Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][CH:5]([NH2:7])[CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:6][CH:5]([NH:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:4]1
Reactant: CC1CC(N)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1CC(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a stirred solution of 3-methylcyclobutanamine hydrochloride (0.100 g, 0.8 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.125 g, 93%). The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=2)=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: O=C(O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)=C(C)C1=O
Yield: 20.6 %

Procedure:
Using p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6yl)propionate (187 mg, 0.5 mmol) and O benzyl-L-tyrosine (136 mg, 0.5 mmol) and following the procedure of Example 4, there was obtained 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-tyrosine (43 mg), melting at 170° C.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].Cl.O1CCOCC1.N(OCCC(C)C)=O.[N-]=[N+]=[N-].N[C@H:38]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[OH:61])=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][S:44]([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>CN(C=O)C.C(OCC)C.C(N(CC)CC)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:38]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:61])[OH:62])=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][S:44]([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45])=[O:6])[CH2:3][OH:4]
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Temperature: -15 °C

Procedure:
2.13 Grams of Z-Ser-NHNH2 was dissolved in 20 ml of DMF and 4.20 ml of 6N-hydrochloric acid/dioxane was further added, then the mixture was cooled to -15° C., 1.13 ml of isoamyl nitrite was added under stirring. After the reaction mixture shows negative reaction in hydrazid test, then a cold solution of 3.53 ml of triethylamine with 1.20 ml of DMF was added dropwise to neutralize the reaction mixture. This mixture containing the azide was added to a cold DMF solution of H-Lys(Tos)-Glu-OH obtained in above-mentioned step 2(a) with 1.96 ml of triethylamine, then this mixture was stirred at -10° to -15° C. for 2 hours and at 4° C. for 20 hours. Dimethylformamide was removed by distillation, the residue thus obtained was extracted with ethyl acetate, then the ethyl acetate layer was washed with 1N-citric acid and a saturated aqueous solution of sodium chloride, then dried with anhydrous sodium sulfate, and ethyl acetate was removed by distillation under a reduced pressure. The residue thus obtained was solidified by adding ethyl ether and reprecipitated from ethyl acetate-ether to obtain 4.14 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].O.CO>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cc(Cl)cc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1c(F)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-6-fluorobenzonitrile (3.87 mmol) in 15 mL THF was added a solution of BH3 (15.5 mmol, 1M in THF) and the mixture was stirred at 60° C. for 1 h. After cooling to 0° C., water was added followed by MeOH and the mixture was then heated to 70° C. for 10 min. The solvent was evaporated, the residue was taken up in water and EtOAc. The aqueous phase was separated, basified with 1M NaOH and it was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([N:20]([CH:30]2[CH2:32][CH2:31]2)CC2C=CC(OC)=CC=2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:32][CH2:31]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: C=C(C)c1cc(C#N)cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=C(C)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (748 mg, 1.46 mmol) and anisole (4.00 mL, 36.6 mmol) in DCM (23 mL) and TFA (23 mL, 290 mmol) was left stirring at room temperature overnight. The solvents were removed and the yellow solid was suspended in DCM. This was washed with saturated aq. NaHCO3 solution and dried with sodium sulfate. The solvent was removed and the residue was suspended in a mixture of EtOAc: hexane=1:1. This was filtered to give 2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (365 mg) as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].[CH2:34](O)[CH:35]([CH3:37])[CH3:36].Cl.O1CCOCC1>>[CH2:34]([O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: CC(C)CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.8 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol) was combined with isobutyl alcohol (876 μL, 9.5 mmol). A solution of 4 M HCl in dioxane (282 μL, 1.1 mmol) was added, and the resulting mixture was stirred for 15 minutes at room temperature. The mixture was concentrated by rotary evaporation and the product lyophilized to yield the title compound (19 mg, purity 99%) as a white powder TFA salt. MS m/z [M+H]+ calc'd for C26H28ClFN4O5, 531.17. found 531.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:7]([NH2:19])[CH:6]=1.N1C=CC=CC=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([NH:19][S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=1
Reactant: COC(=O)c1cc(N)cc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(OCc2ccccc2)c1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A suspension of 3-amino-5-benzyloxy-benzoic acid methyl ester hydrochloride (D50) (5.0 g, 17 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol) and pyridine (3.5 g, 44 mmol, 2.6 equiv) followed by 3-chloropropanesulfonyl chloride (3.54 g, 20 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), dried over MgSO4 and concentrated in vacuo to give 3-benzyloxy-5-(3-chloro-propane-1-sulfonylamino)-benzoic acid methyl ester (D52) (6.0 g, 97%) as a pale pink solid. [M+H]+=366.1, RT=2.34 min
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:40]5[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=5)[CH:3]=4)[N:8]([S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:9]=3)[CH:12]=[N:13]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccc(F)cc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 29.41 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.129 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 17) (50 mg, 0.155 mmol) using sodium carbonate (41 mg, 0.387 mmol) and Pd(PPh3)2Cl2 (4 mg, 0.0064 mmol) in DME/water (10/1 ml). This afforded 25 mg (29.41% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=660.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Br[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]1)=O>>[CH3:47][C:43]1([CH3:48])[CH2:44][CH2:45][CH2:46][N:41]([CH2:39][CH2:38][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:42]1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 59 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (23 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][OH:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.C[N+]1([O-])CCOCC1.CCOC(C)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CO)c21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(C=O)c21
Reaction time: 1.5 h

