Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Reactant: NCCCN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-aminopropyl morpholine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.22 (t, J=5.3 Hz, 1 H), 8.57 (s, 1 H), 7.76 (s, 1 H), 7.22 (dd, J=8.5, 5.5 Hz, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.39 (t, J=8.0 Hz, 2 H), 4.13 (s, 2 H), 3.84-3.82 (m, 4 H), 3.53 (q, J=6.6 Hz, 2 H), 3.38-3.34 (m, 4 H), 3.06 (t, J=6.5 Hz, 2 H), 2.71-2.62 (m, 6 H), 2.17 (m, 2 H), 1.98-1.93 (m, 6 H); HRMS C30H38FN5O6S (M+H)+ calcd 616.2527, found 616.2609.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17](Cl)[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccc(O)cc1
Reaction time: 0.08 h
Yield: 110.9 %

Procedure:
A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol was stirred at 25° for five minutes. Hydrogen gas was bubbled into the solution, and the mixture was stirred under hydrogen gas (1 atm.) at 25° for 2 hours. The mixture was filtered, and the resulting solution concentrated in vacuo to furnish 0.75 g of 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ9.75 (bs, 1H); 7.55 (s, 1H); 6.91 (A2B2, 4H); 5.80 (bs, 1H); 5.35 (s, 2H); 4.45 (s, 2H); 2.89 (t, 2H); 1.44 (quint, 2H); 1.21 (sext., 2H); 0.80 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 190.9 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.6 g), aminoguanidine hydrochloride (0.24 g), concentrated hydrochloric acid (0.45 ml), water (0.45 ml) and ethanol (20 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 150) (0.73 g) as colorless crystals.
Reaction SMILES: C[C@H]1P(CCP2[C@H](C)CC[C@H]2C)[C@H](C)CC1.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH:22]=1.[H][H]>CO>[CH3:17][O:18][C:19](=[O:31])[CH2:20][CH:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: [H][H]
Agent: C[C@@H]1CC[C@@H](C)P1CCP1[C@H](C)CC[C@H]1C
Solvent: CO
Product: COC(=O)CC1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (12 mg) and (R,R)-Me-BPE (6.5 mg) was added methanol (2.5 mL) sufficiently substituted with argon gas, and the mixture was stirred at room temperature for 15 min. This was added to methyl(6-hydroxy-1-benzofuran-3-yl)acetate (51 mg), and the mixture was stirred at 70° C. for 3 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 47.9%, and the yield was 41.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[OH2:11].[OH-:12].[Na+]>>[Cl:1][C:2]1[C:3]([C:8]([OH:12])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Cl
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ncccc1Cl

Procedure:
64.1 g of 10B was refluxed in 460 ml of 2N aqueous sodium hydroxide solution for 1 hour. The mixture was cooled, acidified to pH=2.5 with concentrated hydrochloric acid, stripped of water under reduced pressure, then azeotroped with methanol. The residue was stirred with 250 ml of a 1:1 v:v mixture of methylene chloride and methanol, and the resulting mixture was filtered. The filtrate was stripped of volatiles (water bath temperature 60° C). This purification procedure was repeated, to give 3-chloropicolinic acid (10C), as a yellow solid, m.p.: 125.5°-127.5° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[N:20][CH:21]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), 0-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and cyclopropanamine (11.15 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 41.2 mg (50%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.81 (s, 1H), 9.85 (br. s., 1H), 8.61 (d, J=2.3 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 8.01 (dd, J=9.0, 2.4 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.42-4.64 (m, 3H), 4.24 (br. s., 2H), 3.92-4.01 (m, 1H), 3.42 (br. s., 2H), 2.94-3.26 (m, 4H), 2.75-2.86 (m, 1H), 2.58-2.73 (m, 1H), 2.03-2.12 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.6 Hz, 1H), 1.31-1.61 (m, 3H), 0.62-0.73 (m, 2H), 0.46-0.57 (m, 2H). [M+H] calc'd for C25H31N7O2, 462; found, 462.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:20])=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2ccc(Cl)nc12

