Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC(=O)c1c(Cl)ccc([N+](=O)[O-])c1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ether, the combined organic layers washed with sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate/hexanes in 83% yield as a white solid. m.p. 147°-149° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:16]=[CH:17][C:18]4[C:22]([CH:23]=3)=[N:21][N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=4)[CH:6]=2)[CH2:2]1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:24]([N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([C:7]3[CH:6]=[C:5]([CH:3]4[CH2:4][N:1]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:2]4)[N:13]4[C:8]=3[C:9]([NH2:14])=[N:10][CH:11]=[N:12]4)[CH:16]=[CH:17]2)=[N:21]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
A mixture of 7-azetidin-3-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.051 mmol), N,N-dimethylglycine (5.7 mg, 0.056 mmol), EDCl (11.6 mg, 0.061 mmol), HOBt (8.2 mg, 0.061 mmol), and N,N-diisopropylethylamine (26 μL, 0.15 mmol) in DMF (1 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 5 mg (21%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 7.79-7.85 (m, 2 H), 7.67 (s, 1 H), 7.29-7.37 (m, 5 H), 7.25 (d, 1 H), 6.81 (s, 1 H), 5.65 (s, 2 H), 4.70 (t, 1 H), 4.25-4.54 (m, 4 H), 3.18 (s, 2 H), 2.38 (s, 6 H); ES-MS m/z 481.10 [M+H]+, HPLC RT (min) 2.07.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH3:10])[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:12].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[C:36](O)=[O:37])[CH:29]=[CH:28][CH:27]=1>>[F:24][C:20]1[CH:19]=[C:18]([C:17]2[S:16][C:15]([CH3:25])=[N:14][C:13]=2[C:11]([N:4]2[CH2:5][CH:6]([O:9][CH3:10])[CH2:7][CH2:8][CH:3]2[CH2:2][NH:1][C:36]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[N:26]=[CH:27][CH:28]=[CH:29]3)=[O:37])=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC1CCC(CN)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1
Reactant: O=C(O)c1cccc2cccnc12
Product: COC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1

Procedure:
The title compound was prepared according to general procedure A using (2-(aminomethyl)-5-methoxypiperidin-1-yl)(5-(3-fluorophenyl)-2-methylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. (ESI) 519 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH2:16][CH2:15]1.ClCCl.O>O1CCOCC1>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[C:22]([NH:23][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-(4-methylpiperazin-1-yl)aniline (127 mg, 0.663 mmol). The mixture was heated in microwave at 120° C. Dichloromethane and water were added, and the product extracted in dichloromethane. The organic layer was then dried over Na2SO4 and concentrated under reduced pressure to yield 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=337)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(N)ccn1
Reactant: O=C(Cl)C(=O)c1ccccc1
Product: Cc1cc(NC(=O)C(=O)c2ccccc2)ccn1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H]+) was prepared from 4-amino-2-picoline and benzoylformic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11].C([O-])([O-])=O.[Na+].[Na+].Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:22]=[C:21]([S:33][CH3:34])[N:20]=1>CN1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:22]=[C:21]([S:33][CH3:34])[N:20]=1
Reactant: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Reactant: NCCc1c(F)cccc1Cl
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2cc(NCCc3c(F)cccc3Cl)nc(SC)n2)cn1
Temperature: 175 °C
Yield: 94.5 %

Procedure:
A mixture of 2-(2-chloro-6-fluoro-phenyl)-ethylamine [1.02 g, 5.88 mmol, Intermediate (23)], Na2CO3 (1.65 g, 19.6 mmol), and 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.05 g, 3.92 mmol, Intermediate (38)] in N-methyl pyrrolidine (10 mL), is heated to 175° C. for 3 hours. The reaction mixture is diluted with water, and extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue is subjected to short-path chromatography on silica gel eluting with EtOAc to afford [2-(2-chloro-6-fluoro-phenyl)-ethyl]-[6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidin-4-yl]-amine [1.5 g, Example 30]. LCMS: RT=3.37 minutes, MS: 405 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[C-:14]#[N:15].[K+].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH3:25]>CN(C=O)C.CCOC(C)=O>[C:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([C:14]#[N:15])=[C:2]([Br:1])[C:3]=1[O:13][CH2:24][CH3:25])(=[O:12])[CH3:11]
Reactant: [C-]#N
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Temperature: 85 °C
Reaction time: 18 h

