Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[CH:3]=1.C[O:28][C:29]1C=C(OC)C=C[C:30]=1[CH2:31][NH:32]CCCO.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>C(O)CCC.C(N(C(C)C)C(C)C)C.C(Cl)Cl>[NH2:8][C:6]1[N:7]=[C:2]([NH:32][CH2:31][CH2:30][CH2:29][OH:28])[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[N:5]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: COc1ccc(CNCCCO)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCO)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
78 mg (0.21 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]pyrimidine-2,4-diamine (from example 60), 190 mg (0.84 mmol) of 3-[(2,4-dimethoxybenzyl)amino]propan-1-ol in 1 ml of 1-butanol and 0.37 ml of N-ethyl-diisopropylamine are, in a closed pressure vessel, heated at 130° C. overnight. Volatile components are removed under reduced pressure, and the residue is purified by preparative HPLC. The substrate obtained is taken up in 2 ml of DCM, and 0.5 ml of TFA is added. The mixture is stirred at RT for 20 min and then poured into ethyl acetate and extracted with sat. sodium carbonate solution. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)C=C.B(Br)(Br)Br.CCCCCC.CO>ClCCl>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([OH:4])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCC=C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: C=CCOc1cc(O)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Methyl 3,5-diallyloxy-2-(4-methoxybenzoyl)phenyl-acetate (100 mg, 0.25 mmol) obtained in Example 15, Step 1 was dissolved in dichloromethane (10 mL). After the solution was cooled to −78° C., a 1.0 mol/L solution of boron tribromide in hexane (0.50 mL, 0.5 mmol) was added thereto, followed by stirring at −78° C. for 30 minutes. To the reaction mixture were successively added methanol and a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 18 (54 mg, 61%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:11][C:10]1([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:2]([CH3:3])([CH3:1])[CH2:12]1
Reactant: CC(C)(C)O
Reactant: C=C(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A mixture of 117.26 g of α-Methylstyrene (Aldrich 99%, 0.98 mol) and 73.0 g of t-Butanol (Aldrich 99%, 0.97 mol) were slowly added (1 hour) to a mixture of 200 g of acetic acid and 200 g of sulfuric acid, previously warmed at 40° C. The suspension so-obtained was stirred 30 min at 40° C. and then the 2 layers were separated. The organic layer was washed with a 0.7 M NaOH acqueous solution (3×50 ml, neutrality) and water (2×50 ml). The opaque yellow solution obtained was then distilled at 26 mbar. At about 100° C. a colourless transparent liquid was distilled off (28.43 g), which was characterized by NMR as pure 1,1,3,3 tetramethylindane (16.6% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=O.CCO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC(C)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A round bottomed flask was charged with palladium on carbon (327 mg, 0.308 mmol) and a stirbar. Ethyl 3-(2-nitrophenylamino)butanoate (776 mg, 3.08 mmol) in 1:1 EtOH:EtOAc (40 mL) was added, and the flask was evacuated and purged with hydrogen three times. Stirred at room temperature for 3 h. The mixture was filtered and concentrated to yield ethyl 3-(2-aminophenylamino)butanoate as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:29]3[CH:28]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[O:31][N:30]=3)=[O:33])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1cc(CN2CCOCC2)on1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cc(CN2CCOCC2)on1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.2 g, 0.72 mmol), 5-(morpholinomethyl)isoxazole-3-carboxylic acid (0.15 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.37 mL, 2.15 mmol) and EDCI (0.2 g, 1.07 mmol) using DMF (10 mL) as the solvent using the method of Example 34(d). Yield 72 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.39 (m, 4H), 3.56 (m, 4H), 3.71 (s, 2H), 4.34 (m, 2H), 4.46 (m, 1H), 6.62 (s, 1H), 6.76 (m, 1H), 7.83 (m, 1H), 7.88 (d, 1H), 8.03 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[B:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)([OH:30])[OH:26]
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanoic acid (15 g, 61.7 mmol) in anhydrous THF (150 mL) was added at −78° C. under argon a 2.5 M solution of n-butyllithium in hexane (37 ml, 92.6 mmol) dropwise, followed by triisopropyl borate (43 ml, 185.1 mmol). After the addition, the reaction mixture was stirred at −50° C. for 2 hrs and allowed to warm up to room temperature and stirred over night. The reaction mixture was quenched with 1 N HCl then extracted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 13 g of product as a white solid in 99% yield. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 6H), 7.25-7.27 (d, 2H), 7.29-7.47 (dd, 1H), 7.68-7.70 (d, 1H), 12.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C

