Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(C)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Experimental Procedure: Triphenylphosphine (92.0 mg, 0.35 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (DIAD, 71.0 mg, 0.35 mmol) were dissolved to a 1:1 mixture of THF and toluene (4 mL); then mono-demethylated piperlongumine (50.0 mg, 0.18 mmol) was added. After 10 min, 2-(dimethylamino) ethanol (31.0 mg, 0.35 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum, and the crude product was subjected to flash chromatography (hexane/ethyl acetate=100/0 to 50:50), to afford the desired product in 90% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[BH-](OC(C)=O)(OC(C)=O)O[C:54](C)=O.[Na+].CC(O)=O>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]([CH2:44][N:45]5[CH2:51][CH2:50][CH2:49][N:48]([CH3:54])[CH2:47][CH2:46]5)[CH:38]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCCN(C)CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (30 mg, 0.051 mmol) was added 1-methylhexahydro-1H-1,4-diazepine (5.16 mg, 0.051 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified by Gilson HPLC (acidic conditions) and basified with an amine cartridge to afford 22.9 mg (62%) of the title compound. LC-MS m/z 681 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][CH:4]=1.[CH2:11]([Mg]Cl)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C[O:24]CC1>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:24])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: C1CCOC1
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 4-(methylthio)benzonitrile (25.0 g, 0.17 mol) in THF (100 mL) under N2 atmosphere was added phenethylmagnesium chloride (1.0 M in THF, 210 mL, 0.21 mol). The solution was heated to reflux for 4 hours, cooled to 0° C., and quenched carefully with water (10 mL). The resulting slurry was treated with 6 N hydrochloric acid (200 mL) and stirred at room temperature overnight. The THF was evaporated from the mixture, and the residue was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 2M NA2CO3, dried over Na2SO4, filtered, and concentrated to give a solid material. Recrystallization from EtOAc-Hex (1:4) afforded the title compound (41.5 g, 96%) as greenish plates. mp 105° C. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.5 Hz, 2H), 7.32-7.19 (m, 7H), 3.24 (t, J=6.8 Hz, 2H), 3.06 (t, J=6.8 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.2, 145.8, 141.3, 133.2, 128.48, 128.42, 128.38, 126.1, 125.0,40.2,30.2, 14.7; mass spectrum (API-TIS) m/z 257 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1SCc1ccccc1
Temperature: 140 °C
Yield: 71.49 %

Procedure:
In a stirred suspension of 96.37 g potassium carbonate in 700 gm dimethyl formamide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 g benzyl mercaptan in 300 gm dimethyl formamide was added in a period of two hours maintaining reaction temperature 80-90° C. The temperature of the reaction was raised up to 140° C. and then maintained for another three hours. 500 g water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 110 g white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 71.49% yield (Assay by HPLC 99.23%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccnc1Cl

Procedure:
A solution 2-Chloro-nicotinic acid (3.0 grams, 19.0 mmole), potassium carbonate (6.5 grams, 48.0 mmole) and benzyl bromide (2.8 ml, 24.0 mmole) in dimethylformamide (20 ml) was stirred at room temperature over night. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent (2.8 g). MW 247.69; MS (m/e) 247 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1S.OCC[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[N:10]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: OCCN1CCNCC1
Reactant: Sc1cccs1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1csc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
2-[1-(2'-hydroxyethyl)piperazino] thiophene 18 was prepared by warming a solution containing thiophene-2-thiol (1.16 g, 10.0 mmol.) and 1-(2-hydroxyethyl) piperazine (1.43 g, 11.0 mmol.) in toluene to reflux under an argon atmosphere for two hours. Completion of the reaction was confirmed by thin layer chromatography using a 4:1 ratio blend of hexane and ethyl acetate as the eluent. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was then concentrated onto 5 g of silica. The silica was added to a medium pressure chromatography column packed with silica. The column was eluted with a 4:1 ratio blend of hexane and ethyl acetate to yield the pure piperazino-thiophene 18 (1.62 g, 76.4% yield) as a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][C@H:38]([CH2:41][CH3:42])[CH2:39][OH:40]>>[OH:40][CH2:39][C@H:38]([NH:37][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:41][CH3:42]
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 89.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7]1.[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>ClC(Cl)C>[Cl:20][C:21]([Cl:26])([Cl:25])[C:22]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH3:5])[CH:10]=3)[CH:12]=2)[NH:17][CH:18]=1)=[O:23]
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
76.3 g of AlCl3 are suspended in 600 ml of dichloroethane under argon, and 22.7 g of the product 2 prepared above are incorporated in portions. During this addition, the orange solution changes colour to dark brown. After 10 min, 19.2 ml of trichloroacetyl chloride are slowly added dropwise. The reaction batch is cooled here using a water bath. When the addition is complete, the mixture is stirred at RT for a further 6 h before the suspension is filtered off with suction and the filter cake is washed with dichloromethane and water. The filter cake is transferred into a flask, and water is carefully added with ice-water cooling. The beige solid is filtered off with suction, likewise rinsed and subsequently dried at 70° C. in a vacuum drying cabinet for 3 h, giving 20.6 g. The acidic mother liquor is poured into ice-water, the suspension is likewise filtered off with suction as described above and dried, giving 10.3 g. The mother liquor is left to stand for 12 h, and precipitated product is filtered off with suction and dried, giving 0.4 g. The solids are combined; HPLC-MS: Rt=2.132 min; [M+H+]: 345.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.ClC1C=CC(O)=CC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C@H:14]([C@H:13]2[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:15])=[CH:22][CH:21]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: Oc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cc1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-chloro-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 565.6 [(M+H)+].
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C([O:15][C:16](=[O:54])[CH:17]([C:35]1[S:36][C:37]([CH2:40][N:41]2[C:45]([C:46]([O:48]C)=[O:47])=[C:44]([C:50]([O:52]C)=[O:51])[N:43]=[N:42]2)=[CH:38][CH:39]=1)[NH:18][C:19](=[O:34])[CH:20]([CH2:29][S:30]C(=O)C)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>O.CO>[C:50]([C:44]1[N:43]=[N:42][N:41]([CH2:40][C:37]2[S:36][C:35]([CH:17]([C:16]([OH:54])=[O:15])[NH:18][C:19](=[O:34])[CH:20]([CH2:29][SH:30])[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:39][CH:38]=2)[C:45]=1[C:46]([OH:48])=[O:47])([OH:52])=[O:51]
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2nnc(C(=O)OC)c2C(=O)OC)s1
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: O=C(O)c1nnn(Cc2ccc(C(NC(=O)C(CS)CCc3ccccc3)C(=O)O)s2)c1C(=O)O
Yield: 27.4 %

