Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:20][C:21](=[O:34])[CH:22]([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:36]>C1COCC1>[CH2:13]([O:20][C:21](=[O:34])[C:22]([Br:36])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(CCOCc1ccccc1)C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(Br)(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 47.6 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.01 mL, 2.54 mmol) was added to a solution of diisopropylamine (0.376 mL, 2.658 mmol) in THF (10 mL) at −30° C. under a nitrogen atmosphere. Stirring at −30° C. was continued for 45 min, and the reaction mixture was cooled to −78° C. A solution of 4-benzyloxy-2-methylbutyric acid benzyl ester (0.721 g, 2.416 mmol) in THF (8 mL) was added over 5 min and stirring at −78° C. was continued for 1 h. A solution of carbon tetrabromide (CBr4) (1.20 g, 3.62 mmol) in THF (2 mL) was added and the mixture was slowly warmed to 0° C. over 3.5 h. The reaction mixture was quenched by addition of a saturated solution aqueous of NH4Cl and then extracted with EtOAc (×2). The combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-18% EtOAc in cyclohexane) affording 4-benzyloxy-2-bromo-2-methylbutyric acid benzyl ester (0.434 g), used in the following step without further purification.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[CH:18]2>C(=S)=S>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([C:16]1[CH:15]=[CH:14][C:13]([OH:12])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:23])[NH:21]2)=[O:4]
Reactant: CCC(Br)C(=O)Br
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(Br)C(=O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 50 °C
Yield: 70.1 %

Procedure:
50 g of α-bromobutyric acid bromide (V), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (VI). The resulting mixture was heated at a temperature of 50° C for 13 hours and the carbon disulfide layer was removed by decantation. Crushed ice was added to the residue to crystallize the product, and the crystals thus formed were filtered, washed with water and then recrystallized from methanol to obtain 27 g of 5-(α-bromobutyryl)-8-hydroxycarbostyril (VI) having a melting point of 218°-219° C (with coloring and decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[CH2:7]2
Reactant: CN1C(=O)Cc2cccc(F)c21
Reactant: O=[N+]([O-])O
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7-Fluoro-1-methyl-1,3-dihydro-indol-2-one (7, 2.00 g, 0.0119 mol) is added portion wise to 70% nitric acid (10 ml) at −10° C. After the addition is complete, the reaction is allowed to warm to room temperature and then stirred for 20 hours. The mixture is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a solid. HPLC r.t. 4.40 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[Cl:15].Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7]([N:19]([CH3:20])[CH3:18])=[CH:6][C:5]=1[Cl:15]
Reactant: CNC
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N(C)C)cc1Cl
Temperature: 65 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a stirred solution of 6.00 g (22.5 mmol) 2-Chloro-4-fluoro-5-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 15 h at 65° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 20a was obtained in 59% yield (3.87 g, 13.3 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[CH:14]=2)=[O:9])[CH:7]=1.Cl>CO>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]([C:10]1[N:11]=[N:12][N:13]([CH3:15])[CH:14]=1)=[O:9]
Reactant: Cn1cc(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])nn1
Agent: Cl
Solvent: CO
Product: Cn1cc(C(=O)c2cc(Cl)ccc2N)nn1
Temperature: 100 °C

