Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[CH2:9]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[CH2:9][Cl:3]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Cl)cc(Cl)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 12.5 g of thionyl chloride in 20 ml of chloroform is added dropwise, at RT, to a solution of 14.5 g of 3,5-dichlorobenzyl alcohol in 150 ml of chloroform, followed by heating at 40-50° C. for 8 hours and stirring at RT overnight. The mixture is concentrated under vacuum to give 16 g of the expected product, which is used without further processing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]1)[CH:5]=[O:6]
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (40.0 g) in DMF (533 mL), 4-methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added at room temperature, and the reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with tert-butyl methyl ether to obtain 10.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN([CH:33]=[O:34])C.[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:7]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:33]=[O:34])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A cooled (−78° C.) yellow solution of 1-(triphenylmethyl)imidazole (25.000 g; 80.542 mmol) in anhydrous THF (750 ml) was treated dropwise (in 55 min.) with a 1.6M solution of butyllithium in hexanes (55.35 ml; 88.560 mmol). After addition, the resulting pink homogeneous solution was further stirred at −78° C., under nitrogen, for 30 min. before a solution of anhydrous DMF (6.8 ml; 88.186 mmol) in anhydrous THF (40 ml) was added dropwise (in 40 min.). The resulting mixture was additionally stirred at −78° C., under nitrogen, for 1 h before aq. sat. NH4Cl (50 ml) was added dropwise. Ether (300 ml) and water (400 ml) were successively added, and this mixture was allowed to warm-up to rt. The yellow organic layer was additionally washed with water (300 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=30/1) to give the pure product 1-trityl-1H-imidazole-2-carbaldehyde as a pale yellow solid which was further dried under HV (20.660 g; 76%). LC-MS: tR=1.03 min.; [M+H]+: no ionisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14]OC)[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[NH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: NC(CCCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4-(4-Chlorophenyl)-4-(methoxyimino)butanoic acid (Intermediate 53) (6.43 g, 26.61 mmol) in tetrahydrofuran (30 mL) was cooled, under an atmosphere of nitrogen, in an ice-methanol bath. Borane-tetrahydrofuran complex (1.0M in THF) (93 mL, 93.12 mmol) was added dropwise over a period of 20 minutes. The resulting solution was allowed to warm to room temperature, stirred for 1 hour then heated at reflux for a further 6 hours. After cooling in ice-water the mixture was treated with water (20 mL) dropwise with stirring over 10 minutes. The mixture was again allowed to warm to room temperature and stirred for 2 hours before evaporating the bulk of the solvent. The residue was then cooled in ice-water and 50% NaOH (aq.) (20 mL) added dropwise with stirring. The resulting mixture was stirred and heated at 90° C. for 4 hours then cooled to room temperature and extracted three times with Et2O. The combined extracts were washed with water followed by brine, dried over MgSO4 and evaporated to dryness. The crude product was then purified by flash silica chromatography (eluent 0-10% 7N ammonia in MeOH/DCM) and pure fractions evaporated to afford 4-amino-4-(4-chlorophenyl)butan-1-ol (3.88 g, 73.0%) as a colourless, transparent gum.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([S:23][CH3:24])[NH:17][C:16]2=[O:25]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([S:23]([CH3:24])=[O:9])[NH:17][C:16]2=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Br)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
m-Chloro-perbenzoic acid (3.3 g, 19 mmol) was added to a solution of 6-bromo-2-methylsulfanyl-3H-quinazolin-4-one (2.5 g, 9.2 mmol) in dichloromethane (200 ml), and the mixture was stirred at room temperature for 24 hours. The obtained solution was washed with an aqueous potassium carbonate solution and then concentrated, and the precipitated solid was filtered out and washed with aqueous hydrochloric acid to obtain 6-bromo-2-methylsulfinyl-3H-quinazolin-4-one.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 392.88 g/mol.
Reaction SMILES: C(OC([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([NH:29][C@H:30]2[CH2:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[C:19]=1[CH3:43])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=O)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[NH:32]1[CH2:33][CH2:34][CH2:35][C@H:30]([NH:29][C:20]2[C:19]([CH3:43])=[C:18]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=3)[N:23]3[N:24]=[CH:25][CH:26]=[C:22]3[C:21]=2[C:27]#[N:28])[CH2:31]1.[F:44][C:45]([F:50])([F:49])[C:46]([O-:48])=[O:47]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(C)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c3ccnn23)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(Nc2c(C)c(N[C@H]3CCCNC3)c(C#N)c3ccnn23)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
The crude product of tert-butyl (3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyphenyl)amino]-4-cyano-6-methylpyrazolo[1,5-a]pyridin-5-ylamino}piperidinecarboxylate (45) (6.1 mg) was dissolved in dichloromethane (350 μL). To this solution, trifluoroacetic acid (150 μL) was added and the mixture was stirred at room temperature for 1 h. The solvent and trifluoroacetic acid were removed under reduced pressure and the residue was purified with preparative HPLC to obtain the title compound (85) as trifluoroacetate salt (1.81 mg, Yield 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[CH3:24][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:16]=2)[CH:12]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1C
Reaction time: 0.25 h