Procedure:
To a suspension of (5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (675 mg, 1.889 mmol), 4-methylmorpholine 4-oxide (443 mg, 3.78 mmol), and molecular sieves (337 mg, 1.889 mmol) in dichloromethane (10 mL) at room temperature was added tetrapropylammonium perruthenate (19.9 mg, 0.057 mmol). After 1.5 h, the crude reaction mixture was loaded directly onto a pre-conditioned column of silica gel (silica gel/dichloromethane). The solvent was then switched directly to 12% EtOAc/Hex and the column run in that solvent system to give 565 mg (84%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 10.31 (s, 1H), 8.11 (d, J=1.8, 1H), 8.05 (s, 1H), 8.03 (d, J=1.8, 1H), 6.04 (s, 2H), 3.45 (m, 2H), 0.81 (m, 2H), −0.12 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 188.9, 135.4, 135.0, 134.2, 130.0, 129.3, 123.0, 114.0, 81.2, 66.4, 17.8, −1.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[C:21]1=[O:30].N1C2C(=CC=CC=2)CC1=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:20]2([NH2:19])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)C(N)c2ccccc21
Agent: Cl
Agent: O=C1Cc2ccccc2N1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-J), the title compound, as a ˜1:1 diastereomeric mixture at C3 of the indolinone, was prepared as a white solid having a decomposition point of 215-220° C. Purification was by flash chromatography eluting with 3:1 CH2Cl2/EtOAc gradient to straight EtOAc followed by recrystalization from CHCl3. Rf=0.16 and 0.22 (EtOAc). C20H19F2N3O3 (MW=387.39); mass spectroscopy (MH+) 387.0. Anal. Calcd for C20H19F2N3O3: C, 62.01; H, 4.94; N, 10.85. Found: C, 61.76; H, 5.17; N, 10.65.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C:18](=[CH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]2=[O:29])=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]2=[O:29])=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(N2CCCC(=Cc3cccnc3)C2=O)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCCC(Cc3cccnc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 98.7 %

