Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18](=[N:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1OC)[O-:19].[CH3:29]S(C)=O>>[CH3:29][O:19][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(C)=O
Reactant: COc1ccccc1N=[N+]([O-])c1ccccc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [SH-]
Product: COc1ccccc1N(Nc1ccccc1)OC
Temperature: 75 °C
Yield: 88 %

Procedure:
85 Parts of an aqueous solution of 36 percent technical sodium hydrosulphide, containing 1 percent sodium thiosulphate, were added to a mixture comprising 51.6 parts of 2,2'-dimethoxy azoxybenzene in 100 parts dimethyl sulfoxide at 60° within one hour. Subsequently, the temperature of the reaction mixture was raised to 75° C and maintained at 70° C-75° C for 2 1/2 hours. The pH of the reaction mixture was maintained between 9.5 and 10.0. After this period the starting material was shown to be entirely reduced. Then the reaction mixture was cooled down to 0° C, the separated product was filtered off and washed with water until alkali-free. After drying below 70° C, 43.0 parts of high quality 2,2'-dimethoxyhydrazobenzene of a melting point of 100° C to 102° C were obtained, this repesenting a yield of 88 percent of the theory.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16](Br)=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]>O.CS(C)=O>[CH:4]([O:7][C:8]([N:10]1[C:19]2[C:14](=[N:15][C:16]([N:2]([CH3:3])[CH3:1])=[CH:17][CH:18]=2)[C@H:13]([N:21]([C:37](=[O:39])[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:12][C@@H:11]1[CH2:40][CH3:41])=[O:9])([CH3:6])[CH3:5]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(Br)ccc2N1C(=O)OC(C)C
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(N(C)C)ccc2N1C(=O)OC(C)C
Temperature: 100 °C
Yield: 57 %

Procedure:
Add N,N-dimethylamine 40% in water (0.5 mL) to a solution of (+/-)-cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-bromo-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (60 mg, 0.098 mmol) in dimethylsulfoxide (0.2 mL) and heat the mixture at 100° C. in a sealed tube for 15 h. Cool the reaction mixture to room temperature, add water and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue overa silica gel cartridge, eluting with hexanes/ethyl acetate to provide the title compound (32 mg, 57%). MS (ES+): 575 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl.CCN(C(C)C)C(C)C>[N:25]1([C:23]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][N:12]([CH2:13][CH2:14][CH3:15])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([NH:1][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:22][CH2:21]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)C(=O)Cl
Reactant: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-morpholin-4-yl-methanone (200 μL of 0.25 M in dichloromethane, 50 μmol ) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-(7-{[1-(morpholine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobutyramide (8.6 mg) 96, [M+H]+=485.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2ccccc2)n1
Yield: 84.2 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 10 min, benzylbromide (273 μL, 2.33 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-benzyl-3-nitro-1H-pyrazole (303 mg, 84%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 5.33 (2H, s), 6.84 (1H, d, J=2.7 Hz), 7.26 (2H, m), 7.32 (3H, m), 7.40 (1H, d, J=1.5 Hz).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:31])[CH3:30].N1C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][C:29](=[O:31])[CH3:30])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate is reacted with 1.1 equivalent of acetyl chloride and 1.0 equivalent of pyridine in benzene to yield ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-acetoxypentanoate. Similarly, using n-propanoyl chloride and isopropanoyl chloride yield the respective 3-n-propanate and 3-isopropanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc2nc(-c3ccc(O)c(Cl)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as an off-white solid, m.p. 254–256° C.; MS m/e 262 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Clc1ccc2c(c1)CNC2
Agent: Cl
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(Cl)cc4C3)cn2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-chloroisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.08 (2H, t, J=5.9 Hz), 3.90 (2H, s), 3.92 (2H, s), 4.20 (2H, t, J=6.0 Hz), 7.24 (2H, s), 7.31 (1H, s), 7.56 (1H, d, J=4.8 Hz), 7.80 (1H, s), 7.88 (1H, s), 8.27 (1H, s), 8.61 (1H, d, J=4.9 Hz). [M+H] Calc'd for C19H17ClN4O2, 369. Found, 369.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OS(=O)(=O)C(F)(F)F