Procedure:
To 51 mg (0.19 mmol) of (5-Chloro-2-nitro-phenyl)-(1-methyl-[1,2,3]triazol4-yl)-methanone in 2 ml of methanol were added 0.05 ml of 12M HCl and 200 mg (0.89 mmol) of stannous (II) chloride monohydrate, and the mixture was heated at 100° C. for four hours. The mixture was then cooled to ambient temperature, partitioned between 1M NaOH and ethyl acetate, and the phases were separated. The ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a solid. The solid was chromatographed to give the title product as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Pt].CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CCO)c1ccc2ncccc2c1
Agent: [Pt]
Solvent: CO
Product: CC(CCO)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of 3-quinolin-6-ylbut-3-en-1-ol (1.0 g, 0.0050 mol), platinum on carbon (5 wt. % supported on activated carbon, wet, Degussa type F101 ra/w, 0.20 g) in methanol (15.0 mL) was stirred under hydrogen (with a balloon) at RT for 5 h. The mixture was filtered and the filtrate was concentrated to give the desired product (1.0 g, 99%). LCMS: (M+H)=202.1.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 69.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 303 mg of methyl 2-amino-5-fluorobenzoate and 308 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of dimethylformamide. 310 mg of methyl 5-fluoro-2-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=[O:8].[C:25]1([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([NH:37][C:33]4[N:32]=[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:36]=[CH:35][N:34]=4)[CH:3]=[N:4][CH:5]=3)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: Nc1nccc(-c2ccccc2)n1
Reactant: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Nc4nccc(-c5ccccc5)n4)c3)cc2)CC1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
A mixture of 5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide (45.6 mg, 0.1 mmol) and 4-phenylpyrimidin-2-amine (25.7 mg, 0.15 mmol), KOBut (22.4 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 2 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder (20 mg, 38%). MS (ESI+) m/z 479.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F-].[NH4+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1OC
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc(O)ccc1OC
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-(t-butyldimethylsilyloxy)benzoate (11.1 g. 37.4 mmol) and ammonium fluoride (6.94 g, 0.187 mmol) in methanol (150 mL). Heat to reflux. After 1 hour, evaporate in vacuo to give a residue. Partition the residue between ethyl acetate and water, separate the layers, extract the organic layer with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-hydroxybenzoate: mp; 110-112° C. Rf=0.27 (silica gel, 5% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[C:15]2[C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(CCCCc2ccc3c(c2)OCO3)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1cc3c(cc1CCCC2)OCO3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
In 1 ml of dichloromethane, 73 mg (0.21 mmol) of 1-(3,4-methylenedioxyphenyl)-4-(3,4,5-trimethoxyphenyl)butane were dissolved. The solution was added with 0.1 ml of trifluoroacetic acid and 190 mg (0.41 mmol) of ferric perchlorate, followed by stirring at room temperature for 20 minutes. The reaction mixture was dissolved in 20 ml of ethyl acetate. After the resulting solution was washed with 2N-HCl and then with saturated NaCl, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:5 mixed solvent of ethyl acetate and hexane), whereby 9 mg of the title compound were obtained as colorless oil (yield: 12%). In addition, the starting material were recovered as colorless oil (13 mg, recovery: 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0° C. was added dropwise methanesulfonyl chloride (3.5 ml) then pyridine (0.5 ml). The mixture was left at 0° C. for 1 hour, then brought to RT for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water to give 2-Methoxy-5-nitro-methanesulfonylaminobenzene (5.2 g, 71%) as an off-white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].Cl>C(Cl)Cl.CN(C=O)C>[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH:31][C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:12]([O:14][CH3:15])=[O:13])=[O:7]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1ccc(OC)c(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C(=O)Nc2c(F)cccc2F)c1
Yield: 52 %

Procedure:
2-(Methyloxy)-5-[(methyloxy)carbonyl]benzoic acid (1.96 g, 9.33 mmol) was suspended in 60 mL of DCM with stirring. DMF (0.036 mL, 0.46 mmol) was added via syringe. Oxalyl chloride (7.0 mL, 2.0M in dichloromethane, 14 mmol) was added dropwise via addition funnel. The addition funnel was rinsed with 10 mL of DCM. The reaction was stirred for 2 hours and concentrated in vacuo. The resultant solid was further dried under high vacuum pressure. The solid was dissolved in 60 mL of DCM with stirring. Pyridine (3.8 mL, 47 mmol), (4-dimethylamino)pyridine (0.0570 g, 0.467 mmol), and 2,6-difluoroaniline (3.0 mL, 28 mmol) were added to the solution. The reaction was stirred for 18 hours and poured into 1N HCl. The layers were separated, and the aqueous layer was washed once with DCM and once with diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 1.56 g (52%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.8, 2.0 Hz, 1H), 7.38 (m, 1H), 7.31 (d, J=88 Hz, 1H), 7.22-7.13 (m, 2H), 3.97 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:9]([OH:11])[CH3:10]>S(=O)(=O)(O)O>[F:1][CH:2]1[CH2:4][C:3]1([CH3:8])[C:5]([O:11][CH2:9][CH3:10])=[O:6]
Reactant: CC1(C(=O)Cl)CC1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1F
Yield: 85 %

