Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C1(S([N:22]2[C:26]3=[CH:27][N:28]=[CH:29][CH:30]=[C:25]3[CH:24]=[CH:23]2)(=O)=O)C=CC=CC=1.CN(C)CCN(C)C.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]=[O:46].[Cl-].[NH4+]>O1CCCC1>[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([C:23]1[NH:22][C:26]2=[CH:27][N:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1)[OH:46]
Reactant: O=Cc1ccccn1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccncc21
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccccn1)c1cc2ccncc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of diisopropylamine (0.43 mL, 3.07 mmol) in tetrahydrofuran (4 mL) was cooled to −78° C. under a nitrogen atmosphere. n-Butyllithium (1.24 mL of a 2.5 M solution in hexanes) was added dropwise and the reaction mixture was stirred for 30 min at −78° C. and then warmed to −30° C. A solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (Reference Example 12) (400 mg, 1.55 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.24 mL, 1.59=mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred for 30 min. A solution of 2-pyridinecarboxaldehyde (0.30 mL, 3.14 mmol) in tetrahydrofuran (3 mL) was added dropwise at −30° C. The reaction mixture was allowed to warm to ambient temperature over 1.5 h. Saturated ammonium chloride solution (7 mL) was added to quench the reaction mixture. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed successively with water and brine, dried over sodium sulfate and concentrated to dryness. Purification by Biotage chromotography (silica, 2 to 18% methanol in methylene chloride) produced (pyridin-2-yl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (67 mg, 12%) as an off-white solid: mp 166-169° C.; 1H NMR (500 MHz, CD3OD) δ6.05 (1H, s), 6.39 (1H, s), 7.34-7.36 (1H, m), 7.50-7.52 (1H, m), 7.72 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=6.0 Hz), 8.00 (1H, d, J=5.6 Hz), 8.52 (1H, d, J=4.8 Hz), 8.62 (1H, s); ESI MS m/z 226 [C13H11N3O+H]+; HPLC (Method A) 98.9% (AUC), tR=13.1 min.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])(=[O:6])=[O:5].[OH-].[Na+].O>O1CCCC1>[CH:3]([S:4]([CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])=[O:5])=[CH2:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)S(=O)(=O)CCCl)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)CCCCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 8-(2-chloroethylsulfonyl)-12-acetoxyheptadecanoate (43.5 g., 0.09 mole), sodium hydroxide (14.4 g., 0.36 mole), water (150 ml.) and tetrahydrofuran (600 ml.) is stirred at 25° C. for 24 hours. Most of the tetrahydrofuran is removed by evaporation in vacuo keeping the temperature of the evaporating solution at 30° C. or below. The residue is diluted with water (300 ml.) and extracted with ether. The aqueous solution is acidified with dilute hydrochloric acid. The oily product is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated to leave the product as a yellowish, very viscous oil. Purification is effected by column chromatography on silica gel with benzene-dioxane as eluting solvent mixture. The title compound is obtained as a colorless viscous oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.C[O:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][C:19]1[C:18](=[O:17])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:15])[C:5]2[N:6]=[C:7]([S:13][CH3:14])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: CSc1ncc(C=O)c(NC[C@@H](C)O)n1
Reactant: COC(=O)COc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@@H](C)O)c2n1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
To a mixture of 4-((R)-2-hydroxy-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (17.7 g, 78 mmol) and (2,4-difluorophenoxy)acetic acid methyl ester (31.6 g, 156 mmol) in anhydrous dimethyl formamide (300 mL) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60° C. and after 18 hours, reaction mixture was cooled and DMF was distilled off. Residue suspended in water (300 mL) and extracted with dichloromethane, washed with brine and dried over magnesium sulfate. Filtered and concentrated under vacuum to give 29.5 g crude material which was chromatographed on silica gel column eluding with 1% methanol in dichloromethane to give 17.5 g 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec M+1=274).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15][C:14](OCCCl)([O:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[I-].[Na+]>ClCCl.CN(C=O)C.O.C(=O)([O-])O.[Na+].[BH4-].[Zn+2].[BH4-].C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:15][CH2:16]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C12CCC(OCCCl)(OCCCl)CC2
