Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:29][CH3:30])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:31][CH3:32])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:29][CH3:30])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:31][CH3:32])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Agent: O=C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccccc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (92 mg, 0.206 mmol from Example 7) was purified using chiral supercritical fluid chromatography (SFC) to afford 28.4 mg of peak A (Example 7A) and 27.4 mg of peak B (Example 7B). SFC Method: Chiralpak OJ-H (30×250 mm, 5 μM), 40% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 70 mL/min for 16 min, absorbance 268 nm, injection 1 mL of 15 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=5.0 min, tR (peak B) 12.3 min. The absolute stereochemistry of individual enantiomers (Examples 7A and 7B) was not determined. LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 7).
Reaction SMILES: [Cu][C:2]#[N:3].[I-].[K+].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1>N1C=CC=CC=1>[F:19][C:9]1[CH:8]=[C:7]([C:2]#[N:3])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: N#C[Cu]
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 151 °C
Reaction time: 24 h

Procedure:
Copper (I) cyanide (10.69 g, 0.12 mol) and potassium iodide (6.21 g, 0.037 mol) are added to a stirred pyridine solution (10 mL) of 4-bromo-2-fluorobiphenyl (10 g, 0.040 mol). The reaction mixture is heated at 150-152° C., 5 mL pyridine is distilled out and heating is continued at 150-152° C. for 24 hrs. The reaction mixture is cooled to 95-1000, toluene (100 mL) is added to it. It is cooled to 35-40° C. and an aqueous ammonia solution (25%, 100 mL) is added. After stirring for half an hour, toluene layer is separated and washed with aqueous ammonia solution (2×50 mL), then demineralized water (3×100 mL). The toluene layer is charcoalized and concentrated to give 2-fluorobiphenyl-4-carbonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:17]([CH3:22])([CH2:20]O)[CH2:18]O)[CH3:16]>>[CH2:15]([C:17]1([CH3:22])[CH2:20][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:18]1)[CH3:16]
Reactant: CCC(C)(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CCC1(C)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-ethyl-2-methyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-ethyl-5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 184° to 185° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[N:7]1([CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.40 ml of methyl bromoacetate was added dropwise to a mixture of 0.25 g of indoline, 2 ml of dimethylformamide and 0.87 g of anhydrous potassium carbonate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.30 g of the title compound having Rf=0.63 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:20])[CH:13]=[C:14]([OH:19])[C:15]=43)[C@@H:6]1[CH2:5][C@@H:4]([OH:21])[C@@H:3]2[OH:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:19][C:14]1[C:15]2[C@@H:16]3[C@@H:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[C@@H:3]([O:22][S:24]([CH3:23])(=[O:26])=[O:25])[C@H:4]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:5]4)[CH2:8][CH2:9][C:10]=2[CH:11]=[C:12]([O:20][S:24]([CH3:23])(=[O:26])=[O:25])[CH:13]=1)([CH3:23])(=[O:26])=[O:25]
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1C[C@@H](OS(C)(=O)=O)[C@@H]2OS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of 400 mg. of 8α-estra-1,3,5(10)-triene-1,3,16α,17β-tetrol in 5 ml. of pyridine is combined at 0° C. with 2 ml. of methanesulfonic acid chloride, and the mixture is agitated for 3 days at 0°-10° C. Thereafter, the mixture is introduced into ice water (acidified with HCl), filtered off, and the residue dissolved in methylene chloride. After purification by chromatography on SiO2, 220 mg. of rac.-1,3,16α,17β-tetrakis(mesyloxy)-8α-estra-1,3,5(10)-triene is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[O:19]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:26][CH2:25][N:24]([CH:21]4[CH2:22][CH2:23][O:19][CH2:20]4)[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CCOC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CCOC4)CC3)cc2n1
Yield: 60 %

