Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=S)=[S:11]>CO>[F:9][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:10]([SH:11])=[N:1][C:2]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1ccc(F)cc1N
Solvent: CO
Product: Fc1ccc2[nH]c(S)nc2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98.2 %

Procedure:
A mixture of 3,4-diamino-1-fluorobenzene (10 g, 79.3 mmol), carbon disulfide (70 ml, 1164 mmol), and methanol (100 ml) was stirred at room temperature for 86 hours and 50 minutes. After the reaction mixture was concentrated, the residue was suspended in hexane. The resultant precipitate was collected by filtration and washed with hexane to obtain the title compound (13.1 g, yield: 98.2%) as a brown solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[C:20](=[O:36])[NH:21][C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[C:24]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:18][C:19]1[C:20](=[O:36])[N:21]([CH2:8][C@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])[C:24]=1[CH3:25]
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 4a (638 mg, 2.62 mmol) in THF (10 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methylpyrimidine-2,4(1H,3H)-dione 1d.1 (869 mg, 2.62 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (906 mg, 3.93 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 hours and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 2b (1.39 g, 95.4%). MS (CI) m/z 456.10, 458.10 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[C:21]([CH3:23])[CH:22]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[C:21]([CH3:23])[C:22]=23)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)nc1
Product: Cc1n[nH]c2nc(-c3ccc(Cl)nc3)c(-c3ccncc3)c(-c3ccc(Cl)nc3)c12
Yield: 9 %

Procedure:
Following a similar procedure to that described in example 1 method A, but using 1-(6-chloropyridin-3-yl)-2-(4-pyridyl)ethanone (obtained in example reference 9) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, the title compound was obtained (yield: 9%).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:8]1[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:11])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Oc1ncccc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(Br)cc1OC(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
As shown in step 3(a)-iv of Scheme 3(a), 3-(difluoromethoxy)pyridin-2-ol (986 mg; 6.12 mmol) was dissolved in 25 mL of glacial acetic acid and sodium acetate (79 mg; 9.6 mmol) was added. The mixture was cooled in an ice bath and bromine (780 μL; 1.63 g; 10.22 mmol) in 10 mL of glacial acetic acid was added over 10 minutes. The reaction was stirred for 30 minutes at 10-15° C. The volatiles were removed under reduced pressure and the residue was partitioned between brine/saturated sodium carbonate solution and ethyl acetate. After the evolution of gas ceased, the organic and aqueous layers were separated and the aqueous solution extracted three additional times with EtOAc. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The residue was purified twice by silica gel chromatography (first a DCM to 10% MeOH/DCM gradient then 1:1 EtOAc/hexanes) to provide 5-bromo-3-(difluoromethoxy)pyridin-2-ol as a light yellow powder (Compound 2009, 810 mg, 55% yield): ESMS (M+H) 241.9/243.9; 1H NMR (CDCl3) δ 13.2 (br m, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.18 (d, 1H, J=2.1 Hz), 6.92 (t, 1H, J=75 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:10](=[O:12])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of the 4-acetylphenoxy acetic acid (97 mg, 0.5 mmol) and 3-amino benzoic acid methyl ester (113 mg, 0.75 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) gave 3-[2-(4-acetyl-phenoxy)acetylamino]-benzoic acid methyl ester as a white solid (158 mg, 97% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: C[Si](C)(C)C#CCCO
Reactant: O=C1NC(=O)c2ccccc21
Product: C[Si](C)(C)C#CCCN1C(=O)c2ccccc2C1=O
Yield: 48.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from 4-(trimethylsilyl)but-3-yn-1-ol (3.20 g, 22.5 mmol) and phthalimide (3.50 g, 23.8 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 3.1 g (11 mmol, 51%) of 2-(4-(trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[S:4][N:3]=1.[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]([NH2:11])=[O:31])[S:4][N:3]=1
Reactant: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-(3-methylisothiazol-5-ylamino)-4-(2-oxoazepan-3-ylamino)benzonitrile (143 mg, 0.263 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 3 h. HOAc (1 mL) was added. The mixture was then purified by HPLC to give the titled compound (72 mg). MS 360.3 (M+H); UV 202.1, 300.7 nm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=2)[N:37]=[CH:36][N:35]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(F)c(F)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.27 g, 5.23 mmol) in dry THF (2 mL) was added dropwise over 2 minutes with stirring to 1.01M LiHMDS/THF (5.75 mL, 5.81 mmol) at −78° C. under argon. After 5 min at −78° C., the cold bath was removed and the reaction was allowed to stir at “rt” for 30 min. A portion of this enolate solution (5.1 mL, 3 mmol enolate) was added dropwise over 2-3 min to a stirred homogeneous solution of 4-chloro-6,7-difluoroquinazoline (600 mg, 2.99 mmol) in dry THF (3 mL) at 0° C. under argon. The reaction was stirred for 30 min at 0° C., and was then quenched with 1M NaH2PO4 (50 mL) and extracted with EtOAc (1×50 mL). The organic layer was washed with 4M NaCl (1×50 mL), dried (Na2SO4), and concentrated. The residue was purified with silica flash chromatography (3:1 hexanes/EtOAc) to afford the title compound as a yellow oil (451 mg, 37%). LC/MS (ESI): calcd mass 407.2, found 408.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH3:14]ON(C)C(C1CCC1)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12][CH2:14]1)=[O:10]
Reactant: Cc1ccc(N)c(C(=O)C2CC2)c1
Reactant: CON(C)C(=O)C1CCC1
Product: Cc1ccc(N)c(C(=O)C2CCC2)c1
Yield: 80 %