Reactant: C1COCCN1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Br)ccc2C12CCC(OCCN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of zinc borohydride (0.25 M in diethyl ether, 3.48 mL, 0.87 mmol) was added dropwise over a 5 minute period to a stirred, cooled (ice-bath) suspension of 6′-bromo-4,4-bis(2-chloroethoxy)spiro[cyclohexane-1,3′-indolin]-2′-one (preparation 14a, 0.81 g, 1.9 mmol) in dichloromethane (5 mL). Subsequently, trimethylsilyl chloride (0.46 mL, 3.64 mmol) was added dropwise and the mixture was warmed to ambient temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the mixture and stirring was continued for 1 hour. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give a white solid. The solid was taken up in N,N′-dimethylformamide (6 mL), morpholine (0.45 mL, 5.1 mmol) and sodium iodide (0.2 g, 1.6 mmol) were added, and the mixture was heated with stirring to 85° C. in a sealed tube. After stirring overnight, the mixture was diluted with water, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was extracted with 2M aqueous hydrochloric acid solution (3×20 mL) and the combined aqueous layer was washed with ethyl acetate. The resulting aqueous solution was made strongly basic with solid sodium hydroxide and then extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated and the residue was purified by flash chromatography (100:1 to 25:1 dichloromethane/methanol) to give the title compound (0.21 g, 28%, 92:8 mixture of isomers) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:21]>CS(C)=O.CCOCC.O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([Cl:21])[CH3:9])[CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CC(O)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CC(O)C1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]cyclobutanol (170 mg, 0.628 mmol) in dimethyl sulfoxide (1 mL) was added cyanuric chloride (64 mg, 0.34 mmol). After stirred overnight, the reaction mixture was diluted with ether and water. The aqueous layer was extracted with ethyl acetate once. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with silica gel column to give the desired product (39.6 mg, 22%). LCMS calculated for C14H18ClO2(M−Cl)+: m/z=253.1; Found: 253.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH2:19][OH:18])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1CCO
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.347 mmol) in anhydrous DMF (5 mL) under a nitrogen atmosphere was added ethyl carbonate (122 mg, 1.387 mmol), K2CO3 (96 mg, 0.694 mmol), and 18-crown-6 (18.31 mg, 0.069 mmol). The reaction mixture was heated to 80° C. for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-6-(2-hydroxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (80 mg, 0.291 mmol, 84% crude yield) The material was carried on without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2, 275.1]; 1H NMR (400 MHz, MeOD) δ 9.55 (s, 1H), 8.87 (d, J=5.6 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.44 (dd, J=8.4, 2.0 Hz, 1H), 4.57 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][N:6]1[CH:14]([CH:15]([N+:17]([O-])=O)[CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:20])[CH3:2]>[Pd].C(O)(=O)C.O>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[CH:14]([CH:15]([NH2:17])[CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:20])[CH3:23]
Reactant: CCOC(CN1C(=O)c2ccccc2C1C(C)[N+](=O)[O-])OCC
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(CN1C(=O)c2ccccc2C1C(C)N)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
A mixture of the two isomers of 2,3-dihydro-2-(2,2-diethoxyethyl)-3-(1-nitroethyl)-isoindol-1-one (2.5 g, described in Example 30) and 10% palladium on carbon (0.25 g) in acetic acid-water (4:1, 50 ml) is stirred under an atmosphere of hydrogen at 50 psi and 25° C. for 18 hr and filtered. The filtrate is evaporated and dissolved in 2% hydrochloric acid. The solution is washed with diethyl ether, basified to pH 9 with ammonium hydroxide and extracted with ethyl acetate. The organic extract is dried, evaporated and chromatographed on silica gel using acetone-benzene (2:3). Evaporation of the eluates gives isomer A (1.14 g) of the title compound, ir (CHCl3) 1675, 1120 and 1050 cm-1 and isomer B (0.88 g) of the title compound, ir (CHCl3) 1675, 1120 and 1050 cm-1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20][CH2:19]2>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19]2
Reactant: COc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 6-methoxy-1,2,3,4-tetrahydroquinoline (1.0 g, 6.13 mmol) using method A to give 4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid as an off-white solid. Yield: 358 mg (46%). 1H-NMR: 8.04 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0, 3.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 3.75-3.70 (m, 5H), 2.29 (t, J=7.0 Hz, 2H), 1.53-1.45 (m, 2H).