Procedure:
Into a solution of ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (0.9 g) in DMF (10 ml) was added at 0° C. sodium hydride (60%, 0.14 g), and the resulting mixture was stirred for 15 minutes. Into the reaction mixture was added methyl iodide (0.22 ml), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration of the organic layer under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:4) and further to recrystallization (ethyl acetate/hexane) to obtain ethyl 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylate (0.80 g) as colorless crystals.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N:11]([Na])=[N+:12]=[N-:13]>CN(C=O)C.[Cl-].[Li+]>[C:2]1([C:1]2[NH:13][N:12]=[N:11][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=N[Na]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of benzonitrile (60.0 g, 581.9 mmol, 1.00 equiv) in DMF (anhydrous) (600 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. Ammonium chloride (40.5 g, 757.2 mmol, 1.30 equiv) was added, followed by the addition of lithium chloride (2.0 g, 47.2 mmol, 0.08 equiv). To the mixture was added azidosodium (49.4 g, 756.8 mmol, 1.30 equiv). The resulting solution was stirred overnight, while maintaining the temperature at 100° C. The solids were filtered out and washed with EtOAc. The filtrates were combined and concentrated under vacuum. The residue was dissolved in 350 ml of 10% NaOH aqueous solution. The resulting solution was extracted with 100 mL of EtOAc and the aqueous layers were combined. The pH value of the solution was adjusted to 2 with concentrated HCl. The solids were filtered out and dried over reduced pressure to yield 78.0 g (91%) of 5-phenyl-1H-tetrazole as a white solid. ES m/z: [M+H]+ calcd for C7H6N4, 147.1. found 147.1.
Reaction SMILES: [N:1]1([C:5]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[N:1]1([C:5]2([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#CC1(N2CCC2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(c1ccccc1)C1(N2CCC2)CCCC1
Yield: 47 %

Procedure:
The title compound (0.45 g, 47%) was prepared from 1-(1-azetidinyl)cyclopentanecarbonitrile D13 (0.60 g, 4.0 mmol), and phenyllithium in ethers (2.6 ml of a 1.7M solution; 4.4 mmol) in THF (5 ml), followed by reaction with sodium borohydride (0.456 g, 12 mmol) in methanol (5 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.67 (1H, m), 1.06 (1H, m), 1.32 (4H, m), 1.48 (2H, m), 1.91-2.03 (4H, m), 3.24 (4H, m), 3.83 (1H, s), 7.20-7.32 (3H, m), 7.44 (2H, m).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH2:28])[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH:28][C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][CH:7]=2)[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (1.38 g) and 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.38 g) in 250 ml of ethyl acetate was refluxed for 45 minutes. The solvent was removed under vacuum at 35° C. yielding a solid residue which was purified by chromotography using 200 g of silica gel eluting with benzene-acetone to give 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.Cl.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C@@H:14]2[CH2:15][CH2:16][O:12][CH2:13]2)[C:5]([CH3:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Reactant: N[C@@H]1CCOC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(Cl)nc1N[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.8 %

Procedure:
A mixture of 2,4,6-trichloro-5-methylpyrimidine (2 g, 10.2 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (1.12 g, 9.2 mmol) and Et3N (2.1 g, 20.3 mmol) in EtOH (20 mL) was stirred at room temperature for 14 h., concentrated under vacuum and the residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/0 to 2/1) to give the (R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (1.25 g, 53% yield) as a white solid. ESI-LCMS (m/z): 248.1 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH2:13]>C(#N)C.[Cl-].[Na+].O>[CH3:12][NH:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50 mL) at 0°. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2× with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(methylaminomethyl)nitrobenzene (4.04 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccccc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 58.6 %