Procedure:
A solution of N-benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethylene)piperidin-1-yl)thiazole-5-carboxamide (0.024 g, 0.053 mmol) in ethyl acetate (10 mL) was hydrogenated in the presence of catalytic amount of palladium on carbon (20% w/w) at ambient temperature and under atmospheric pressure for 3 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was recrystallized from hexanes/ethyl acetate to afford the title compound as a yellow solid (0.022 g, 92%): mp 140-141° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.44 (br s, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.42-7.16 (m, 6H), 6.07 (br s, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.33-4.21 (m, 1H), 3.98-3.86 (m, 1H), 3.43-3.29 (m, 1H), 3.91-3.73 (m, 2H), 2.62 (s, 3H), 2.11-2.98 (m, 1H), 1.96-1.74 (m, 2H), 1.62-1.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.6, 156.8, 152.1, 150.4, 147.9, 137.9, 136.9, 128.8, 128.7, 127.9, 127.6, 123.6, 119.6, 47.9, 44.1, 43.8, 34.6, 24.9, 21.3, 17.4; MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(N(CC)CC)C.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])[CH:1]=[O:13]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=O)cc(OC)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a round-bottomed flask (100 mL) equipped with magnetic stir bar and addition funnel (10 mL) was charged 1b (3.0 g, 16.5 mmol), CH2Cl2 (50 mL) and triethylamine (3.3 g, 33 mmol, 2 equiv). The mixture was cooled to 0° C. in an ice bath. The funnel was charged with Tf2O (6.9 g, 4.18 mL, 24.8 mmol, 1.5 equiv) which was added dropwise over 1 h. After several hours at 0° C., the mixture was allowed to warm up to room temperature and washed with H2O. The organic phase was washed with brine (25 mL), separated and dried over anhydrous MgSO4. The organic phase was treated with decolorizing charcoal, filtered and evaporated under reduced pressure. Compound 2b was obtained as colorless crystals by recrystallization from hexanes (4.5 g, 87%), mp. 105-107° C., lit.21 108-110° C. 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.17 (s, 2H), 3.99 (s, 6H); 13C NMR (CDCl3): δ 190.65, 153.45, 136.13, 132.25, 118.85 (q, 1JCF=321.2 Hz), 106.15, 56.89; 19F {13C} NMR (CDCl3): δ −74.08. Anal. Calcd for C10H9F3O6S: C, 38.22; H, 2.89. Found: C, 38.43; H, 2.89.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH2:4][CH2:5][CH3:6])[CH3:3].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)=[CH:11][CH:12]=1)([CH2:4][CH2:5][CH3:6])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCCC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 100 %

Procedure:
Following procedure A, 4-(2-methylpentan-2-yl)phenol (52 mg, 0.29 mmol, 1.00 eq) and 2-chloro-5-nitropyridine (57 mg, 0.36 mmol, 1.23 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (66 mg, 0.48 mmol, 1.65 eq) was added and the reaction mixture was stirred at room temperature for 27 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as colourless solid (86 mg, 0.29 mmol, 98% yield). Rf=0.50 (EtOAc/PE 1:10). HRMS (ESI) calcd. for C17H21N2O3+ [M+H]+ 301.1547. found: 301.1545. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=2.7 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.45-7.35 (m, 2H, aromatic H), 7.14-7.05 (m, 2H, aromatic H), 6.99 (dd, J=9.0, 0.6 Hz, 1H, aromatic H), 1.65-1.54 (m, 2H, C(CH3)2CH2CH2CH3), 1.32 (s, 6H, C(CH3)2CH2CH2CH3), 1.19-1.05 (m, 2H, C(CH3)2CH2CH2CH3), 0.84 (t, J=7.3 Hz, 3H, C(CH3)2CH2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 167.17, 150.43, 147.69, 145.21, 140.26, 134.90, 127.44, 120.72, 111.29, 47.27, 37.74, 29.07, 18.08, 14.87.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([F:24])([F:23])[F:25])[N:3]=1
Reactant: O=Cc1ccc2[nH]nc(Cl)c2c1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Product: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 3-Chloro-1H-indazole-5-carbaldehyde and 1-Bromomethyl-4-chloro-2-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1nc2ccccc2s1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3nc4ccccc4s3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-benzothiazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([C:7]([O:10]C)=[CH:8][CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:3]([F:12])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1ccc(Br)c(F)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-2-fluoro-6-methoxy-benzaldehyde (9.8 g, 42.06 mmol,) in dichloromethane (200 mL) at −50° C. was added a dichloromethane solution (1 M) of BBr3 (126 mL, 126 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give 3-bromo-2-fluoro-6-hydroxy-benzaldehyde as a off white solid (Yield: 9 g, 98%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:11][CH2:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 115 °C
Reaction time: 1 h

Procedure:
2-Nitro-phenol (168.7 g) and toluene-4-sulfonic acid 2-chloroethyl ester (100 g) were dissolved in 500 ml DMF and were stirred for 1 h at 110-120° C. after careful addition of 199 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (8 L) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. Yield: 100-120 g.