Procedure:
Crude (2-amino-5-methyl-phenyl)-cyclobutyl-methanone (80%, oil) was prepared in a similar fashion as described for (2-amino-5-methyl-phenyl)-cyclopropyl-methanone using cyclobutanecarboxylic acid methoxy-methyl-amide instead of cyclopropanecarboxylic acid methoxy-methyl-amide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:21]COC)=[C:9]([C:11]2[N:16]=[CH:15][C:14]([C:17](F)(F)F)=[CH:13]N=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[C:9]([C:11]2[CH:25]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1ccc(C(C)(C)C)cc1-c1ncc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1ccc(-c2cc(C(C)(C)C)ccc2O)nc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 1427.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-2-(methoxymethoxy)phenyl)-5-(trifluoromethyl)pyrimidine (0.23 g, 0.68 mmol) in methanol (10 mL) was added a catalytic amount of para-toluenesulfonic acid (10 mg) and the reaction mixture stirred at 40° C. open to air for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 4-(tert-butyl)-2-(5-methylpyridin-2-yl)phenol (0.20 g, 100% yield) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[N:23]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:38])[N:24]=[N:25][C:26]=4[C:27]([F:30])([F:29])[F:28])=[CH:16][C:15]=3[CH3:39])=[CH:11][CH:12]=2)[N:7]([CH:40]([CH3:42])[CH3:41])[N:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O.CO>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]4[CH:40]([CH3:41])[CH3:42])=[CH:12][CH:11]=3)=[C:15]([CH3:39])[CH:16]=2)=[C:26]([C:27]([F:28])([F:30])[F:29])[N:25]=[N:24]1
Reactant: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(OCc4c(C(F)(F)F)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2c(C(F)(F)F)nnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(C(=O)O)nn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 6-{4-[3-(2,6-dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (0.13 g, 0.21 mmol) in a 1:1:1 mixture of THF, methanol, water (4.5 mL) is added LiOH (0.09 g, 2.10 mmol). The reaction is stirred for 18 h at room temperature. The reaction is adjusted to pH 3 with 1N HCl and extracted with EtOAc to yield the title compound (0.12 g, 92%). LC-ES/MS m/e 602.0 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cncn4CC)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1cncc1/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(CC(=O)O)cc3)oc2C)c(OC)c1
Yield: 54.7 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (385 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (202 mg, yield 55%). melting point: 148-149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][S:16][C:15]1[S:14][C:13]([C:18]#[N:19])=[CH:12][C:11]=1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)(=[O:10])=[O:9]
Reactant: C1CCNCC1
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 9.9 %

