Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.[Li]CCCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][NH:15][S:12]([CH:9]1[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: NS(=O)(=O)C1CC1
Reactant: COCCl
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCNS(=O)(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Step 15IId) To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C., was added n-BuLi (6.4 mL, 10.2 mmol, 1.6 M in hexane) and the reaction mixture was stirred for 1 h. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly allowed to warm to room temperature overnite. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with EtOAc (4×50 mL portions). The combined extracts were dried (MgSO4) and concentrated to afford Example 18, 1-methoxy-methylcyclopropylsulfonylamine tert-butylcarbamate, as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C(ON=O)(C)(C)C.[C:19](#[N:21])C>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:19]#[N:21])=[N:3][CH:4]=1
Reactant: CC#N
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: CC(C)(C)ON=O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Yield: 41 %

Procedure:
Heat a solution of 2-amino-5-bromo-3-nitropyridine (2.18 g, 10 mmol), cuprous cyanide (1.33 g, 15 mmol) and tert-butylnitrite (2.0 mL, 15 mmol) in acetonitrile (50 mL) at 60° C. for 2 hours. Cool the solution and partitioned between ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). Extract the aqueous layer with ethyl acetate (2×50 mL), wash with water (100 mL) and brine (100 mL), dry (MgSO4) and evaporate. Purify the solid by flash chromatography on silica gel (25% ether/75% hexane) to give the title compound as a pale yellow solid (934 mg, 41%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:28]([CH2:27][O:26][CH3:25])[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Solvent: ClCCl
Product: COCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
6-Benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine was dissolved in 200 mL of dichloromethane and methoxyacetyl chloride (1.85 g, 17.1 mmol), diluted in 10 mL of dichloromethane, was added dropwise. After 1 hour, the solvent was removed and the resulting solid was dissolved in 250 mL of 3:1 methanol:water. Aqueous potassium carbonate (6M) was added and the reaction was heated at reflux temperature for 3 hours. The solvent was removed and the residue was partitioned between 200 mL of dichloromethane and 100 mL of water. The aqueous fraction was isolated and extracted three times with dichloromethane. The combined organic fractions were dried, filtered, and concentrated under reduced pressure. The resulting material was purified by flash column chromatography on silica gel eluting with a gradient of 0-4% methanol in dichloromethane. The clean fractions were combined and concentrated to give 4.2 g of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.[Na+]>OCC(CO)O>[OH:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]2[C:3]=1[CH:19]=[CH:14][CH:15]=[N:1]2
Reactant: COc1ccc(O)cc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: OCC(O)CO
Product: COc1ccc(O)c2cccnc12