Procedure:
To a stirred solution of optically enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.25 g, 3.25 mmol) in triethylamine (70 mL) was added ethynylbenzene (0.592 mL, 5.28 mmol), copper(I) iodide (67 mg, 0.352 mmol), and triphenylphosphine (653 mg, 2.464 mmol). Nitrogen was bubbled through the mixture for 10 minutes before adding dichlorobis(triphenylphosphine)-palladium(II) (202 mg, 0.282 mmol) with continued nitrogen gas bubbling. After an additional 10 minutes the reaction mixture was heated to reflux for 16 hours, cooled to ambient temperature, diluted with EtOAc, washed with water (3×), brine, dried over magnesium sulfate, and concentrated in vacuo. Column chromatography (25%-->40% EtOAc/Hex) provided optically enriched (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one which was separated by chiral SFC chromatography (Chiralcel OJ-H preparative column, 30×250 mm, 5 μm, Mobile Phase: 40% MeOH (0.1% DEA) in CO2 @ 150 Bar, Temp: 35° C., Flow rate: 70.0 mL/min. for 16 min, UV monitored @ 280 nM. tR=9.23 min) to provide (1.38 g, 2.99 mmol, 85% yield) of pure single enantiomer (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (d, J=2.21 Hz, 1H) 8.57 (s, 1H) 8.56 (d, J=2.20 Hz, 1H) 8.07 (t, J=2.05 Hz, 1H) 7.58-7.66 (m, 2H) 7.44-7.52 (m, 3H) 7.39-7.45 (m, 1H) 7.28-7.39 (m, 2H) 5.67 (d, J=6.62 Hz, 1H) 5.04 (d, J=6.62 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm 157.28; 157.24 (d, J=240.70 Hz) 155.92 (d, J=245.20 Hz) 151.63; 147.70; 136.78; 135.02; 131.57; 129.43; 128.89; 126.63 (dd, J=14.99, 7.72 Hz) 121.51; 119.47; 117.83 (dd, J=23.60, 9.10 Hz) 117.50 (dd, J=24.50, 8.20 Hz); 114.60 (dd, J=26.34, 4.54 Hz); 92.86; 85.76; 78.12; 59.43; LCMS (ESI) m/z calcd for C22H15F2N2O2: 377.11. found 377.20 [M+H]+; HRMS (ESI) m/z calcd for C22H15F2N2O2: 377.1096. found 377.1096 [M+H]+.
Reaction SMILES: C1(S[O:8][C:9](=O)[CH:10]([CH:26]([OH:28])[CH3:27])[CH:11]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]#[C:13][Si](C)(C)C)C=CC=CC=1.[OH-].[K+].Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C1COCC1.C(#N)C>[CH2:19]([N:18]1[CH:11]([C:12]#[CH:13])[CH:10]([CH:26]([OH:28])[CH3:27])[C:9]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(O)C(C(=O)OSc1ccccc1)C(C#C[Si](C)(C)C)NCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C#CC1C(C(C)O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.054 g (5.0 mmol) of 3-benzylamino-2-(1-hydroxyethyl)-5-trimethylsilyl-4-pentinic acid phenylthio ester dissolved in 40 ml of THF was added 3 ml of 4N potassium hydroxide and the mixture was stirred at room temperature for 3 hours. The resultant was neutralised with 2N hydrochloric acid and extracted with ethyl acetate six times while conducting salting out. The extract was dried with anhydrous magnesium sulfate and concentrated. To the concentrate were added 250 ml of acetonitrile and then 1.57 g (6.0 mmol) of triphenylphosphine and the mixture was vigorously stirred under reflux condition, to which a solution of 1.32 g (6.0 mmol) of 2,2'-dipyridyldisulfide in 50 ml of acetonitrile was added dropwise for 40 minutes. After reflux for 1 hour, the reaction solution was concentrated and purified twice with 50 g of silica-gel chromatography (developer methylene chloride→diethyl ether) and then with 50 g of silica-gel chromatography (developer hexane:diethyl ether 1:4) to give 801 mg of trans-form and 62 mg of cis-form of 1-benzyl-4-ethynyl-3-(1-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:15][O:14][CH2:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:16]([O:18][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:22])=[O:17])[CH2:10]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.4 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (2.00 g, 7.2 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (2.02 g, 7.8 mmol) in MeCN (35 mL) was added triethylamine (1.1 mL, 7.9 mmol). The solution was stirred at room temperature for 24 h and diluted with EtOAc. The solution was washed aqueous HCl (1M) and brine. The aqueous layer was backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide (2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (3.3 g, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:47])([CH3:46])[CH2:10][NH:11][C:12](=[O:45])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:21]=2)=[N:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([CH3:47])([CH3:46])[CH2:10][NH:11][C:12](=[O:45])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:21]=2)=[N:15][CH:14]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl(3-(6-((6-((4-(3-bromopropoxyl)benzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (10 mg) in DCM (3 mL) was added TFA (0.3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give N-(3-amino-2,2-dimethylpropyl)-6-(6-(4-(3-bromopropoxyl)benzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamide (8 mg).