Procedure:
The 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (3.0 g, 11 mmol, from Example 187, Step 2) was dissolved in DMF (24 mL) and potassium cyanide (0.88 g, 13 mmol) was added. The reaction was heated to 85° C. and monitored by LC/MS. After heating for 18 h the reaction was complete. The reaction was allowed to cool to room temperature and then potassium carbonate (3.1 g, 22 mmol) and iodoethane (1.3 mL, 17 mmol) were added. The reaction was heated to 60° C. overnight. After stirring for 18 h the reaction was complete. The crude was diluted with EtOAc and washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile as an oil which solidified (2.1 g, 62%). LCMS calculated for C11H10BrClNO2(M+H)+: m/z=301.9, 303.9. found: 301.6, 303.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2OC)(=[O:11])=[O:10])=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH:3]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].CN([CH:40]=[O:41])C>C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:41][CH3:40])[CH:13]=1)(=[O:10])=[O:11])[CH3:36]
Reactant: COc1ccccc1S(=O)(=O)Nc1ccc(Cl)cc1Cc1ccccc1Cl
Reactant: CN(C)C=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(c1ccc(Cl)cc1Cc1ccccc1Cl)S(=O)(=O)c1cccc(OC)c1
Reaction time: 18 h

Procedure:
To 0.525 g of N-[4-chloro-2-(2-chlorobenzyl)phenyl]-2-methoxybenzenesulfonamide dissolved in 6 ml of DMF is added, at 0° C., 0.065 g of sodium hydride, after 40 minutes at this temperature 0.14 ml of ethyl 2-bromoacetate is introduced, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate solvent mixture to give 0.272 g of the expected product, in the form of an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:14][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH:1]=[O:16])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCc2ccc(C=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of 7-ethenyl-2-methyl-3,4-dihydro-1(2H)-isoquinolinone (181 mg, 0.968 mmol) in 1,4-dioxane (I 5 ml) and water (3 ml) at 0° C. was added sodium periodate (476 mg, 2.226 mmol) and osmium tetroxide (1.1 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (20 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% Ethyl Acetate/Hexane, gave the product (136 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:37]=1[CH:38]=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:38]/[C:37]2[C:36]([Cl:35])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:44])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cccc2Cl)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.89 g, 6.9 mmol) and Ph3P (1.82 g, 6.9 mmol) in DMF (35 mL) was heated at 100° C. for 1 h then 2,6-dichlorobenzaldehyde (1.2 g, 6.9 mmol) was added followed by K2CO3 (1.9 g, 13.75 mmol). The resulting deep-red mixture was stirred at 100° C. for 18 h then was allowed to cool to ambient temperature. To this was added water and the mixture was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography using methylene chloride as eluent to give 4-[(E)-2-(2,6-dichlorophenyl)-vinyl]-3-nitrobenzoic acid methyl ester as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[O:13][N:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH:16]1([C:14]2[O:13][N:12]=[C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:32]5[C:28]([C:21]6[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=6[F:19])=[N:29][N:30]([C:42]([C:55]6[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=6)([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)[CH:31]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[N:15]=2)[CH2:18][CH2:17]1
Reactant: Brc1ccc2ncc(-c3noc(C4CC4)n3)n2c1
Reactant: COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4noc(C5CC5)n4)n3c2)c(F)c1
Yield: 73.4 %

Procedure:
82 mg 6-bromo-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-imidazo[1,2-a]pyridine (compound in Production Example 255), 227 mg 3-(2-fluoro-4-methoxyphenyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole (compound in Production Example 185), 86 mg tripotassium phosphate hydrate and 31 mg tetrakis(triphenylphosphine)palladium were stirred at 80° C. for 14 hours in 3 mL N,N-dimethylformamide under nitrogen atmosphere. Water and ethyl acetate were added thereto, then the reaction solution was filtered through Celite, and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 130 mg of the title compound (colorless oil).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.O1CCOCC1.C(N(CC)C(C)C)(C)C.[CH2:28]([SH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.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].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>[CH2:28]([S:35][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: SCc1ccccc1
Reactant: Clc1cc2cc(Br)ccc2cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2cc(SCc3ccccc3)ccc2cn1
Temperature: 80 °C
Yield: 89.1 %