Procedure:
Following the same procedure as in Example 23-(a), reaction and treatment were carried out using 2.25 g of 3-amino-4-methoxyphenol, 3.7 ml of glycerol and sodium m-nitrobenzene sulfonate to obtain 180 mg of 5-hydroxy-8-methoxyquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29]([CH:31]=O)[C:28]([CH3:33])=[N:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:29]3[C:28]([CH3:33])=[N:27][N:26]([CH3:25])[CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: Cc1nn(C)cc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5cn(C)nc5C)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-4-(4-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (60.0 mg, 0.170 mmol) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (22.2 mg, 0.179 mmol) in EtOH (3.8 mL) was added 1M Na2S2O4 (0.678 mL, 0.678 mmol, freshly prepared) and the solution was heated to 80° C. and stirred for 16 h whilst being open to air. Once cooled, the reaction was evaporated in vacuo and the residue dry loaded onto silica. Purification was accomplished by flash chromatography on silica gel (3×14) eluting with MeOH/CH2Cl2 (5-7.5%) to yield the title compound as a pale yellow solid. Recrystallisation in EtOAc/Et2O gave the title compound (20 mg, 27%) as an off white solid. The filtrate was concentrated in vacuo, an additional amount of title compound (12 mg, 16%) as a pale yellow solid. 1H-NMR (500 MHz, CDCl3) 2.60 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.81 (app t, J=4.5 Hz, 4H, CH2), 3.76 (s, 2H, —CH2—), 3.87 (app s, 4H, CH2), 3.90 (s, 3H, NCH3), 7.77 (br s, 1H, CHar), 7.96 (br S, 1H, CHar), 12.18 (s, 1H, NH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.CC(OC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)C(=O)O)cc1Br
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H](O)C(=O)O)cc1Br
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 2.9 g (11.3 mmol) 3-(3-bromo-4-methyl-phenyl)-2-oxo-propionic acid and 2.0 mL (15.1 mmol) triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.44 g (17.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C.; the reaction mixture was kept for 1 h at this temperature, then the cooling bath was removed and the mixture was stirred overnight at RT. To complete the reaction another 3.0 g (9.4 mmol) (1R)—B-chlorodiisopinocampheylborane were added and the mixture was stirred for a further 5 h. While cooling with ice 30 mL 1 M NaOH and 30 mL TBME were added dropwise and the mixture was stirred for 15 min. The aqueous phase was separated off, the organic phase was extracted with 15 mL 1 M NaOH and 25 mL water. The combined aqueous phases were acidified with 2 M HCl while cooling with ice, extracted three times with 40 mL TBME and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])([C:13]([O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[O:14])[C:5](=[O:27])[C:4]=1[C:28]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][C:31]=2[S:30](=[O:44])(=[O:43])[N:29]=1.[CH3:45][O:46][C:47](Cl)=[O:48].C(N(CC)CC)C>ClCCl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@:6]([C:13]([O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:47]([O:46][CH3:45])=[O:48])=[O:14])([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:5](=[O:27])[C:4]=1[C:28]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][C:31]=2[S:30](=[O:44])(=[O:43])[N:29]=1
Reactant: CC(C)CC[C@@]1(C(=O)OC[C@H]2CCCN2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC[C@@H]1COC(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 173 (0.079 mmol) in dry dichloromethane (1 mL) at 0° C. was added methylchloroformate (0.12 mL, 1.55 mmol) and triethylamine (33 μL, 0.24 mmol). The resulting mixture was stirred at rt 3 h and partitioned between H2O (5 mL) and dichloromethane (3×5 mL). The combined organic layers were dried over Na2SO4, the drying agent was filtered off, and the solvent was removed in vacuo. To a solution of the resulting residue in methanol (1 mL) was added K2CO3, and the resulting mixture was stirred at rt 90 min. The mixture was partitioned between N HCl (5 mL) and ethyl acetate (3×5 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% methanol in chloroform, and the title compound was obtained as a lt. yellow solid (48 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 0.43 (m, 1 H), 0.67 (m, J=6.62 Hz, 3 H), 0.71 (d, J=6.62 Hz, 3 H), 0.89 (m, 2 H), 1.33 (m, 1 H), 1.45 (m, 3 H), 1.67 (m, 1 H), 2.10 (m, 1 H), 2.40 (m, 1 H), 2.70 (m, 1 H), 3.02 (s, 3 H), 3.74 (m, 1 H), 3.93 (m, 1 H), 4.13 (m, 1 H), 7.16 (m, 1 H), 7.49 (m, 5 H), 8.12 (m, 1 H), 10.01 (s, 1 H), 14.54 (br s, 1 H); MS (ESI) m/z=689 [M+H].
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:59]([S:63][S:64][CH2:65][C@@H:66]([C:68]([OH:70])=[O:69])[NH2:67])([CH3:62])([CH3:61])[CH3:60].Cl>ClCCl.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C:10](=[O:11])[NH:67][C@H:66]([C:68]([OH:70])=[O:69])[CH2:65][S:64][S:63][C:59]([CH3:62])([CH3:60])[CH3:61])[NH:1][C:13](=[O:14])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A solution of Fmoc-Phe-OH (4 g, 10.32 mmol) and N-hydroxysuccinimide (1.19 g, 10.32 mmol) in dichloromethane (20 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.98 g, 10.32 mmol) was added and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (1.80 ml, 10.23 mmol) and S-(t-butylthio)-L-cysteine (H-Cys(StBu)-OH) (2.16 g, 10.32 mmol) were added and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and 2 M hydrochloric acid were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-benzyl-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP663, Fmoc-Phe-Cys(StBu)-OH) (4.22 g, 71%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)=[C:22]([C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:26][CH:25]=1
Reactant: O=C(CCCl)c1ccc2c(c1)CCO2
Reactant: CNCCOc1ccc(C(=O)c2ccc(O)cc2)cc1
Product: CNCCOc1ccc(C(=C(CCCl)c2ccc3c(c2)CCO3)c2ccc(O)cc2)cc1
Yield: 72.4 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 3-chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (0.85 g, 1.0 eq) was reacted with (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone (1.0 g, 1.0 eq) to give 1.2 g desired product (85%, Z/E=1/1). 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.02-7.54 (m, 6H), 6.70-6.84 (m, 5H), 4.22 (t, J=8.4 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 3.48 (t, J=5.6 Hz, 2H), 2.89-3.05 (m, 4H), 2.42 (s, 3H), 2.13 (t, J=8.4 Hz, 2H); m/z=450[M+1]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1coc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2occ(CCO)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4; filtered and concentrated. The product, 2-(5-methoxy-1-benzofuran-3-yl)ethanol, obtained as white oil, was pure enough and taken to the next step without purification. Yellow oil; Yield: 900 mg (93%); 193 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:24])=[CH:4][N:3]=1.[NH:25]1[C:29]2[N:30]=[CH:31][CH:32]=[C:33](B(O)O)[C:28]=2[CH:27]=[CH:26]1.[C:37](=O)([O-])[O-:38].[K+].[K+].[C]=O>C1(OC)C=CC=CC=1.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>[Cl:24][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)(=[O:11])=[O:10])[C:2]([C:37]([C:33]2[C:28]3[CH:27]=[CH:26][NH:25][C:29]=3[N:30]=[CH:31][CH:32]=2)=[O:38])=[N:3][CH:4]=1
Reactant: OB(O)c1ccnc2[nH]ccc12
Reactant: CCc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [K+]
Solvent: COc1ccccc1
Product: CCc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1C(F)(F)F
Yield: 3.1 %