Procedure:
A solution of sodium sulphide nonahydrate (1.09 g) in water (6 ml) was added to a stirred solution of 2-[5-{4,5-di(methoxycarbonyl)triazol-1-ylmethyl}thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 71) (400 mg) in methanol (6 ml). The mixture partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was crystallised by trituration with ether and ethyl acetate, and the solid filtered off and washed with ether then dried under vacuum to give the title compound (92 mg). vmax (nujol) 3294, 1732, 1643 cm-1. m/z (M-H-).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH:15]([CH3:16])[C:14]([F:19])([F:18])[F:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(O)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC(C)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
To a solution of 630 mg (3.06 mmol) of methyl 5,6-dichloronicotinate (from Step A) and 349 μL (3.06 mmol) of 1,1,1-trifluoro-2-propanol in 10 mL of THF at −78° C. was added 3.1 mL (3.06 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). After stirring at −78° C. for 30 min and at 0° C. for 5 h, the reaction was quenched by adding 10 mL of saturated NH4Cl. The mixture was poured into brine and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on a Biotage 40M cartridge using 3:97 v/v Et2O/hexanes as the eluant gave 627 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.56 (d, J=6.4, 3H), 3.93 (s, 3H), 5.86 (m, 1H), 8.27 (d, J=2.1, 1H), 8.67 (d, J=2.0, 1H).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9]CCl.Cl.Cl[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([F:38])([F:37])[F:36])=[CH:32][CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:17]=1)=[O:15]>CO.O1CCCC1>[ClH:9].[NH:7]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:17]=1)=[O:15])[C:6]([NH2:8])=[NH:5]
Reactant: ClCCl
Reactant: O=C(Cl)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 14 cm3 (7 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.67 g (7 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran, 40 cm3 of dichloromethane and 0.525 g (1.4 mmol) of 3-chlorocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm3 of tetrahydrofuran, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.1 g of 3-guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 238° C. Mass spectrum (EI): m/e 397 (M+•), m/e 339 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:34]3)[CH2:32]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[O:28]CCO3)=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:56].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:56][C:16]([C:18]3[N:19]=[CH:20][C:21]([CH:24]=[O:28])=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:35]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[O:34]3)[CH2:32]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccc(C3OCCO3)cn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccc(C=O)cn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]hexane-1,4-dione (276 mg) in acetic acid (2 mL) was added ammonium acetate (466 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (80.0 mg, yield 32%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1ccc(N)c(C)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c(C)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,4-dimethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (90%) as a colorless solid: mp 207-208° C.; 1H NMR (300 MHz, DMSO-d6) δ9.95 (s, 1H), 7.69-7.61 (m, 1H), 7.49-7.34 (m, 2H), 7.31-7.13 (m, 4H), 7.09-6.95 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.71 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.25 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 167.7, 161.6, 161.2, 142.8, 136.6, 135.6, 134.4, 133.9, 133.5, 132.7, 131.3, 130.8, 129.1, 128.4, 127.8, 126.9, 126.7, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 65.4, 57.5, 41.4, 28.8, 21.0, 18.4, 15.6; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:36])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (271 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (1.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (271 mg, 90%) as a pale-yellow solid.
Reaction SMILES: Cl.Cl[C:3]1C=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44](C)(C)[CH3:45])=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][CH2:44][CH2:45][CH2:3][CH3:4])=[O:42])[CH2:38]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: CCCCNC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).