Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Br.BrCCBr.[Cl:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[Cl:17][Si:18]([CH3:20])([CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]([CH3:2])=[CH:11]2
Reactant: CC1=Cc2cccc(Br)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1=Cc2cccc([Si](C)(C)Cl)c2C1

Procedure:
To 11.9 g (0.496 mol) of magnesium turnings in 80 mL of dry THF a solution of 50.0 g (0.239 mol) of 2-methyl-7-bromo-1H-indene and 45.0 g (0.239 mol) of 1,2-dibromoethane in 620 mL of THF was added dropwise by vigorous stirring in such rate that the mixture is refluxed. Then, this mixture was additionally refluxed for 30 minutes. Further on, to a solution of 110 g (0.853 mol) of dichlorodimethylsilane in 100 mL of THF the above-obtained solution of the Grignard reagent was added dropwise with vigorous stirring at room temperature using water bath to cool the reaction mixture. The resulting mixture was additionally stirred for 12 hours at ambient temperature, evaporated to dryness, and then 200 mL of dry ether was added. The obtained suspension was stirred for 20 minutes at room temperature and then filtered through glass frit (G3). The precipitate was additionally washed with 2×200 mL of ether. The combined filtrate was evaporated to dryness, and the residue was rectificated in vacuum, b.p. 105° C.-110° C./1 mm Hg. Yield 42.5 g (80%) of the title product. 1H NMR (CD2Cl2): δ 7.37-7.41 (m, 2H, 4,6-H), 7.30 (m, 1H, 5-H), 6.57 (m, 1H, 3-H), 3.51 (m, 2H, 1,1′-H), 2.23 (m, 3H, 2-Me), 0.81 (s, 6H, SiMe2). Anal. Calc. for C12H15ClSi: C, 64.69; H, 6.79%. Found: C, 64.56; H, 6.85%.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:24])[NH:20][N+]([O-])=O)=[O:12])=[O:8].CO.Cl>[Pd].O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:24])=[O:12])=[O:8]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1)C(=O)O
Reaction time: 5 h
Yield: 126.2 %

Procedure:
After 0.60 g (0.87 mmol) of Z-PyroGlu-Pro-Arg(NO2)-CHA was suspended in a solvent mixture of 112.5 ml of MeOH, 35.8 ml of H2O and 1.7 ml of 1N-HCl, 1 g of palladium black was added to the suspension followed by catalytic reduction at 30° C. for 5 hours. After the reaction, the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was purified through TOYOPEARL HW40F column using MeOH as a developing solvent to give 0.42 g (87.5%) of H-PyroGlu-Pro-Arg-CHA.HCl
Reaction SMILES: C(O[CH:4]=[C:5]([CH:18]=C(C#N)C#N)[CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)C.[NH2:24][C:25]1[NH:26][C:27](=[O:32])[CH:28]=[C:29]([NH2:31])[N:30]=1>C(O)(=O)C>[NH2:24][C:25]1[N:26]=[C:27]([OH:32])[C:28]2[CH:4]=[C:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[CH:18]=[N:31][C:29]=2[N:30]=1
Reactant: Nc1cc(=O)[nH]c(N)n1
Reactant: CCOC=C(C=C(C#N)C#N)CCc1ccc(C(=O)OC)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCc2cnc3nc(N)nc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Two grams of methyl 4-(3-ethoxymethylene-5,5-dicyanopent-4-en-1-yl)benzoate, 0.93 g of 2,4-diamino-6(1H)-pyrimidone, and 30 mL of acetic acid are heated at reflux with stirring for 4 hours. The reaction mixture is allowed to cool to room temperature and the solid which forms is collected by filtration, washed with water and diethyl ether and dried to yield methyl 4-[2-(2-amino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoate, m.p.>300° C; IR (KBr) vmax 3220, 2950, 1720, 1657, 1626, 1610, 1455, 1280, 1251, 1148, 1109, and 834 cm-1 ; 1H NMR (dTFA, d6DMSO) delta 8.38 (s 1H (7)-H), 7.99 (s, 1H, (5)-H), 7.55 (d, J=8.0 Hz, 2H, Ar), 6.87 (s, 1H (3)-H), 6.82 (d, J=8.0 Hz, 2H, Ar), 3.56 (s, 3H, --CH3), 2.77-281 (m, 2H, (6)-CH2 --), 2.67-2.73 (m, 2H, benzyl).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCC#Cc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 5 h
Yield: 98.2 %