Procedure:
40 ml of ethanol are added dropwise at 20° C. and with stirring to 20 g (0.12 mol) of 2-fluoro-1-methyl-cyclopropane-carbonyl chloride (cis/trans mixture). After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for one hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under reduced pressure. In this manner, 18.4 g (85% of theory) of ethyl 2-fluoro-1-methyl-cyclopropanecarboxylate (cis/trans mixture) are obtained in the form of a liquid of boiling point 42°-45° C. at 18 mbar.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][N:16]2[CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(CCN3CCOCC3)c3cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(C3CCNCC3)cn(CCN3CCOCC3)c2c1
Yield: 123.7 %

Procedure:
4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 5.81 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 2.5 g (95%) of a white solid. MS (electrospray): exact mass calculated for C19H26ClN3O, 347.18; m/z found, 348.2 [M++H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21](O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In tetrahydrofuran (50 ml), methyl 4-hydroxybenzoate (1.01 g), (3R)-1-tert-butoxycarbonyl-3-pyrrolidinol (1.36 g) and triphenylphosphine (1.73 g) were dissolved, followed by the dropwise addition of a 40% solution (2.87 ml) of diethyl azodicarboxylate in toluene under ice cooling. The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture, ethyl acetate and a 10% aqueous solution of potassium carbonate were added to separate the organic layer. The organic layer so separated was washed with a 10% aqueous solution of potassium carbonate and water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (1.60 g, 76%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:25])([F:24])[O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CN(C=O)C.CC(OC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:8]([F:25])([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1
Reactant: FC(F)(F)CCCOc1ccc(OC(F)(F)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
554 mg (2.469 mmol) of Pd(OAc)2, 2.70 g (7.41 mmol) of dicyclohexyl(2′-methylbuphenyl-2-yl)phosphine, 35 g (82 mmol) of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}benzene, 17.2 ml (123 mmol) of triethylamine and 14.84 ml (165 mmol) of methyl acrylate are solubilised in 500 ml of DMF and heated to 130° C. After 2 hours, the solution is diluted to room temperature and diluted with 500 ml of TBME. The solution is filtrated over a plug of Hyflo. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallisation from toluene/heptane mixture yields 23 g of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.O[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1cncc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Reaction time: 15 h
Yield: 79 %

Procedure:
To a mixture of [3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.92 g), methyl 5-hydroxynicotinate (1.0 g), tributylphosphine (1.98 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.47 g) at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (2.21 g, 79%) of methyl 5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-97° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=4)=[O:24])=[CH:18][CH:17]=3)=[O:14])=[N:11][CH:12]=2)[CH2:3]1.Cl.F[CH2:37][C:38](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:39]F>>[C:31]([C:29]1[O:28][N:27]=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:4]4[CH2:5][N:2]([CH:38]([CH3:39])[CH3:37])[CH2:3]4)=[CH:12][N:11]=3)=[CH:21][CH:20]=2)[CH:30]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CNC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 19 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylazetidin-3-yloxy)picolinamide (25 mg, 19%) was prepared as an off-white powder using a procedure analogous to that described in Example 20, substituting 5-(azetidin-3-yloxy)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 493 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.48 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.08 (dd, J=1.32, 8.67 Hz, 1H), 7.81 (d, J=7.35 Hz, 2H), 7.50 (dd, J=2.64, 8.67 Hz, 1H), 7.41 (d, J=7.16 Hz, 2H), 6.50 (d, J=1.88 Hz, 1H), 4.94 (t, J=5.46 Hz, 1H), 3.73 (t, J=6.40 Hz, 2H), 3.00 (t, J=6.03 Hz, 2H), 2.29-2.41 (m, 1H), 1.29 (d, J=1.88 Hz, 9H), 0.77-0.95 (m, 6H).