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=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of trifluoromethanesulfonic acid 5-fluoro-2-nitrophenyl ester (4.0 mmol) in DME (10 mL) are added phenylboronic acid (4.8 mmol), Pd(PPh3)4 (0.4 mmol), and K3PO4 (3.2 mmol) at room temperature. After stirring at 80° C. for 6 h, the reaction mixture is filtered through celite, and the filter cake is washed with AcOEt. The filtrate is diluted with water and extracted with ether (×2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=6:1) to give the title compound; 1H NMR (CDCl3), δ 7.12-7.19 (2H, m), 7.29-7.32 (2H, m), 7.42-7.45 (3H, t), 7.94 (1H, dd).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-piperidone (12 mmol) in 200 mL of methylene chloride. is added triethylamine (18 mmol) in a single portion at room temperature and the reaction mixture cooled to 0° C. Benzyl chloroformate (12 mmol) is added dropwise via addition funnel and the reaction mixture allowed to warm to room temperature. Stirring is continued for 2 hours at room temperature. The reaction mixture is diluted with ethyl acetate (200 mL) and washed with 1N hydrochloric acid (3×100 mL), water and brine. The organic layer is worked up to provide N-Benzyloxycarbonyl-3-piperidone.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[C:25]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)CC(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Cu]I>[CH3:15][C:12]([CH3:13])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(NS(=O)(=O)c3ccccc3)nc12
Temperature: 153 °C
Yield: 98.3 %

Procedure:
A mixture of 1-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.25 g, 0.61 mmol), benzenesulfonamide (0.143 g, 0.91 mmol, 1.5 equiv.), CuI (0.023 g, 0.12 mmol, 20 mol %), N,N-dimethylglycine (0.013 g, 0.12 mmol, 20 mol %) and K3PO4 (0.323 g, 1.53 mmol, 2.5 equiv.) in DMF (2 mL) was heated under an argon atmosphere in a microwave oven at 153° C. overnight. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with DCM. The combined organic extracts was washed with H2O and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc in hexane (15% to 50% gradient over 20 min) to give 0.215 g of product as a pale yellow foam. 1H NMR (CDCl3): δ 8.50 (s, 1H), 8.29 (s, 1H), 7.99-7.96 (m, 2H), 7.61-7.47 (m, 3H), 5.67 (s, 2H), 2.64-3.58 (m, 2H), 1.38 (s, 9H), 1.00-0.94 (m, 2H), 0 (s, 9H); MS [M+H]+: 489.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Li+].[CH2:11](Br)[CH2:12][C@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14]>C(OCC)C.C1COCC1.[Cu](Cl)Cl>[CH3:14][C@@H:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:12][CH2:11][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=CCC[C@H](C)CCBr
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCC[C@H](C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A flask was charged with 100 mL of dry THF and cooled to 0° C. To this flask was added 103 mL (205 mmol) of 2 M cyclohexylmagnesium chloride in diethylether. Then 2.30 g (17 mmol) copper (II) chloride was taken up in 60 mL of THF and added as a slurry to the Grignard reagent. To this mixture was added 0.73 g (17.1 mmol) lithium chloride, and the mixture was stirred at 0° C. for 30 minutes. Then 13.5 mL (68.4 mmol) of (S)-citronellyl bromide was added, and the mixture was stirred 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of sat. aq. NH4Cl until bubbling ceased. The THF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The combined ether layers were dried over MgSO4. The drying agent was removed by filtration. The solvent was removed under reduced pressure to yield 11.48 g (76% yield) of a clear oil. The crude long-chain alkyl was not readily characterized, and was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH:27]=O>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:27][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][C:19]=4[F:18])[C:23]#[N:24])[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: N#Cc1ccc(F)c(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (119 mg, 45%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (150 mg, 0.56 mmol) and 4-fluoro-3-formylbenzonitrile (83 mg, 0.56 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 7.15 (t, 1H), 7.00 (s, 1H), 5.00 (d, 1H), 4.20 (m, 1H), 3.60 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 401.09; Observed: 402.1 (M++1).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH:18]1([C@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](C1CCCCC1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 63.8 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 127 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 210 mg of the desired product as a colorless powder. Yield: 64%. m.p. 147-148° C.; [α]20D=−5.13° (C=0.658 AcOEt); MS(EI+) 329(M)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccccc1C1=CCCCC1
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