Procedure:
To a suspension of 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide in 100 mL of toluene at 0° C. was added dropwise phosphorus oxychloride (35.8 mL, 391 mmol) followed by 2 mL of DMF and the mixture was stirred at RTovernight. The solvent was evaporated under vacuum and the residue which crashed out of water, was filtered and washed with water, methanol and acetone in sequence. The solid was air dried to give 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=2)=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH2:35][C:34]2[CH:51]=[CH:52][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)cc2)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.69 (s, 1H), 9.21 (brs, 0.6H), 9.09 (brs, 0.4H), 8.40 (s, 1H), 8.07–7.96 (m, 2H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.36 (d, 2H), 7.02 (d, 0.6H), 7.01 (d, 1H), 6.94 (d, 2H), 5.12 (s, 2H), 4.81 (s, 1.2H), 4.64 (s, 0.8H), 4.37 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.08 (q, 1.2H), 3.76 (s, 3H), 3.62 (t, 1.2H), 3.47 (t, 1.2H), 3.43 (t, 0.8H), 3.28 (t, 0.8H), 1.24 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([O-:13])=O)[CH3:7].[Br:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:19](C(Cl)=O)=[C:18]([F:27])[C:17]=1[F:28].Cl>O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1>[Br:15][C:16]1[C:17]([F:28])=[C:18]([F:27])[C:19]([C:11]([CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14])=[O:13])=[C:23]([F:26])[C:24]=1[F:25]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1c(F)c(F)c(Br)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
n-Butyllithium (192 ml, 2.4M in hexane) was slowly added to a stirred solution of 30.24 g monoethylmalonate and 15 mg 2,2'-bipyridine in 500 ml tetrahydrofuran cooled to -60° to -70° C. under nitrogen. After about half of the butyllithium had been added, the temperature of the mixture was raised to -20° to -25° C. at which temperature the remainder of the butyllithium was added. The reaction mixture was then recooled to -60° to -70° C. and 33.41 g 4-bromo-2,3,5,6-tetrafluorobenzoyl chloride in 10 ml tetrahydrofuran was added. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then poured into 460 ml 1M hydrochloric acid. The organic layer was separated, dried (magnesium sulfate) and concentrated. The residue was dissolved in ether, washed with aqueous potassium bicarbonate solution, dried (magnesium sulfate), concentrated and distilled to give 34.18 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate, b.p. 112° -117° C. (0.8 mm).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C(OCC)(=O)C>[CH3:24][NH:25][C:21]([C@@H:20]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:23]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (SM1-B, 10 g, 32 mmol) in DMF (100 ml) was added HATU (15.5 g, 42 mmol), followed by DIEA (12.4 g, 96 mmol) while the temperature was maintained below 0° C. After stirring for 2 h at this temperature, methylamine (2M in THF, 32 mL, 63 mmol) was added. The reaction mixture was warmed to rt and stirred for 16 h. The solution was diluted with ethyl acetate (500 mL); washed with water (200 mL), 0.1 M hydrochloride (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL); dried over Na2SO4; and concentrated and purified by column chromatography (DCM:MeOH=200:1) to give product (2-B) (10 g, 96%) as a white solid. LC-MS (M+H)+=330.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:9][O:10][CH3:11])[N:6]([CH3:8])[CH:7]=1.OCC1N(C)C(COC)=NC=1.[Cl:23]N1C(=O)CCC1=O.O1CCOCC1>C(OCCO)C>[Cl:23][C:7]1[N:6]([CH3:8])[C:5]([CH2:9][O:10][CH3:11])=[N:4][C:3]=1[CH2:2][OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1nc(CO)cn1C
Agent: COCc1ncc(CO)n1C
Solvent: CCOCCO
Solvent: C1COCCO1
Product: COCc1nc(CO)c(Cl)n1C

Procedure:
A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methylimidazole and 5-hydroxymethyl-2-methoxymethyl-1-methylimidazole and 7.3 g (55 mmol) of N-chlorosuccinimide was heated to 50° C. in 48 mL of ethylene glycol monoethylether and 70 mL of dioxane for 10 hours. Then the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel; methylene chloride/ethanol=99:1 to 90:10) to obtain the isomerically pure title compound. Yield: 3.4 g (36% of theory); Rf value: 0.40 (silica gel; methylene chloride/ethanol=19:1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH:23]=[O:24].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:23]([C:22]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=1[F:20])[OH:24]
Reactant: Clc1cccnc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78° C. and the mixture was stirred for 10 minutes. Then, 3-chloropyridine (1.13 g, 10 mmol) was added to the resulting mixture. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added to the mixture. The mixture was warmed gradually to 0° C., at which stirring was conducted for further 10 minutes. An aqueous solution of ammonium chloride was added and the mixture was diluted with ethyl acetate (80 ml). The organic layer obtained by separation was washed with brine and then dried. After filtration, the filtrate was concentrated under reduced pressure. The precipitate thus obtained was triturated with ethanol to yield the title compound (1.33 g, 52%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:12]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[OH-].[Na+]>O.C(O)C>[CH2:1]([C:3]1[C:4]([CH:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CSC(CC)c1cc2c(cc1CC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(cc1C(CC)SCC(=O)O)OCO2
Yield: 77 %