Procedure:
A solution/suspension made of 97 mg (0.22 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-ethyl-3-trifluoromethyl-benzenesulfonamide, 140 mg (0.87 mmol) of 1H-pyrrolo[2,3-b]pyridine-4-boronic acid (mixture with its neopentyl glycolate ester and 1H-pyrrolo[2,3-b]pyridine), 240 mg (1.74 mmol) of potassium carbonate and 15 mg (0.022 mmol) of bis(triphenylphosphine)dichloropalladium(II) in 1 mL of anisole was stirred at 150° C. under 10 atm pressure of carbon monoxide for 2 h. After cooling down and decompression the mixture was introduced onto a flash column and eluted with 50-100% ethyl acetate in hexanes. Fractions containing the product were repurified on reverse-phase HPLC and free based to give 3.5 mg of the product as a yellow solid. LC-MSD, m/z for C22H16ClF3N4O3S [M+H]+=509.0, 511.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:13][C:10]1[C:9]([NH:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:25]([OH:27])=[O:26])[CH:33]=3)=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)CCc1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)CCc1ccccc1
Temperature: 88 °C
Reaction time: 1 h

Procedure:
N-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-phenyl-propionamide (0.100 g, 0.26 mmol), 3-carboxyphenylboronic acid (0.052 g, 0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.03 mmol), and potassium carbonate (0.072 g, 0.52 mmol) were combined in 2:1 DME:H2O. The mixture was purged with N2 and stirred at 88° C. in a sealed container for 1 hour. After aqueous workup the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[ClH:19].C(O[CH2:24][CH3:25])(=O)C.[CH3:26]N(C)C=O>O1CCOCC1.ICCC>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:26][CH2:24][CH3:25])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCI
Product: CCCSC(=N)Nc1cccc(-c2cc(OC)ccn2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (104 mg) in N,N-dimethylformamide (2 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.2 ml) and iodopropane (0.195 ml), and the mixture was stirred at 50° C. for 2 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)-S-propylisothiourea dihydrochloride (143 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[Br:23][C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)=[O:30])[N:28]=1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2N)C1
Reactant: O=C(O)c1csc(Br)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2NC(=O)c2csc(Br)n2)C1
Reaction time: 17 h

Procedure:
A solution containing 1 eq each of tert-butyl (1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.3 M, was stirred for 17 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (1S,3R,5S)-3-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate, LCMS (m/z): 495.1/497.1 (MH+); LC Rt=3.17 min.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[OH-:30].[Li+].C[O:33]CCOC>O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]([OH:22])=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:30]
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 17.6 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyldihydrofuran-2-(3H)one in 710 ml of ethylene glycol dimethyl ether and 352 ml of water is treated dropwise, at 20° C. and within the space of 10 min, with 176 ml of a 1M lithium hydroxide solution. After that, the reaction mixture is stirred at RT for 1.5 h, and the solvent is then evaporated off. The residue is poured onto 1 l of cold 10% citric acid, and this acidic solution is extracted three times with 800 ml of ethyl acetate on each occasion. The combined extracts are washed first with 800 ml of water and then with 800 ml of saline. After the organic solution has been dried over sodium sulfate, the solvent is distilled off. The crude title compound is employed in the next stage without any further purification. FAB-MS (M+H)+ =414.