:30])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1
Reactant: Cc1nc2c(OCc3ccccc3F)cc(C(=O)O)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3ccccc3F)cc(CO)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a mixture of 100 mg of 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid, 28 μl of 4-methylmorpholine, and 0.7 ml of dimethoxyethane was added 34 μl of isobutyl chloroformate under ice-cooling, followed by stirring at room temperature overnight. The insoluble material was removed by filtration, and then to the filtrate were added 16 mg of sodium borohydride and 210 μl of methanol under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added a saturated aqueous ammonium chloride solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 21 mg of 8-[(2-fluorobenzyl)oxy]-6-(hydroxymethyl)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34]C)=[O:33].[OH-].[Na+].CO.Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1cccc2c1c(Br)c(C(=O)O)n2CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (22 mg), NaOH (0.167 ml), methanol (1.5 ml) and tetrahydrofuran (1.500 ml) was stirred at room temperature for 36 hours, acidified with HCl and concentrated. The residue was purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 minutes) on a C18 column to provide the title compound. 1H NMR (500 MHz, dichloromethane-d2) δ 8.30-8.40 (m, 1H), 7.79-7.85 (m, 1H), 7.56 (d, J=8.54 Hz, 1H), 7.47-7.55 (m, 2H), 7.43 (d, J=8.24 Hz, 1H), 7.35 (t, J=7.93 Hz, 1H), 7.28-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.18 (m, 1H), 6.93 (d, J=7.02 Hz, 1H), 6.75 (d, J=7.63 Hz, 1H), 4.78-5.03 (m, 2H), 4.16 (t, J=5.65 Hz, 2H), 2.37-2.54 (m, 2H), 2.01 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23].[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23]
Reactant: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2OC(F)(F)F)c1

Procedure:
Compound 38 was synthesized using the procedure described above for preparing 13.3 using compound 37.3 and 2-fluoro-5-methoxyphenylboronic acid 38.1 (available from Aldrich). MS ESI (neg.) m/e: 463 (M−H). 1H NMR (400 MHz, CD3CN) δ ppm 7.47-7.54 (3H, m), 7.22 (1H, t, J=7.8 Hz), 7.12-7.17 (1H, m), 6.98 (1H, dt, J=9.0, 3.5 Hz), 6.90-6.93 (2H, m), 6.85 (2H, dd, J=8.0, 2.2 Hz), 5.16 (2H, s), 3.79 (3H, s), 2.86 (2H, s), 2.56-2.62 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccc1)O2
Yield: 74.7 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 362 mg CDI (2.23 mmol) and 235 mg benzylamine (2.20 mmol) produced 507 mg of N-benzyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a brown oil.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C(Cl)(Cl)Cl.[CH3:38][OH:39]>>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C@@H:16]([O:29][C:38]([CH2:6][C:7]([C:31]([OH:33])=[O:32])([CH3:24])[CH3:8])=[O:39])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: CO
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 70 %

Procedure:
yield 70% (starting with 542 mg of betulinic acid); crystallization from MeOH gave colorless needles; mp 274°-276° C.; [α]D19+23.5° (c=0.71), CHCl3-MeOH [1:1]); Positive FABMS m/z 585 (M+H)+; Negative FABMS m/z 583 (M−H)−; HR-FABMS calcd for C36H57O6 585.4155, found m/z 585.4161; 1H NMR (pyridine-d5): 0.73, 0.92, 0.97, 1.01, 1.05 (each 3H, s; 4-(CH3)2, 8-CH3, 10-CH3, 14-CH3), 1.55 (6H, s, 3′-CH3×2), 1.80 (3H, s, 20-CH3), 2.89, 2.97 (each 1H, d, J=15.5 Hz, H-2′), 3.53 (1H, m, H-19), 4.76 (1H, dd, J=5.0, 11.5 Hz, H-3), 4.78, 4.95 (each 1H, br s, H-30).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([O:14][CH3:15])=[O:13].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Li+].C[Si]([N-:46][Si](C)(C)C)(C)C.Cl>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].C1COCC1>[NH2:46][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1cccc2cc(Cl)ncc12