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:10][C:9]([N:24]2[C:32](=[O:33])[NH:31][C:30]3[C:25]2=[N:26][C:27]([CH3:36])=[N:28][C:29]=3[O:34][CH3:35])=[C:8]([Cl:37])[CH:7]=1)(O)=[O:2].[C:38](N1C=CN=C1)([N:40]1C=CN=C1)=O.CN.Cl>O1CCCC1>[Cl:37][C:8]1[C:9]([N:24]2[C:32](=[O:33])[NH:31][C:30]3[C:25]2=[N:26][C:27]([CH3:36])=[N:28][C:29]=3[O:34][CH3:35])=[CH:10][C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[C:6]([CH:7]=1)[O:5][CH2:4][C:1]([NH:40][CH3:38])=[O:2]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1OCC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 9-[4-carboxymethoxy-2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)phenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (80 mg) in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (48 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylamine (40% methanol solution, 1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=6/1) to give the title compound (63 mg).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:13][C:14](=[O:39])[C@@H:15]([N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](=[O:12])[CH2:10][F:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:30]([NH:29][C:25]1[C:24](=[O:38])[N:23]([C@@H:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([NH:13][CH:8]([C:9](=[O:12])[CH2:10][F:11])[CH2:7][C:6]([OH:40])=[O:5])=[O:39])[CH:28]=[CH:27][CH:26]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(=O)CF
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 3(R,S)-[2(S)-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (776 mg, 1.41 mmol) in dichloromethane (6 mL) was cooled to 0° C. Trifluoroacetic acid (2 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 3 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The solid was then dried to constant weight under vacuum. This gave the title product as a pink solid (627 mg, 90%); 1H NMR (400 MHz, d6-DMSO) δ 2.59-2.95 (2H, m), 3.34-3.47 (2H, m), 4.30-4.81 (2H, m), 5.15-5.33 (2H, m), 5.87-6.09 (1H, m), 6.38 (1H, t), 7.15-7.32 (5H, m), 7.60-7.78 (4H, m), 7.92 (2H, d), 8.17-8.21 (1H, m), 9.01-9.11 (1H, m), 9.28 (1H, m), 12.51 (1H, br s); 19F NMR (376 MHz, d6-DMSO, proton-decoupled) δ−226.8, 232.6; M+H 494.4, M−H 492.4.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:5][CH:6]=[CH2:7].[OH-].[K+].Cl>O.CO>[CH2:7]=[CH:6][CH2:5][CH:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 95.6 %

Procedure:
13 g of the compound (5) and 6 g of potassium hydroxide were dissolved in a solution mixture of 70 ml of water and 30 ml of methanol, and reflux was carried out for 6 hours. After addition of the reaction solution to 400 ml of water, the mixture was then adjusted approximately to pH 1 with concentrated hydrochloric acid. The white precipitate generated was collected by filtration, washed with water, and dried at 40° C. under reduced pressure, to obtain 12 g of the compound (6). (Yield: 96%)
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH2:7][CH2:6]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: COc1cccc(CCl)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CN2CCc3cc(O)ccc3C2)c1
Reaction time: 5 h

Procedure:
4.3 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide, 3.1 g of 3-methoxybenzyl chloride and 2.8 g of finely powdered potassium carbonate are first stirred at room temperature for 2 hours and then at 80° C. for 5 hours. After cooling, the solvent is removed in vacuo, the residue is taken up with water/methylene chloride, and the organic phase is again shaken with water and dried over magnesium sulfate. After evaporation in a rotary evaporator, a yellow oil remains, and this crystallizes after trituration with ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:21]
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
In a pressure sealed vial, 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 107, mg, 0.19 mmol), 3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (WO2010079443, 50 mg, 0.17 mmol) and potassium carbonate (70 mg, 0.51 mmol) were stirred at 90° C. in dimethyl sulfoxide for 18 hours. The mixture was cooled down to room temperature and treated with 2M hydrochloric acid (5 mL). The mixture was stirred for 1 hour and the resulting precipitate was filtered and purified by preparative HPLC to afford the title compound (17 mg, 18%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1.Cl>CCO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1F
Yield: 58 %

Procedure:
4-Bromo-2-fluoroaniline and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, to give ethyl 4-(4-bromo-2-fluoroanilino)-6-chloronicotinate (58%); m.p. (EtOH/water) 150-152° C. 1H NMR [400 MHz, CDCl3] δ 9.74 (br s, 1H), 8.81 (s, 1H), 7.41 (dd, J=9.6, 2.2 Hz, 1H), 7.38-7.35 (m, 1H), 7.25 (t, J=8.3 Hz, 1H), 6.71 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (FAB+) 375 (16%).