Procedure:
4.0 g of ethyl [{1-(6-ethyl-1,3-benzodioxol-5-yl)propyl}thio]acetate and 2.6 g of sodium hydroxide were dissolved in a mixture comprising 20 ml of water and 20 ml of ethanol. The obtained solution was heated under reflux for 2 hours and distilled to remove the ethanol. The residue was washed with ether. The aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.8 g of the title compounds as a colorless crystal.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33](I)[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33]([C:4]#[C:3][CH:2]([CH3:5])[CH3:1])[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1
Reactant: C#CC(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 209a, 3-methyl-1-butyne (0.22 g, 3.2 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (0.97 g, 9.6 mmol), and dichlorobis(triphenylphosphine)palladium (11.2 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 50 mg, 28%)
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]1.[CH2:15]=O>O1CCOCC1>[OH:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:15][C:3](=[CH2:4])[C:1]#[N:2])[CH2:8]1
Reactant: C=O
Reactant: OCC1CCCNC1
Reactant: N#CCC(=O)O
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCCC(CO)C1

Procedure:
Cyanoacetic acid (25.5 g., 0.3 mole) was dissolved in 75 ml. of dioxane, cooled to 0°-10° C., and with the cooling bath in place, 3-piperidinemethanol (34.5 g., 0.3 mole) dripped in. The temperature then rose upon the addition of 37% aqueous formaldehyde (50 g., 0.6 mole) to 30° C. with the cold bath removed. After mixing overnight at room temperature, the mixture was concentrated in a rotary evaporator, saturated with sodium chloride and extracted with ether. The organic phase was washed with sodium carbonate solution, dried and concentrated. The residue yielded 43.8 g.; 38 g. was fractionally distilled and the product isolated, 22.4 g., b.p. 137° C./0.4 mm.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])C(C)=O.[SH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>Cl>[ClH:17].[ClH:17].[NH2:20][C:8]1[CH:7]=[CH:6][C:5]([NH2:1])=[CH:19][C:9]=1[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCS
Reactant: CC(=O)Nc1ccc(N)c(C(O)c2ccccc2Cl)c1
Agent: Cl
Product: Nc1ccc(N)c(C(SCCC(=O)O)c2ccccc2Cl)c1

Procedure:
107.3 g of 5-acetamino-2-amino-2'-chlorobenzhydrol are heated to 90° for 1 hour together with 36.8 g of 3-mercaptopropionic acid in 290 ml of 6N hydrochloric acid. After cooling, the crystals are filtered off. There is obtained 3-[(2,5-diaminophenyl)(2-chlorophenyl)methylthio]propionic acid dihydrochloride of melting point 234°-235° (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[O:25])[CH:14]=[CH:15][C:16]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([NH2:44])=[O:43].O.[C:49]([OH:53])(=[O:52])[CH:50]=O>>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([O:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:50]([NH:38][C:39]3[CH:47]=[CH:46][CH:45]=[C:41]([C:42](=[O:43])[NH2:44])[CH:40]=3)[C:49]([OH:53])=[O:52])=[CH:31][CH:30]=2)=[O:25])[CH:14]=[CH:15][C:16]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1cccc(N)c1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C

Procedure:
Using a procedure analogous to that used to prepare 2D, 16I (0.134 g, 0.25 mmol) was reacted with m-aminobenzamide (0.035 g, 0.26 mmol) and glyoxylic acid monohydrate (0.023 g, 0.25 mmol) to give, after purification by reverse phase HPLC, 16J (134 mg, 78%) as a pale yellow foam. MS (ESI) m/z 683.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[CH:20]1([N:23]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)(=[O:26])=[O:25])[CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].O>C(C(C)=O)C.CCOC(C)=O>[CH:20]1([N:23]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:11][CH2:10][O:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:39][CH2:38]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)(=[O:25])=[O:26])[CH2:22][CH2:21]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccc(C(OCCI)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
1-[Bis(4-fluorophenyl)-methoxy]-2-iodoethane (36) (294 mg, 0.79 mmol) was dissolved in 5 mL of methyl ethyl ketone and the mixture was added to N-cyclopropyl-N-(4-piperidinyl)-3-(trifluoromethyl)benzenesulfonamide (200 mg, 0.57 mmol) and K2CO3 (157 mg, 1.1 mmol). The mixture was then heated at 80° C. overnight. Water was added to the mixture, and EtOAc was used to extract the product. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by silica gel column eluting with CH2Cl2 and CH2Cl2/EtOAc (4:1) to afford the title compound 38 as a yellow oil. 1H NMR (CDCl3): δ 8.127 (s, 1H), 8.061-8.042 (d, 1H), 7.856-7.833 (d, 1H), 7.694-7.655 (t, 1H), 7.282-7.233 (m, 4H), 7.035-6.972 (m, 4H), 5.302 (s, 1H), 3.882-3.806 (t, 1H), 3.551-3.491 (t, 2H), 2.965-2.887 (d, 2H), 2.670-2.605 (t, 2H), 2.127-2.064 (t, 2H), 1.986-1.939 (m, 3H), 1.531-1.493 (d, 2H), 0.992-0.952 (m, 2H), 0.794-0.760 (m, 2H). LC: 100%. MS (e/z): 596 (M+H+).