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(N)ncc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A 20 mL microwave vial was charged with methyl 3-chloroisoquinoline-8-carboxylate (0.56 g, 2.57 mmol), [1,1′-biphenyl]-2-yldicyclohexylphosphine (90 mg, 0.257 mmol), LHMDS (3.0 mL, 3.08 mmol) and Pd2(dba)3 (118 mg, 0.125 mmol) and then with 12 mL of THF. Reaction mixture was capped and stirred at 65° C. overnight. Then 2M HCl (1.2 mL, 2.57 mmol) was added and stirred at rt for 20 min. The reaction mixture was filtered and added with sat bi carb. Extracted with EtOAc. Combined organic layer was dried, filtered, concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded 90% Methyl 3-aminoisoquinoline-8-carboxylate (27-2).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([CH:67]([CH3:69])[CH3:68])[C:56]([NH:58][C@@H:59]([CH:64]([CH3:66])[CH3:65])[C:60]([O:62][CH3:63])=[O:61])=[O:57].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([NH:54][C@@H:55]([CH:67]([CH3:69])[CH3:68])[C:56]([NH:58][C@@H:59]([CH:64]([CH3:65])[CH3:66])[C:60]([O:62][CH3:63])=[O:61])=[O:57])=[O:12])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
247 mg of Z-Phe-OH (0.825 mmol, 1 eq) were dissolved in 10 ml of dry DMF at 0° C. under argon. Then 56 mg of 1-hydroxybenzotriazole (0.5 eq), 221 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (1.4 eq) and 346 μl of Hünig's base (2.4 eq) were added, and the mixture was stirred for 30 min. 190 mg of the compound from Example 143a) were then added, and the mixture was stirred at RT for 20 h. The reaction mixture was mixed with 50 ml of saturated NaHCO3 solution and extracted with ethyl acetatet (2×30 ml). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was chromatographed on silica gel with heptane/ethyl acetate mixtures. 314 mg of the desired compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:27][C:28]([CH3:31])=[N:29][N:30]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D9) using the procedure outlined in WO 96/19477 (23%). This was converted to the oxalate salt, which precipitated from acetone/ether as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])=[O:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:16][CH2:17][O:18][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
To a solution of methyl 4-formyl-3-nitrobenzoate (9.0 g, 43.0 mmol) in toluene (150 mL) was added ethylene glycol (7.20 mL, 129 mmol) followed by p-TsOH (0.409 g, 2.152 mmol) and the reaction mixture was heated at reflux temperature with azeotropic removal of H2O using a Dean-Stark trap for 4 h. The reaction mixture was then cooled and diluted with DCM. The DCM layer was then washed with saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated to yield a residue. The residue was dissolved in minimal quantity of DCM and purified by silica gel chromatography to yield the desired product (8.53 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.00 (dt, J=3.8, 1.9 Hz, 2H), 3.94 (dt, J=3.8, 1.9 Hz, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: C[O-].[Na+:3].[F:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:22](CCC#N)(=[O:24])=[O:23])[CH:16]=[CH:15]2>O1CCCC1.CO.C(OCC)C>[F:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:22]([O-:24])=[O:23])[CH:16]=[CH:15]2.[Na+:3]
Reactant: N#CCCS(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: O=S([O-])c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Sodium methoxide (0.68 g, 12.6 mmol) was added to a solution of 3-{[6-(2,4-difluorophenyl)-2-naphthyl]sulfonyl}propanenitrile (Step 2, 4.04 g, 11.3 mmol) in tetrahydrofuran/methanol (1:1, 120 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction mixture was diluted with diethyl ether (120 mL) and stirred for 30 minutes. The solid precipitate was collected by filtration to give sodium 6-(2,4-difluorophenyl)naphthalene-2-sulfinate (3.58 g). 1H NMR (500 MHz, CD3OD) δ 8.14 (1H, s), 8.03-7.97 (3H, m), 7.84 (1H, d, J=8.4 Hz), 7.66 (2H, dd, J=8.6, 20.2 Hz), 7.10-7.08 (2H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[C:11]1([N:17]2[C:21]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:20](=[O:27])[NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO.C1C=CC=CC=1>ClC(Cl)Cl>[O:27]=[C:20]1[C:21]2([CH2:22][CH2:23][N:24]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:25][CH2:26]2)[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][NH:19]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1cccs1)N1CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 11.