Procedure:
A pressure vessel was charged with 6-bromo-3-chloroisoquinoline (1.3307 g, 5.49 mmol), Xantphos (0.159 g, 0.274 mmol), and Pd2(dba)3 (0.126 g, 0.137 mmol). The vessel was flushed with Ar (g), then 1,4-dioxane (10.97 ml), N,N-diisopropylethylamine (1.917 ml, 10.97 mmol), and benzyl mercaptan (0.682 ml, 5.76 mmol) were added in sequence. The vessel was sealed and heated in an 80° C. heating bath for 16 h. The mixture was cooled, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (25-g silica gel loading column, 0 to 30% EtOAC/Heptane) to give 6-(benzylthio)-3-chloroisoquinoline (1.398 g, 4.89 mmol, 89% yield) as a light-yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.94 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.55 (d, J=0.2 Hz, 1H), 7.50-7.39 (m, 4H), 7.38-7.28 (m, 3H), 4.30 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH2:4]=[O:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl>CC#N>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)cc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COc1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of MgCl2 (3.48 g, 37.0 mmol), TEA (12.8 mL, 92.1 mmol) and paraformaldehyde (5 g, 167 mmol) in MeCN (100 mL) was added 4-methoxy-phenol (3 g, 24.2 mmol). The mixture was refluxed for 8 hours, cooled to room temperature, then poured into 5% HCl (300 mL), extracted with ethyl acetate (200 mL×3). The combined organic layer was dried, concentrated and purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/5) to give 2.3 g of 2-hydroxy-5-methoxy-benzaldehyde (4A).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a suspension of 5-(hydroxymethyl)-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.853 mmol) in DCM (4 mL) was added thionyl chloride (0.124 mL, 1.705 mmol) dropwise under nitrogen. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water, adjusted pH about 7 and extracted with DCM. The organic layer was separated and concentrated to afford the title compound (250 mg, 0.802 mmol, 94% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[C:14](=O)[N:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C([O:53]N1C(=O)C=CC=C1)=[N+](C)C)C>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:33][CH2:32]2)=[O:18])[CH2:14][NH:13][C:12]1=[O:53])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: O=C(O)[C@@H]1C(=O)N=CN1C(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CNC(=O)N3C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 435.5 %

Procedure:
To (S)-(−)-oxo-1,5-imidazolinedicarboxylic acid 1-benzylester (10 g) and 1-(2,5-dimethylphenyl)-piperazine (7.92 g) in N,N-dimethylformamide was added O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluorborate (TPTU) (12.36 g) and triethylamine (15.8 mL), and the reaction mixture was stirred at ambient temperature over night. Additional amounts of the reagents were added, 1-(2,5-dimethylphenyl)-piperazine (1.44 g), TPTU (2.25 g) and triethylamine (2.9 mL), and stirring was continued until no starting material could be detected. The solvent was evaporated and the residue redissolved in ethyl acetate/1M aqueous solution of Na2CO3. The inorganic phase was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4), filtered and evaporated. Purification by column chromatography (SiO2, dichloromethane/methanol 95:5) yielded (S)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-2-oxo-imidazolidine-1-carboxylic acid benzyl ester (14.4 g) as a white solid. MS: 435.3 ([M−H]−)
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[C:5]([CH3:23])=[C:6]([C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:22])[C:20]=2[OH:21])=[O:15])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36].C(OCC)(=O)C>O1CCCC1>[F:24][CH:2]([F:1])[O:3][C:4]1[C:5]([CH3:23])=[C:6]([C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:22])[C:20]=2[O:21][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:15])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CCSC(=O)Cl
Reactant: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1OC(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OC(F)F)c2C)cnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-1-methylpyrazol-4-yl 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone (89 mg) in dry tetrahydrofuran (5 mL) were added triethylamine (50 mg) and 96% S-ethyl chlorothiolformate (40 mg) at room temperature. After the reaction solution was stirred for 1 hour, 150 mL of ethyl acetate was added. The mixture was washed twice with a saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as an oil.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([C:17]1[S:18][C:19]([CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:21]=1)[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])C=C.C1([SiH3])C=CC=CC=1.C(OCC)(=O)C.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C@@H:7]([C:17]1[S:18][C:19]([CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:21]=1)[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(CNC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)s1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of prop-2-en-1-yl{(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}methyl)thiophen-2-yl]ethyl}carbamate (1.2 g, 1.841 mmol) in dichloromethane (18.4 mL) was treated with phenylsilane (6.3 mL, 5.52 mmol) and Pd(PPh3)4 (106 mg, 0.092 mmol) for 1 hour at room temperature. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with brine, dried, and then concentrated under reduced pressure. The concentrate was purified on silica gel using 5%-65% ethyl acetate in hexane to afford the title compound. 1H NMR (CD3OD) δ 7.40-7.15 (11H, 6.79 (1H), 6.40 (1H), 4.98 (1H), 4.38 (1H), 4.21 (2H), 3.82 (1H), 3.70 (1H), 3.52 (3H), 0.91 (9H), 0.10 (6H).