Procedure:
Prepared from 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-(tetrahydro-furan-3-yl-piperazine under reductive amination conditions described in Reference Example 39, to give after silica chromatography, the title compound as a white solid (217 mg, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][CH:12](Br)[CH:13]1[O:30][C@H:16]2[CH2:17][C@@H:18]([OH:29])[C@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:15]2[CH2:14]1)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1.Cl.P([O-])([O-])([O-])=O>>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11]/[CH:12]=[C:13]1/[CH2:14][C@@H:15]2[C@@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:18]([OH:29])[CH2:17][C@@H:16]2[O:30]/1)=[O:5])[CH3:2]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OCC(=O)OCC)O[C@H]2C[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)OCC(=O)OCC)O[C@H]2C[C@H]1O
Reaction time: 2.5 h
Yield: 74.7 %

Procedure:
A mixture of 287 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid ethoxycarbonylmethyl ester (prepared as described in Example 7) and 1 ml of DBU was stirred for 2.5 hours at 50°-60° C. under a nitrogen atmosphere. The solution obtained was cooled to 0° C.-5° C., 5 ml of 1 N hydrochloric acid and 5 ml of a phosphate buffer with a pH of 6.86, cooled to 0°-5° C., were added and the mixture was extracted with diethyl ether. The extract was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on Florisil using as eluent a mixture of ethyl acetate and n-hexane (1:1) containing 0.1% v/v of triethylamine to give 181 mg of the title compound having the following physical characteristics.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[CH:25][C:18]=23)=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[N:6][CH:7]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[CH:25][C:18]=23)=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(NCc5cccc(F)c5)ncc4Cl)ccnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(CNc2cc(-c3ccnc4[nH]c(C5CCNCC5)cc34)c(Cl)cn2)c1

Procedure:
A solution of Example 307B (50 mg, 0.09 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred for 15 minutes and concentrated. The residue was purified by reverse phase chromatography (C18 column) eluting with 10%-70% acetonitrile in 0.1% TFA water solution to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.69-1.86 (m, 2H), 2.21 (d, 2H), 2.96-3.13 (m, 3H), 3.37 (d, 2H), 4.53 (s, 3H), 5.96 (s, 1H), 6.63 (s, 1H), 7.02 (d, 1H), 7.04-7.12 (m, 1H), 7.12-7.23 (m, 2H), 7.34-7.42 (m, 1H), 7.51 (s, 1H), 8.15 (s, 1H), 8.24 (d, 1H), 8.26-8.39 (m, 1H), 8.66 (d, 1H), 11.89 (s, 1H), LCMS: 436 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[CH3:9][CH:10]([CH3:39])[C@@H:11]([NH:20][C:21]1[CH:22]=[C:23]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=3)[NH:29][CH:28]=2)[CH:24]=[N:25][CH:26]=1)[C:12](=[O:19])[NH:13][CH2:14][C:15]([F:18])([F:17])[F:16].CCN(C(C)C)C(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH3:3])[C:36]([C:33]1[CH:34]=[C:35]2[C:27]([C:23]3[CH:24]=[N:25][CH:26]=[C:21]([NH:20][C@H:11]([CH:10]([CH3:39])[CH3:9])[C:12](=[O:19])[NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])[CH:22]=3)=[CH:28][NH:29][C:30]2=[N:31][CH:32]=1)=[O:37]
Reactant: CNC
Reactant: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(C(=O)O)cc23)c1)C(=O)NCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(C(=O)N(C)C)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0° C. solution of 2M dimethylamine/THF (58 uL, 0.115 mmol), 3-(5-(3-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)butan-2-ylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid 3-1b (25 mg, 0.057 mmol) and DIPEA (0.025 ml, 0.144 mmol) in DMF (0.7 ml) was slowly added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.078 ml, 0.115 mmol). The reaction was allowed to warm to room temperature and stir 18 hr. PyBOP (59.8 mg, 0.115 mmol) was then added and let stir 18 hr. The reaction was diluted with DMF (0.7 mL), filtered, and purified by reverse-phase HPLC. Lyophilization of pure fractions gave the title compound as a solid. LRMS (ESI) m/z 463.2 [(M+H)+; calcd for C22H25F3N6O2: 463.2].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH3:40])[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][N:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:9]=4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4cccc(F)c4)n3)cc2)cc1
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5cccc(F)c5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(3-fluorophenyl)-1H-pyrazol-3-yl]-phenoxy}phenol and 5-bromo-5-(2-methoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+531.2 (M+H)+, ESI 529.4 (M−H)−.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:7]>Cl.CC(C)=O>[NH2:15][C:11]1[CH:10]=[C:9]([N:8]2[C:3](=[O:18])[CH2:4][NH:5][C:6]2=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CNC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1cccc(N2C(=O)CNC2=O)c1
Yield: 85.2 %