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8 parts of methanol and 54 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and dissolved in trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is crystallized from methanol. The product is filtered off and dried, yielding 2 parts of N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-thiophenecarboxamide; mp. 194° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4]1)[C:17](=[O:18])[O:19][CH2:20][CH3:21]
Reactant: CNC1CCc2c([nH]c3ccccc23)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N(C)C1CCc2c([nH]c3ccccc23)C1
Reaction time: 5 h

Procedure:
A solution of 0.05 mol of 2,3,4,9-tetrahydro-N-methyl-1H-carbazol-2-amine in 450 ml of CH2Cl2 and 185 ml of saturated aqueous NaHCO3 was stirred vigorously at room temperature and treated dropwise during 30 min with a solution of 0.15 mol of ethyl chloroformate in an equal volume of CH2Cl2. After stirring vigorously for 5 hr, the CH2Cl2 layer was separated, washed in succession with 10% aqueous K2CO3, H2O, 0.1 N hydrochloric acid, H2O, and dried over anhydrous Na2SO4. The residue remaining after evaporation of the CH2Cl2 was recrystallized from ethanol to give the title compound, mp 167°-168°.
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:15]([O:22][CH2:23][C@@H:24]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:34]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[CH:49]=[C:50]([N+]([O-])=O)[CH2:51][CH2:52][CH2:53][CH3:54])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:35])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[C:42]([O:41][C:39]([C:38]1[CH:46]=[CH:47][C:48]([C:49]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:50]=2[CH2:51][CH2:52][CH2:53][CH3:54])=[C:36]([C:34]([N:25]2[C@H:24]([CH2:23][O:22][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:35])[CH:37]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1Cc2ccccc2C[C@H]1CO[Si](C)(C)C(C)(C)C)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Yield: 64.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-phenylhydrazono)acetate (133 mg, 0.690 mmol) and of (S)-tert-butyl 3-(3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(2-nitrohex-1-enyl)benzoate (420 mg, 0.690 mmol) were converted to the title compound (335 mg, 65%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.15-8.06 (m, 2H), 7.51-7.39 (m, 5H), 7.22-6.80 (m, 5H), 5.02-4.98 (m, 1H), 4.39-4.04 (m, 3H), 3.82-3.28 (m, 2H), 3.04-3.00 (m, 1H), 2.90-2.78 (m, 1H), 2.61-2.24 (m, 2H), 1.61 (s, 9H), 1.32-0.90 (m, 7H), 0.77 (s, 9H), 0.59 (t, J=8 Hz, 1.5H), 0.55 (t, J=8 Hz, 1.5H), 0.00 (s, 9H); MS(ESI+) m/z 752.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[N:16][CH:17]=1>C1COCC1>[N:3]1([CH2:7][CH2:8][CH2:9][O:10][C:15]2[CH:14]=[CH:13][C:12]([Br:11])=[CH:17][N:16]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Fc1ccc(Br)cn1
Reactant: OCCCN1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(OCCCN2CCC2)nc1
Reaction time: 0.17 h
Yield: 121.7 %

Procedure:
Sodium hydride (1.364 g, 56.82 mmol) was added to 3-(azetidin-1-yl)propan-1-ol (2.62 g, 22.73 mmol) in THF (20 mL) at ambient temperature under an inert atmosphere and the reaction stirred for 10 minutes. 5-Bromo-2-fluoropyridine (2.0 g, 11.36 mmol) was added and the resulting solution stirred for 1 h before being quenched with water (20 mL) and extracted with EtOAc (5×50 mL). The organics were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired material (3.75 g, 122%) as a white solid. NMR Spectrum: 1H NMR (300 MHz, CDCl3) δ 1.80 (2H, m), 2.11 (2H, m), 2.55 (2H, t), 3.18 (4H, t), 4.328 (2H, t), 6.64 (1H, d), 7.62 (1H, dd), 8.16 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=271.