Procedure:
To a solution of 400 mg of 5,6-diphenyl-2-(5-hydroxy-1-pentyn-1-yl)pyrazine in 20 ml of ethanol, 80 mg of 5% palladium-carbon was added and the mixture was hydrogenated at 30° C. for 5 hours. After 40 mg of 5% palladium-carbon was further added, hydrogenation was continued for one hour. The catalyst was removed by filtering the reaction solution through celite and the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 398 mg of the desired compound as a yellow oily substance.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[F:29])=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[F:29][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:32]=[CH:30][S:31][CH:19]=1
Reactant: O=C(CBr)c1ccc(O)cc1F
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: NC=O
Product: Oc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0 mmol) in dioxane 40 ml) was added formamide (4.8 g, 106 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) in dioxane (14 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (864 mg, 86% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(C=CC1CCNCC1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(4-fluorophenyl)-1-[2-(1-t-butoxycarbonylpiperidin-4-yl)-ethenylsulphonyl]-piperazine (1.96 g) and trifluoroacetic acid (5 ml) was stirred at ambient temperature for 5 hours. The mixture was evaporated to dryness, diluted with water, basified with aqueous 2M sodium hydroxide and extracted with ethyl acetate (2×20 ml). Removal of the solvent gave 4-(4-fluorophenyl)-1-[2-(piperidin-4-yl)-ethenylsulphonyl]-piperazine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][C:29]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=3[N:7]=2)=[CH:30][C:31]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccnc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-(3-[2,3′]bipyridinyl-4-yl-3-oxo-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M296) (305 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (201 mg, 82%).
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[N:3][OH:4].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[Cl:11])=[N:3][O:4][C:17]=1[CH3:18])=[O:19])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Yield: 27.4 %

Procedure:
Combine chloro(4-chloro(3-pyridyl))(hydroxyimino)methane (2.40 g, 0.013 mol) with ethyl-2-butynoate (3.66 mL, 0.031 mol) in diethyl ether (150 mL) under a nitrogen atmosphere. Add triethylamine (2.27 mL, 0.016 mol) in a dropwise manner and stir over a weekend at ambient temperature. Quench the mixture with water and extract with ethyl acetate. Concentrate the combined extracts and elute over silica gel with methanol/dichloromethane to give the desired isoxazole (0.95 g, 27%) as an oil. ES(EI): M+ 266.0, 267.0, 268.0 m/z.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=[O:46])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:37])[C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N+:19]([O-:46])=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: COc1ccc(N(C)c2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N(C)c2ccc(C(Cc3cc[n+]([O-])cc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
To a solution of 4-[2-[3,4-bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-methoxyphenylamino)3-pyridyl]ethyl}pyridine from Example 112 (60 mg, 0.11 mmol) in a mixture of 3.0 mL of CH2Cl2 and 0.3 mL MeOH, was added 84 mg (0.136 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was then washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 40% to 50% EtOH/ethyl acetate) to afford 27 mg (45%) of the title compound
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccccc1-c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
0.01 mol of 4'-hydroxybiphenylcarboxylic acid and 0.02 mol of potassium hydroxide were dissolved in a mixture of 300 ml of alcohol and 30 ml of water. Then, 1.2 ml of n-octyl bromide was added thereto, and the resultant mixture was refluxed for 12 hours. A 10% potassium hydroxide solution containing 1.12 g of KOH was added and the resultant mixture was refluxed for 2 hours to cause hydrolysis. The product was recrystallized in a mixture of ethanol and glacial acetic acid to obtain 4'-n-octyloxybiphenyl carboxylic acid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>CN(C)C=O>[C:10]([O:9][C:7](=[O:8])[CH2:6][NH:4][CH2:3][CH2:1][OH:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCCO

Procedure:
The compound is prepared, in analogy with Example 1, from ethanolamine (18.33 g; 0.3 mol) and tert-butyl bromoacetate 58.6 g; 0.3 mol) in the presence of triethylamine (30.7 g; 0.3 mol) in anhydrous N,N-dimethylformamide (300 ml). The crude product is purified by chromatography on silica gel (eluent: chloroform/methanol, 16:1). Yield: 33.65 g (64%).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18](Br)[CH:19]=[N:20][CH:21]=1.[Li]CCCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([B:1]([OH:6])[OH:2])[CH:19]=[N:20][CH:21]=1
Reactant: COc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cncc(B(O)O)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Triisopropyl borate (29.3 mL, 128 mmol) was added over 2 min to a solution of 5-methoxy-3-bromopyridine (20.00 g, 106.4 mmol) in toluene (140 mL) and tetrahydrofuran (35 mL) at −40° C. To this solution was added 2.5 M n-BuLi (51.1 mL, 128 mmol) drop-wise over 35 min while maintaining the temperature at −40° C. After the addition was complete, the reaction was stirred an additional 30 min at −40° C. and then was warmed to −15° C. over one hour. Into the reaction was poured 1 N HCl (175 mL), and the mixture was stirred vigorously for 30 minutes. The layers were separated, and the organic washed once with water (15 mL). The aqueous phases were combined and neutralized (to pH 7) with 5 N NaOH, at which point the boronic acid precipitated out. The biphasic mixture was extracted with THF (3×150 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to yield 15.36 g of 5-methoxy-3-pyridinylboronic acid as a light brown solid (94%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:23]1[S:24][C:25]([CH:29]=[O:30])=[C:26]([Cl:28])[N:27]=1>O1CCCC1>[Cl:28][C:26]1[N:27]=[C:23]([NH:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:11])([F:1])[F:12])=[CH:4][CH:5]=2)[S:24][C:25]=1[CH:29]=[O:30]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: NCc1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1sc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (74, 1.0 g, 5.7 mmol) and N,N-diisopropylethylamine (2.0 mL, 11 mmol) in 100 mL of tetrahydrofuran, 2,4-dichloro-thiazole-5-carbaldehyde (73, 1.1 g, 6.2 mmol) in 10 mL of tetrahydrofuran was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (75, 1.2 g, 66%). MS (ESI)=[M+H+]+=322.11
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccn1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 4 h