Procedure:
A mixture of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (216 mg), phenylboronic acid (98 mg), tetrakis(triphenylphosphine)palladium (46 mg), 1M sodium carbonate solution (1.2 ml). and dimethoxyethane (10 ml) was refluxed for 2 hours and cooled, and to the reaction solution was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1) and washed with water to give colorless crystals of 4-[(1,1′-biphenyl)-4-ylsulfonyl]-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (115 mg), which were dissolved in ethanol and a solution of 4N hydrochloric acid in ethyl acetate. The solution was concentrated under reduced pressure to give amorphous of the title compound.
Reaction SMILES: [C:1]1([CH:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.O.[OH:47]S([O-])(=O)=O.[K+]>CCOC(C)=O>[C:1]1([CH:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([C:29]([F:30])([F:31])[F:32])[C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=2)[CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:47])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COC(c2ccc(OC(COc3ccc(C)cc3)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(c2ccc(OC(COc3ccc(C=O)cc3)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 48 %

Procedure:
90 mg (0.15 mmol) of rac 1-(1-phenyl-2-p-tolyloxy-ethoxy)-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-benzene in 3 ml of a mixture of acetonitrile:water (9:1) were treated with 100 mg (0.18 mmol) of ceric ammonium nitrate at room temperature overnight. An additional 100 mg (0.18 mmol) of ceric ammonium nitrate were added and stirring was continued. EtOAc and 1M KHSO4 were added and the phases were separated. The inorganic one was extracted with EtOAC, the combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Column chromatography on silica gel gave 44 mg (48%) of rac 4-(2-phenyl-2-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzaldehyde, MS: 663 (M+OAc)−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:21]([CH3:24])[CH:22]=O>>[Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([N:10]2[CH2:9][CH2:8][CH2:24][NH:21][CH2:22][CH2:11]2)(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(O)c1ccc(Cl)c2ncccc12
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)c2ncccc12)N1CCCNCC1
Reaction time: 2 h
Yield: 54 %

Procedure:
To 14.2 g of 8-chloro-5-quinolinesulfonic acid were added 142 ml of thionyl chloride and 1.42 ml of dimethylformamide, followed by heating under reflux for 3 hours. Then, the thionyl chloride was removed under reduced pressure and the resultant residue was dissolved in 100 ml of ice water. The pH of the resultant solution was adjusted at 6 with a saturated aqueous sodium hydrogencarbonate solution. The solution was subjected to extraction with 100 ml of dichloromethane. The resultant dichloromethane layer was added dropwise to 100 ml of a dichloromethane solution containing 5.81 g of homopiperazine and 5.6 g of triethylamine over a period of 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 2 hours, washed with a 200 ml of water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a chromatography column packed with 500 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemicals Industries, Ltd., Japan) and using, as a solvent, a mixture of methanol and chloroform (5% methanol), to thereby obtain 10.2 g of 1-(8-chloro-5-quinolinesulfonyl)homopiperazine (54) (yield: 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)=[O:6].[CH2:36](B(O)O)[CH2:37][CH3:38]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=2)[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([CH2:36][CH2:37][CH3:38])[CH:34]=[C:33]([Cl:35])[CH:32]=2)=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc(Br)c2)cc1
Reactant: CCCB(O)O
Product: CCCc1cc(Cl)cc(C(=O)N(CCc2cc(F)cc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in analogy to example 3, using 3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide (Example B177) and n-propylboronic acid. 534.3 [ISP (M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:4][C:3]=1[F:36].C(Cl)Cl.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH3:11])[CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])=[CH:4][C:3]=1[F:36]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CNC[C@@H](CC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 106 (106 mg, 0.204 mmol) in MeOH (2 mL) and a small amount of DCM was added 4 M HCl in dioxane (764 μL, 3.06 mmol). The reaction was stirred at RT for 4 h. The reaction was concentrated and purified by reverse phase column chromatography (SP4) eluting with a MeCN/H2O gradient (0-80% MeCN) to afford 50.7 mg (54.5%) of I-17: LCMS (ACPI-pos) m/z 420.3 (M+H)+.
Reaction SMILES: C([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
Wash Fmoc-phenylalanine on Sasrin resin (1.00 g, 0.69 mmol) with DMF (20 mL×2). Add 20% piperidine in DMF (20 mL), agitate for 5 minutes, and drain the solvent. Repeat two times for 15 minutes. Wash the residue with DMF (20 mL×5) and then CH2Cl2 (20 mL×5). Dry the resin in a vacuum oven at 40° C. for 20 hours to give title resin.