Procedure:
A suspension of [[[(3-nitrophenyl)amino]carbonyl]aminoacetic acid methyl ester (6.9 g, 27 mmol) in 6N aqueous hydrochloride solution (40 mL) and acetone (20 mL) was stirred at reflux overnight. The resulting solution was cooled and concentrated. The resulting yellowish suspension was filtered and the filter cake was washed with water (50 mL), aqueous sodium bicarbonate solution (50 mL), and air-dried to afford the title compound (4.4 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH2:30][CH3:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:28])[CH2:30][CH3:31])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNC
Solvent: CC#N
Product: CCN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 0.3), 85 (3), 84 (3), 73 (5), 72 (bp), 63 (2).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH:18](OCC)=[O:19]>CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:18]=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)NNCc1ccc(F)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN(C=O)Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
To a solution of tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate (0.6 g, 2.50 mmol, 1.0 equiv) in EtOH (2.5 mL) was added ethyl formate (0.81 mL, 9.99 mmol, 4.0 equiv) and the reaction mixture heated to 50° C. (oil bath). After stirring 4 h, the reaction was cooled to ambient temperature and stirred 3 d. The reaction was then heated to 50° C. (oil bath) for 3 h at which time more ethyl formate (1.0 mL, 12.28 mmol, 4.9 equiv) was added. After stirring a further 4 h, the reaction was concentrated in vacuo. The crude product was purified by silica gel chromatography (elute with 10-70% ethyl acetate/hexane) to provide the title compound (0.11 g, 16% yield) as a colorless oil which slowly crystallized. Unreacted tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate was recovered from the mother liquor. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.20-7.25 (m, 2H), 7.00-7.08 (m, 2H), 6.27 (s, 1H), 4.58 (s, 2H), 1.43 (s, 9H); LCMS (ES+, (M+H)+) m/z 269.22.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH2:10][CH3:11].[CH2:18]([O:25][C:26]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53]Br)=[CH:47][C:27]=1[C:28]([NH:30][C:31]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:25][C:26]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:15]2[CH2:16][CH2:17][N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]2)=[CH:47][C:27]=1[C:28]([NH:30][C:31]1[CH:40]=[C:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCN1CCNCC1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC)c2)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Potassium carbonate (0.14 g) and 1-propylpiperazine dihydrochloride (0.12 g) were added to an acetone (1.6 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.080 g), followed by heating to reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.081 g of methyl 2-(2-(benzyloxy)-5-(2-(4-propylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow oily substance.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([C:15]([O:17]CC)=[O:16])=[CH:12][CH:11]=2)=[CH:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2c[nH]c3ncccc23)s1
Temperature: 80 °C
Yield: 88 %

