Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: O
Solvent: CCC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
(see, also, A. K. Ohosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500 (1991)). Under an N2 atmosphere, a solution of 1943 g (6.32 mol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one in 12.0 l of THF and 1.9 l of 1,3-dim-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is cooled down to -75° C. and treated, at an internal temperature of below -70° C., with 14000 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich), and this mixture is subsequently stirred at -75° C. for 20 min. 835 ml (7.00 mol) of benzyl bromide are added dropwise to it over the space of 1 h, during which time the internal temperature is not allowed to exceed -70° C., and the mixture is then thoroughly stirred at -75° C. for 30 min. 2320 ml of propionic acid (90 min) and then 2320 ml of water (1 h) are subsequently added to the clear solution, with the temperature being allowed to rise to -10° C. The reaction mixture is poured onto 30 l of ethyl acetate and 35 l of 10% citric acid solution, and the aqueous phase is separated off and reextracted 2× with 10 l of ethyl acetate. The organic phases are washed with 3×12 l of sat. sodium bicarbonate solution, 20 l of saline and 2×20 l of water, and then concentrated. The oily residue is taken up in 10 l of toluene, and this mixture is evaporated down to a residue volume of approximately 5 l. Filtering the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm), washing with toluene and crystallizing the crude product from hexane (4 l of hexane/kg of crude product) affords the title compound: TLC Rf (D)=0.54; FAB-MS (M+H)+ =414.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([N:27]4[CH:31]=[CH:30][CH:29]=[CH:28]4)=[CH:33][CH:34]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, off-white solid (77 mg, 62%), MS (ISP) m/z=496.4 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: C([N:8]([CH:19]([CH3:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1)C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:35]([C:23]1[CH:22]=[C:21]([CH2:20][CH:19]([NH2:8])[CH3:39])[CH:26]=[CH:25][C:24]=1[OH:27])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)N(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(N)Cc1ccc(O)c(C(C)(C)C)c1
Yield: 96.5 %

Procedure:
A suspension of N-benzyl-2-(4-benzyloxy-3-tert-butylphenyl)-1-methyl-N-(benzyloxycarbonyl)-ethylamine (2.35 g, 4.50 mmol) and 20% palladium hydroxide/carbon catalyst (0.50 g) in methanol (30 ml) was stirred in a hydrogen atmosphere overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to remove the solvent under reduced pressure, giving 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine (T21) (0.90 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>ClCCCl>[Cl:16][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Temperature: 80 °C

Procedure:
To a solution of 6-nitroindazole (2 mmol) in DCE (5 mL), sulfuryl chloride (10 mmol) was added and the resulting mixture was heated 80° C. for 3-5 h. The reaction mixture was concentrated, added with 5% aqueous Na2CO3 solution (20 mL) and extracted with EtOAc (2×15 mL). The combined organics were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous Na2SO4. Removal of volatiles afforded 3-chloro-6-nitro-1H-indazole as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH2:29][CH2:30]3)=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)S(=O)(=O)NC1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CC(C)S(=O)(=O)NC1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 10.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (21 mg, 0.07 mmol), propane-2-sulfonic acid piperidin-4-yl amide hydrochloride (17 mg, 0.077 mmol) and sodium triacetoxyborohydride (19 mg, 0.09 mmol) to afford 4 mg (11%) of the desired product after purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:31])[CH2:25]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2].[NH3:33]>CO.CC(=O)OCC>[NH2:33][CH2:25][CH:24]([OH:31])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]([CH3:32])[CH:9]=3)[O:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: N
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CN)cc3)no2)cc1C