Reaction SMILES: ClC1N=CC=CN=1.Br.Br.Br.NCCN1CCC(N[C:21]2[N:25](CC3C=CC(F)=CC=3)[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)CC1.C(=O)([O-])O.[Na+]>C(O)C>[N:25]1[C:24]2[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=2[NH:22][CH:21]=1
Reactant: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: Clc1ncccn1
Agent: O=C([O-])O
Solvent: CCO
Product: Oc1ccc2nc[nH]c2c1

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 9.66 parts of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-5-ol trihydrobromide, 5 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 5.2 parts (83%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]amino]-1e,uns/H/ -benzimidazol-5-ol; mp. 194.4° C. (compound 64).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[C:24]3[N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]2)=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[C:24]3[N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH:36]=[O:37])[CH2:31][CH2:30]2)=[CH:38][CH:39]=1
Reactant: COc1ccc(COc2cccc3c(N4CCN(CCO)CC4)ccnc23)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cccc3c(N4CCN(CC=O)CC4)ccnc23)cc1
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
To a stirred solution of oxalyl chloride (1.8 mL, 20.33 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (2.8 mL, 40.66 mmol). The reaction mixture was stirred for 10 minutes followed by addition of compound 26 (4.0 g, 10.16 mmol, solution in 10 mL of CH2Cl2). The reaction mixture was stirred at the same temperature for 12 minutes. Then Et3N (8.4 mL, 60.98 mmol) was added and stirring was continued for another 1 hour and 20 minutes allowing the reaction mixture to come to room temperature. The reaction mixture was quenched by addition of water and extracted with CH2Cl2 (3×75 mL). The combined organic layer was washed with water and brine and finally purified by silica gel column chromatography (EtOAc/MeOH, 9.5:0.5) to yield 3.06 g (77%) of compound 27 as thick oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.45-2.90 (m, 4H), 3.02-3.40 (m, 4H), 3.34 (s, 2H), 3.69 (s, 3H), 5.25 (s, 2H), 6.64-7.04 (m, 4H), 7.16-7.56 (m, 4H), 8.60-8.76 (m, 1H), 9.68 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:30][CH2:29][N:28]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.3 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1402.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:32])([C@:11]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)([S:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[CH3:12])[CH3:10].C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[ClH:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:32])([C@:11]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)([S:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(S[C@@](C)(n2cncn2)[C@](C)(O)c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@](SC1CCNCC1)(n1cncn1)[C@](C)(O)c1ccc(F)cc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In 20 ml of ethyl acetate were dissolved 557 mg (1.05 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)piperidin-4-yl]thio]-2-butanol, and 2.63 ml (10.5 mmol) of a 4N hydrogen chloride-ethyl acetate solution were added to the solution, followed by stirring of the resulting mixture at 40° C. for 8 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to obtain 460 mg (yield: 100%) of the desired compound as a colorless powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[OH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37](O)=[O:38])=[CH:32][CH:31]=[CH:30]2>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:37]([C:33]4[C:34]5[C:29](=[CH:28][C:27]([OH:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][CH:32]=4)=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cc(O)ccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 6-hydroxynaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [C-:1]#[C-:2].[Na+].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20].N>>[CH:20]#[C:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:1][CH3:2]