Procedure:
Ethyl 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-2-carboxylate (0.89 g, 3.3 mmol) was partly dissolved in 1,4 dioxane and 10 mL 1N NaOH added. The reaction mixture was heated to 80° C. where it became homogenous. After 2 hours the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and a 10% citric acid solution. A precipitate formed which was filtered off, washed with water and dried to 0.71 g, 2.9 mmol, 88% yield.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O-:18])=[O:17])(=O)C>C1COCC1>[SH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([OH:18])=[O:17]
Reactant: CC(=O)SCCc1c(C(=O)[O-])[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2ccccc2c1CCS
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
To a deoxygenated solution of 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.277 g, 1.0 mmol) in THF (5 mL) was added deoxygenated 0.5 N KOH (10 mL), and the mixture was stirred at room temperature under nitrogen for 20 hours. The volatile solvent was removed under reduced pressure and the resulting aqueous mixture was poured into a mixture of EtOAc/1 N HCl (10 mL/10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (EtOAc/hexanes, 1/1) to give 0.150 g (0.68 mmol, 68% yield) of 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acid as a white solid: 1H NMR (CDCl3) δ 1.49 (t, J=8.0 Hz, 1H), 2.91 (q, J=7.7 Hz, 2H), 3.48 (t, J=7.5 Hz, 2H), 7.19 (ddd, J=1.3, 6.6, and 8.1 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 8.85 (s, 1H); 13C NMR (CDCl3) □ 25.4, 29.5, 112.0, 120.7, 121.1, 122.4, 124.7, 126.6, 127.9, 136.3, 167.0. Anal. Calcd. for C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; S, 14.49. Found: C, 59.58; H, 5.07; N, 6.25; S, 14.28.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]([OH:21])=[O:20]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:18][C:19]([OH:21])=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reaction time: 0.25 h

Procedure:
Sodium hydride (596 mg of a 60% dispersion in oil, 14.9 mmol) was added portionwise to a stirred solution of tert-butyl-4-hydroxypiperidine-1-carboxylate (1.0 g, 5 mmol) in anhydrous THF (20 ml) at rt. After 15 min, bromoacetic acid (1.38 g, 9.94 mmol) was introduced and stirring continued for 5 h. Additional bromoacetic acid (5 mmol) and sodium hydride (5 mmol) were added and stirring continued for 24 h. The reaction was quenched with water (2 ml) and diluted with EtOAc (20 ml), which was washed with saturated aqueous NaHCO3 (20 ml). Using dilute HCl, the aqueous phase was acidified to pH 2 and the precipitate extracted into EtOAc (50 ml). The organic phase was dried (MgSO4), evaporated and the residue was purified by flash chromatography (5% AcOH in IH-EtOAc, 7:3 to 1:1) to afford the title acid: RT=2.89 min; m/z (ES+)=260.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14]2[O:15][C@H:16]3[C:25]4(OCC[O:26]4)[CH2:24][CH2:23][C@:22]4([O:30][CH3:31])[C@@:17]53[CH2:18][CH2:19][N:20]([CH3:33])[C@@H:21]4[CH2:32][C:12]([C:13]=25)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.N>CO>[OH:8][C:9]1[C:14]2[O:15][C@H:16]3[C:25](=[O:26])[CH2:24][CH2:23][C@:22]4([O:30][CH3:31])[C@@:17]53[CH2:18][CH2:19][N:20]([CH3:33])[C@@H:21]4[CH2:32][C:12]([C:13]=25)=[CH:11][CH:10]=1
Reactant: CO[C@@]12CCC3(OCCO3)[C@@H]3Oc4c(OCc5ccccc5)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: Cl
Agent: N
Solvent: CO
Product: CO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reaction time: 8 h

Procedure:
To a solution of (4R,4aS,7aR,12bS)-9-(benzyloxy)-4a-methoxy-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane] (7.3 g, 16.2 mmol) in MeOH (75 mL) was added conc. HCl (50 mL). The mixture was refluxed for 5 hours then cooled with an ice bath. Concentrated ammonia (25%) was added until pH 8 was reached. The mixture was concentrated and the residues stirred with 10% MeOH/DCM (1 L) overnight. The mixture was filtered and the liquors concentrated to give (4R,4aS,7aR,12bS)-9-hydroxy-4a-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one as a dark red oil (5.3 g, quantitative yields).