Procedure:
To a cooled (0° C.) solution of rac-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propane-1,2-diol (619 mg, 1.54 mmol) in THF (15 mL), DIPEA (399 mg, 3.08 mmol) followed by methansulfonyl chloride (247 mg, 2.16 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM, washed with brine (3×50 mL), dried over MgSO4, filtered, concentrated and dried to give crude rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (955 mg) as a light brown oil; LC-MS: tR=0.54 min; [M+1]+=480.10. b) A solution of the above rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (600 mg, 1.33 mmol) in 7 M NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The mixture is diluted with EA and washed with water and brine. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (242 mg) as a pale yellow resin; LC-MS: tR=0.63 min; [M+1]+=400.93.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:34])[C:18]([N:20]([CH3:33])[C:21]([CH3:32])([CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[CH3:22])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:35][CH3:36].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:34])[C:18]([N:20]([CH3:33])[C:21]([CH3:22])([CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[CH3:32])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:35][CH3:36]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(C)C(C)(C)CCC#Cc1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(C)C(C)(C)CCC#Cc1cccs1)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 110 mg of 12i in 3 ml of dioxane a solution of 50 mg of KOH in 1 ml of water was added. The mixture was stirred at 50° C. for 2 hr. After cooling to RT, 15 ml of water was added and the reaction mixture was acidified to pH3 by addition of cold 0.5 N HCl. The product was extracted into ethyl acetate. The extract was once washed with water, dried and concentrated, to provide 100 mg of the acid 12j as colorless amorphous material, used without further purification in the next step; MS-ESI: [M+1] 546.98, 548.98).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.Cl>C1COCC1.CCOCC.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]>[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH:51]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-n2nnc(-c3ccccn3)n2)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2nnn(-c3ccc(C4COCCN4)cc3)n2)nc1
Temperature: 80 °C

Procedure:
To a flask containing 2-[2-(4-bromophenyl)-2H-tetrazol-5-yl]pyridine (150 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.025 mmol), 2-(dicyclohexylphosphino)biphenyl (18 mg, 0.05 mmol), and sodium t-butoxide (67 mg, 0.7 mmol), degassed toluene was added and the resulting mixture was stirred under nitrogen until homogeneity. Morpholine (53 μL, 0.6 mmol) was added to the mixture via syringe, and the reaction was heated to 80° C. The solution was then stirred for 18 h under nitrogen. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3×20 mL), and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with 40% EtOAc in hexanes to afford a yellow solid. This was dissolved in anhydrous THF (10 mL) and HCl (1.5equiv) in ether was added, the precipitate was filtered to afford 2-[2-(4-morpholin-3-ylphenyl)-2H-tetrazol-5-yl]pyridine as a yellow solid. 1H NMR ((CD3)2SO, 300 MHz) δ 8.82 (d, 1H), 8.28 (d, 1H), 8.08 (dt, 1H), 7.51-7.68 (m, 4H), 7.23 (m, 1H), 3.77 (m, 4H), 3.25 (m, 4H). MS (ESI) MS 309 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g) and menthol (10 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:39])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([CH2:28][O:29]C4CCCCO4)[CH:16]=3)=[C:12]([C:36]#[N:37])[CH:11]=[N:10][N:9]2[CH:38]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:39])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([CH2:28][OH:29])[CH:16]=3)=[C:12]([C:36]#[N:37])[CH:11]=[N:10][N:9]2[CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(COC4CCCCO4)c3)c2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(CO)c3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 394 (30 mg, 0.057 mmol) in CH2Cl2 (1 ml) was added TFA (300 μl). The mixture was stirred at rt for 30 min, concentrated and purified by silica gel flash column chromatography to give the title compound (11 mg, 44%) (30% EtOAc—Hexanes). LCMS Found: (M+H)+=443.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([S:33][CH3:34])[N:8]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([S:33]([CH3:34])=[O:48])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylthiopyrimidine (prepared in the above (3)) 100 mg in methylene chloride 3 ml is added at room temperature a solution of m-chloroperbenzoic acid 79 mg in methylene chloride 2 ml, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:31]#[C:30][CH2:29][OH:32]
Reactant: C#CCO
Reactant: Cc1ccc(C)c(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)c(C#CCO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-iodo-2,5-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.70 g) as a brown oil.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].Cl.[CH3:18][NH2:19]>ClC(Cl)C>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([NH:19][CH3:18])([CH3:16])[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Reactant: CN
Agent: Cl
Solvent: CC(Cl)Cl
Product: CNC(C)(C)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 85 °C
Yield: 58.5 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (prepared according to method B, step 1, 1.45 g, 1.5 mmol) in anhydrous dichloroethane (25 mL) are added methylamine hydrochloride (0.66 g, 10.0 mmol) and 1,8-diazabicyclo[5.40]undec-7-ene (3.81 g, 25.0 mmol). The reaction is heated to 85° C. for 16 h. After cooling the reaction mixture to ambient temperature it was washed with saturated NaHCO3 (25 mL). The water layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure. The crude product is purified by chromatography on silica eluting with 0% to 10% methanol/DCM to provide N-(3-tert-butyl-isoxazol-5-yl)-2-methylamino-2-methyl-propionamide (0.21 g, 17%). To a solution of N-(3-tert-butyl-isoxazol-5-yl)-2-methylamino-propionamide (36 mg, 0.15 mmol) in anhydrous dichloroethane (1 mL) are added N-methylmorpholine (82 μL, 0.75 mmol) and 4-chlorobenzenesulfonyl chloride (63 mg, 0.30 mmol). The reaction is concentrated under reduced pressure to give a yellow oil, which is purified by mass-triggered preparative HPLC to afford N-(5-tert-Butyl-isoxazol-3-yl)-2-[(4-chloro-benzenesulfonyl)-methyl-amino]-2-methyl-propionamide (32 mg, 52%). m/z 414 [M+H+]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[C:19]([C:21]1[N:25]([CH3:26])[C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([C:21]1[N:25]([CH3:26])[C:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)(=[O:10])=[O:9])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CC2)c(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
According to general procedure B, 4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (193 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide was provided (87 mg, 42%) after purification. MS (ESI) m/z 369. HPLC purity 99.6% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.N1C=CC=CC=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].Cl>C(Cl)Cl.C(OCC)(=O)C.O>[CH3:22][S:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Yield: 34.8 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (18.6 g.) in dried methylene chloride (140 ml.) was added pyridine, and to the mixture was dropwise added a solution of mesyl chloride (17.2 g.) in dried methylene chloride (20 ml.) under ice-cooling and stirring. The mixture was further stirred for 5 hours at room temperature, and to the mixture was added a mixture of water and ethyl acetate. After adjusting the mixture to about pH 2 with 10% hydrochloric acid under ice-cooling, the precipitates were collected by filtration, washed with ethyl acetate and dried to give ethyl 2-methanesulfonamidothiazol-4-ylacetate (9.2 g.), mp 207° to 208° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[C:18]([C:20]2[CH:21]=[C:22]([Cl:29])[CH:23]=[C:24]3[C:28]=2[NH:27][CH:26]=[CH:25]3)=[O:19])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:17]([CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[C:18]([C:20]2[CH:21]=[C:22]([Cl:29])[CH:23]=[C:24]3[C:28]=2[NH:27][CH:26]=[CH:25]3)=[O:19])=[CH:32][CH:33]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(O)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1