A solution of o-bromofluorobenzene (17.5 g; 0.10 mole) in 150 ml of dry tetrahydrofuran (THF) was chilled to -60° and n-butyllithium (50 ml of 2.4M; 0.12 mole) was added dropwise at a rate such that the reaction temperature did not rise above -55°. When the addition was complete a solution of cyclohexanone (10.0 g; 0.10 mole) in 50 ml of THF was added, again maintaining the reaction temperature below -55°. The reaction was then allowed to come to room temperature over 90 minutes and was quenched by the addition of 10 ml of saturated NH4Cl solution. An additional 400 ml of water was added, then the organic layer was separated and dried. The aqueous phase was extracted again with ethyl acetate, then the combined, dried, organic phases were concentrated to an oil. This oil was dissolved in 200 ml of glacial acetic acid and treated with 1 ml of concentrated H2SO4. The acetic acid was concentrated to about 30 ml on a rotary evaporator, then diluted with 250 ml of water and the solution made basic with 50% NaOH. Extraction with ether, followed by drying and concentration under reduced pressure gave an oil that was distilled at 0.15 mm to give 9.26 g (53%) of 1-(2-fluorophenyl)cyclohexene, b.p. 70°-72°, that was homogeneous to thin layer chromatography (TLC).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[NH:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:17]=1)C.[OH-].[Na+:34]>O1CCOCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:15]2[CH:16]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[NH:17][C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]([O-:32])=[O:3])=[N:14]2)=[CH:30][CH:29]=1.[Na+:34]
Reactant: CCOC(=O)COc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C([O-])COc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.3 %

Procedure:
{2-[4,5-Bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-phenoxy)-acetic acid ethyl ester (35 mg, 0.075 mmol) was dissolved in 1.5 mL of dioxane, and 0.5 M sodium hydroxide solution (1.5 mL, 0.75 mmol) was added. The reaction mixture was stirred at room temperature for 23 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (Biotage system, 12S-C18 reverse phase) eluting with 0-25% acetonitrile in water to afford sodium {2-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-phenoxy}-acetate (22 mg, 63%). HR-MS (ES, m/z) calculated for C23H19N2O3Cl2 [(M−Na+2H)+] 441.0767, observed 441.0767.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[N:11][CH:12]=1.CN(CCN(C)C)C.[I:28]I>C1COCC1>[F:6][C:7]1[C:8]([I:28])=[C:9]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH:10]=[N:11][CH:12]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cncc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cncc(F)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 2.5M solution of nBuLi (30.6 mL, 76 mmol) in hexanes was added drop-wise to a solution of N-(5-fluoropyridin-3-yl)-2,2-dimethylpropanamide 5.0 g, 25.5 mmol) and TMEDA (11.54 mL, 76 mmol) in THF (127 mL) at −78° C. over 1 hour, while ensuring the internal temperature did not go above −70° C. The resulting solution was stirred at −78° C. for 1 hour. Iodine (19.40 g, 76 mmol) in THF (20 mL) was added drop-wise over 30 min ensuring the internal temperature remained below −70° C. The resulting reaction was stirred for 1 hour at −78° C. The reaction was quenched at −78° C. with water and then warmed to ambient temperature. 10% Aqueous sodium thiosulfate was added until the iodine color dissipated and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (8.21 g, 25.5 mmol, 100% yield), MS (ESI): m/z=323.26 (MH+), 100% pure by LCMS.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:31]2[CH2:32][CH2:33][CH:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(CC2CCN(CC3CN(Cc4ccccc4)CC3c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 22 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 0.013 mL of 4-benzyl-piperidine and 24 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9 to provide 14 mg of the title compound. RF: 0.39 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ1.2-1.9 (m, 8H), 2.3-3.0 (m, 11H), 3.7 (ABq, 2H), 7.1-7.4 (m, 15H). Mass Spectrum (NH3 -CI): 425.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:50][CH2:51][C:52]6[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=6)=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCc1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4ccncc4)cc3)cn2)cc1
Yield: 131.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (80.0 mg, 0.121 mmol) obtained in Step A in Example 1-D-19 and 4-(aminomethyl)pyridine (18.5 μl, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-pyridin-4-ylmethyl-benzamide as a brown solid (119 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-264) as a yellow powder (46.7 mg, 76%).