Reactant: CCCC/C=C\CCCCCCCCCBr
Reactant: [C-]#[C-]
Agent: N
Agent: [Na+]
Product: C#CCCCCCCCCC/C=C\CCCC
Reaction time: 3 h

Procedure:
The reaction mixture containing sodium acetylide is then admixed with 1-bromo-Z-10-pentadecene in an amount of 0.8 to 1.2 moles per mole of the sodium acetylide and the reaction is effected at a temperature in the range from -20° to +20° C., usually, for 1 to 5 hours. After completion of the reaction, the reaction mixture is freed from ammonia and washed with water or diluted hydrochloric acid followed by isolation of the pro-duct by a conventional procedure including the methods of solvent extraction, distillation, column chromatography and the like to give the desired Z-12-heptadecen-1-yne in a good yield which is usually in the range from 65 to 85% based on the amount of the sodium metal.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:18]2([CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)OC1>>[ClH:1].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:21]2[CH2:22][CH2:23][C:18]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[CH:12][CH:11]=[CH:10][C:9]=4[O:13][CH3:14])[NH:3]3)[CH2:19][CH2:20]2)=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: COc1cccc(N)c1C(=N)N
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Product: COc1cccc2c1C(N)=NC1(CCN(C(=O)c3ccc(C#N)cc3)CC1)N2

Procedure:
This was prepared with 2-amino-6-methoxybenzamidine dihydrochloride (Example E) and 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal by the method of Example 1 to give the title compound as a yellow solid, m.p. 252°-253° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[CH3:24][C:25](=[CH2:28])[CH2:26][OH:27]>ClC(Cl)C.CN(C)C=O>[CH3:24][C:25]1([CH2:26][OH:27])[O:6][N:5]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH2:28]1
Reactant: C=C(C)CO
Reactant: Cc1ccccc1C=NO
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1ccccc1C1=NOC(C)(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 g of 2-methylbenzaldehyde oxime was dissolved in 1 L of dichloroethane, and then, 65 g of N-chlorosuccinimide and 100 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by thin layer chromatography (TLC). When 2-methylbenzaldehyde oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature of 0° C., and then 56 g of NaHCO3 and 41 mL of 2-methyl-2-propene-1-ol were sequentially added thereto. The reaction mixture was stirred at room temperature overnight, and then washed with water, and then, an separated organic layer was dried and concentrated by using magnesium sulfate, and then, purified by column chromatography to obtain 70 g of (5-methyl-3-o-tolyl-4,5-dihydroisoxazole-5-yl)methanol. The obtained compound was dissolved in 1 L of toluene, and then, 1 L of water, 90 g of NaOH, and 4.5 g of tetrabutylammonium hydrogensulfate were added thereto. After the reaction mixture was stirred for 30 minutes at room temperature, 77 g of 2,6-difluorobenzyl chloride was slowly dropped thereto. The reaction mixture was stirred at a temperature of 60° C. for 5 hours and cooled, and then, a separated organic layer was washed with water and then dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 88 g of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-o-tolyl-4,5-dihydroisoxazole.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]3[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]=3[C:5]=2[CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NOc1ccc(Br)cc1
Agent: Cl
Product: O=C1CCCc2oc3ccc(Br)cc3c21
Yield: 34.8 %

Procedure:
The product of Example 29, step A (1.0 g, 4.45 mmol) and cyclohexane-1,3-dione (750 mg, 6.68 mmol) were reacted following the procedure of Example 44, step A. Purification by flash column chromatography (SiO2, 90:10 hexanes/ethyl acetate) provided 8-bromo-3,4-dihydrodibenzo[b,d]furan-1(2H)-one (410 mg, 35%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J=1.8 Hz, 1H), 7.42 (dd, J=8.7, 2.1 Hz, 1H), 7.33 (dd, J=8.7, 2.7 Hz, 1H), 3.04 (t, J=6.3 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.28 (m, 2H).