Procedure:
The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see intermediate 40, 6 g, 18 mmol) was reacted with (1R)-1-(2-pyridinyl)ethanamine (2 eq., 4.43 g, 36 mmol) in CH3CN (100 ml) and was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-{[(1R)-1-(2-pyridinyl)ethyl]-amino}-3-quinolinecarboxamide which was used in the next step without purification. The carboxamide intermediate (6 g) was treated with an excess of [bis(trifluoroacetoxy)iodo]benzene (19.35 g, 45 mmol) in CH3CN (100 ml), the mixture was stirred at room temperature overnignt. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in DCM and washed with water. The crude product was purified by flash chromatography on silica gel (DCM/MeOH, 95:5), the resulting compound was dissolved in DCM and precipitated from diethylether to give the title compound as an off-white powder (2.5 g, 33%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccc2cc[nH]c2c1
Product: CN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Yield: 69.2 %

Procedure:
Beginning with 1.00 gm (7.4 mMol) 6-fluoro-1H-indole and 1.82 mL (14.8 mMol) 1-methyl-4-piperidone, 1.18 gm (70%) of the title compound were recovered as a colorless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12]CC2C=CC(OC)=CC=2OC)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:9]([NH2:12])(=[O:10])=[O:11])[C:27]([OH:28])([CH3:29])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(Cl)c2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cccc(Cl)c1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.65 g of C-(3-chlorophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 30 ml of THF, and then, at a temperature of −75° C., 6.67 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.86 ml of acetone were added. After stirring for 5 minutes, the reaction solution was admixed with 15 ml of trifluoroacetic acid and allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 2.5 ml of trifluoroacetic acid were added. After stirring at room temperature for 2 hours, the reaction solution was admixed with 50 ml of water, and the solid which precipitated out was filtered off with suction and washed with water. For drying, the product was coevaporated twice more with toluene. This gave the product (1.16 g) with a molecular weight of 263.7 g/mol (C10H14ClNO3S).
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].Cl>CS(C)=O>[F:1][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
Cesium fluoride (97.5 g, 642 mmol) was added under nitrogen atmosphere to a solution of 2-chloro-1-methyl-3-nitrobenzene (73.4 g, 428 mmol) in DMSO (185 ml), and the mixture was stirred at 140° C. for 10 hours. The reaction mixture was then poured into 0.5N hydrochloric acid and extracted twice with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude product was obtained by vacuum concentration, and then purified by reduced-pressure distillation (boiling point: 118° C. to 122° C./15 mm Hg) to yield the title compound (54.4 g, 82%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([NH:21][O:22]C3CCCCO3)=[O:20])[CH:15]=2)[CH2:10]1)=[O:8].Cl>CO>[OH:22][NH:21][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:8])[CH2:18][CH2:17]2)=[O:20]
Reactant: COCCCNC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: COCCCNC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 180 mg of N2-(3-methoxypropyl)-N6-(tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide in 4 ml methanol and 6 ml of an aqueous 0.1 N HCl is stirred overnight at ambient temperature and evaporated. The residue is dissolved in acetonitrile and water and lyophilized. 115 mg of the title compound are obtained. MH+=308.2
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2([C:24](=[O:33])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:23][CH2:22]2)=[O:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](C(N)=O)[CH:6]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[N:56]1C=CC=CC=1>CN(C)C=O>[NH2:56][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:23][CH2:22]3)=[O:20])=[CH:17][C:2]=2[F:1])[CH:10]=[CH:9][N:8]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: c1ccncc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 64 %

Procedure:
4-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (4.81 g) was dissolved in N,N-dimethylformamide (50 ml) under a nitrogen atmosphere, and water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by stirring overnight. Water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by further stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale brown foam (2.878 g, 64%).