Procedure:
200 mg of 5-chloro-1H-indole-7-carboxylic acid [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amide (0.36 mmol) were dissolved in 20 ml EtOAc and hydrogenated for 5 h over 20 mg Pd/C 10%. After removal of the catalyst by filtration, the solution was concentrated in vacuo and the residue purified by column chromatography (8 g silicagel, heptane/EtOAc 2:1) leading to 136 mg of 5-chloro-1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(3-hydroxy-phenyl)-ethyl]-amide (79%) as a light yellow solid. MS (ISP) 461.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1SC(CNCC)=C(C)[N:6]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15](OC)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([NH:6][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:1]
Reactant: CCNCc1sc(C)nc1C
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of 2,4-dimethyl-5-ethylaminomethylthiazole, 1.5 g of 2-chloro-3-nitro-6-methoxypyridine, 5.0 g of potassium carbonate, 20 mL of N,N-dimethylformamide (DMF) were added into a 150 mL of single-neck flask equipped with a magnetic stirrer. And the reaction mixture was stirred at room temperature overnight. And then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.5 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (20/1) as an eluent to obtain 0.49 g of 6-methoxy-N-(2,4-dimethylthiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, having the content of 98%, as a yellow viscous liquid, and solidified after standing. GC-MS (M+) (EI, 70 eV, m/z) calc: 322. found: 322. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.199 (t, J=7.2 Hz, 3H, CH3), 2.383 (s, 3H, CH3), 2.603 (s, 3H, CH3), 3.303 (q, J=7.2 Hz, 2H, CH2), 3.960 (s, 3H, CH3), 4.778 (s, 2H, CH3), 6.151 (d, J=8.7 Hz, 1H, Py H), 8.141 (d, J=9.0 Hz, 1H, Py H).