Procedure:
A mixture of 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carbonitrile (Example 286: step f, 200 mg, 0.534 mmol), piperidine (56 mg, 0.64 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), BINAP (100 mg, 0.16 mmol) and Cs2CO3 in 2 mL of toluene under Ar was stirred at 150° C. for 16 h, then cooled to RT. The mixture was purified directly by PTLC (30% EtOAc/hexane) to give 20 mg of product as a light yellow oil: 1H-NMR (CDCl3; 400 MHz) δ 7.68 (m, 1H), 7.67 (s, 1H), 7.54–7.52 (m, 1H), 7.39–7.32 (m, 2H), 3.16–3.12 (m, 4H), 2.45 (s, 3H), 1.64–1.59 (m, 4H), 1.55–1.50 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H18N2O2S3, 379.1 (M+H), found 379.3.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)[C:10]=1[CH3:11].B(Br)(Br)Br>C(Cl)Cl>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([CH:2]=[O:1])[CH:7]=[N:8]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(-n2ncc(C3OCCO3)c2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C=O)cnn1-c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 4-[1,3]dioxolan-2-yl-1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole (0.2 g, 0.8 mmol) in CH2Cl2 (4 mL) was added boron tribromide (1M in DCM, 2.3 mL, 2.3 mmol) at −78° C. over 5 min. The reaction mixture was stirred at −78° C. for 1 h, and then at room temperature for 4 h. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with CH2Cl2, washed brine, and dried over Na2SO4. After concentrated in vacuo, the title compound was obtained with a yield of 97% (150 mg), which was used to the next step without further purifications; MS (APCI) m/z: 203 (M+1, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][C:31]([O:33][CH3:34])=[O:32])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CNC(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a suspension of 3-aminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride (from Example 76.3., 0.2 mmole) in dichloromethane (2.0 ml) was added at 22° C. methyl chloroformate (0.22 mmole) and stirring was continued at 22° C. for 16 h. The mixture was washed with 1 N aqueous HCl, the organic layer was dried, evaporated and the residue was chromatographed on silica using n-heptane/AcOEt to give 5-fluoro-3-(methoxycarbonylamino-methyl)-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 435.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:16]=1)[CH3:10].[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:10]([N:9]([CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:16]=1)[CH3:8])[CH3:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C)n4)cc23)CC1
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)Cc1nc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 60.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (73 mg, 0.3 mmol) for dimethylamine to afford 25 mg of the title compound (60.4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]([NH:11][C@H:12]([CH3:16])[CH2:13][CH2:14][OH:15])=[O:10])[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:25][CH:24]=1.[Br-].[K+].CC(NC1CC(C)(C)N([O])C(C)(C)C1)=O.Cl[O-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[CH3:39][C:2]1([CH3:1])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]([NH:11][C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])=[O:10])[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:27][CH:28]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C)CCO)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3)cc2)C(C)(C)C1=O
Agent: CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)N[C@H](C)CC=O)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3)cc2)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
56.5 mg of (R)-3-((S)-2-(4,4-Dimethyl-3-(4-(3-phenylureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropanol were dissolved in a mixture of 3 ml of ethyl acetate, 1 ml of toluene and 1 ml of water with 10.8 mg of potassium bromide. After addition of a catalytic amount of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl (=4-acetamido-TEMPO), a mixture of 0.5 ml of sodium hypochlorite solution (13% strength), 0.5 ml of saturated sodium hydrogencarbonate solution and 1 ml of water was added dropwise at 0° C. The mixture was stirred at 0° C. for 25 minutes. After reaction was complete, the mixture was treated with ethyl acetate, and the organic phase was washed with sodium thiosulfate solution and dried over sodium sulfate. After filtration, the solvent was removed on a rotary evaporator and the residue was purified by reversed phase HPLC (water/acetonitrile). Yield: 15 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.CC(OC(C)=O)=O.C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.CO>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C(=Cc1ccc(F)c(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121.6 %

Procedure:
A mixture of 4-fluorophenylacetic acid (2 g, 13 mmol), 3,4-difluorobenzaldehyde (2.5 g, 13 mmol), Ac2O (10 mL) and diisopropylethylamine (2.9 mL) was stirred at room temperature for 12 hours. Upon completion, as monitored by TLC using DCM:MeOH (9:1) as the eluent, 10 mL 10% aqueous HCl was added to the reaction mixture, the precipitate formed was filtered and dissolved in CH2Cl2 (100 mL). The organic layer was washed with 10% aqueous NaOH (3×50 mL) and the basic aqueous solution was acidified with 10% aqueous HCl to pH 3. The precipitate formed was filtered, washed with water (100 mL) and dried to get the product (4.4 g, 41.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(C)cc(O)c2cc1Br
Solvent: CCOCC
Product: COc1cc2nc(C)cc(Cl)c2cc1Br
Temperature: 60 °C
Yield: 76.8 %

Procedure:
A suspension of 4.6 g (17.5 mmol) of 6-bromo-7-methoxy-2-methyl-quinolin-4-ol in 14.8 ml (158 mmol) of POCl3 was heated at 60° C. for 20 h with stirring. It was then cooled to RT and 50 ml of diethyl ether were added. The solid that precipitated was filtered off by suction and dried in a high vacuum to give 3.85 g of the 6-bromo-4-chloro-7-methoxy-2-methyl-quinoline as a dark brown solid. El mass spectrum, m/e: 287 (M calculated for C11H9BrClNO: 287).