Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 99 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.52 (s, 1H), 7.38–7.35 (m, 2H), 7.30–7.22 (m, 4H), 6.93 (d, 1H, J=7.6 Hz), 6.87 (br s, 1H), 3.28 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.45 (m, 1H), 2.36–2.30 (m, 6H), 1.96–1.33 (m, 18H), 1.00 (t, 3H, J=7.6 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:29](=O)[CH2:28][CH2:27]C1=O.C(Cl)CCl.C1(N)CC1>C(Cl)Cl>[CH:19]1([CH2:18][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]([OH:17])[C:14]([NH:24][CH:29]2[CH2:27][CH2:28]2)=[O:16])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(NC(CC1CCC1)C(O)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC(CC1CCC1)C(O)C(=O)NC1CC1)OCc1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (600 mg, 1.95 mmol) in DCM (20 mL) was added HOSu (337 mg, 2.93 mmol), EDC (562 mg, 2.93 mmol). After stirring for 1 hour, cyclopropylamine (223 mg, 3.9 mmol) was added to the above mixture. The product was extracted with EtOAc. The combined organic layer was then washed with HCl (1N), water, NaHCO3, and brine and then concentrated in vacuo to afford benzyl 1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (530 mg). (M+1) 347.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.C(OCC)(=O)C.[CH:16]([NH2:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:18][CH:16]=[O:17])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: NC=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNc1cccc(F)n1
Temperature: 25 °C

Procedure:
A solution of 0.63 g of 2,6-difluoropyridine in 0.2 mL of formamide was stirred for 3 hours at 150° C. The reaction mixture was cooled to room temperature, to which were added water (100 mL) and ethyl acetate (100 mL×3) for extraction. The extract solution was dried over anhydrous magnesium sulfate, followed by concentration to give powdery precipitate of 2-fluoro-6-(formylamino)pyridine. The powdery product was collected by filtration and dried for 2 hours at 40° C. under reduced pressure (0.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[N:7]=[C:8]([CH:10]=O)[CH:9]=1)=[O:4].[NH2:13][OH:14].ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1>C(O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[N:7]=[C:8]([C:10]2[CH2:31][C:30]([C:28]3[CH:29]=[C:24]([Cl:23])[CH:25]=[C:26]([Cl:36])[CH:27]=3)([C:32]([F:33])([F:34])[F:35])[O:14][N:13]=2)[CH:9]=1)=[O:4]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: NO
Reactant: COC(=O)c1cc(C=O)nn1C
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nn1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-Formyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (210 mg) in ethanol (10 mL), was added aqueous NH2OH (50% in water, 0.10 mL). The solution was stirred at room temperature for 4 hours then was concentrated to give a white solid which was then dissolved in dimethylformamide (4 mL). To this solution was added N-chlorosuccinimide (180 mg). The solution was stirred at room temperature for 4 hours. This solution was slowly added to a solution of 1,3-Dichloro-5-(1-trifluoromethyl-vinyl)-benzene (750 mg) (prepared according to WO 2005/085216) in dimethylformamide (6 mL). When the addition was completed, triethylamine (0.2 mL) was added. The solution was stirred at room temperature for 4 hours then the reaction was then quenched by addition of water. After extraction with diethyl ether, the organic phase was separated, dried over magnesium sulfate and concentrated to give an orange oil. The residue was purified by chromatography over silica (heptane/diethyl ether; 1/0 to 7/3) to give 300 mg of 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.48 (m, 2H), 7.39-7.38 (m, 1H), 7.23 (s, 1H), 4.17 (s, 3H), 4.14 (d, 1H), 3.89 (s, 3H), 3.75 (d, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7](C(O)=O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.NCC1OC=CN=1.CNC(N)=O.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cn2c(cc3ccc(C(=O)O)cc32)-c2ccccc2C1
Agent: CNC(N)=O
Agent: NCc1ncco1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3

Procedure:
(5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-[[(2-oxazolylmethyl)amino]carbonyl]-, methyl ester) was prepared from 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-, 10-methyl ester and 2-aminomethyloxazole in a similar manner as described; Analytical thin layer chromatography (5% MeOH/CH2Cl2) Rf=0.40; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2Õ0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=528.23, HPLC Rt=2.040 min.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O)(=O)C>C(Cl)Cl>[CH:13]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Yield: 68.7 %

Procedure:
Following the procedure of Example 2, 16.0 g of pyridinium chlorochromate, 10.0 g of (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 36.0 g of crushed 4 Å molecular sieves and 4.5 ml of glacial acetic acid in 250 ml of methylene chloride gives 6.8 g of the product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9](Br)[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[N:6][N:7]=1.[CH:21]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Al](C)C>C[Si](C)(C)N[Si](C)(C)C.C1COCC1.Cl[Pd]Cl>[NH2:1][C:2]1[C:3]2[N:10]=[C:9]([CH3:21])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1nnnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd]Cl
Agent: C[Al](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1nc2c(N)nnnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 310 %

Procedure:
The compound from Step A (112 mg, 0.3 mmol) was heated at reflux in hexamethyldisilazane (15 mL) for 16 hours. The mixture was evaporated to dryness to give a syrup which was dissolved in dry THF (12 mL). PPh3 (10 mg; 0.04 mmol), PdCl2 (3.5 mg; 0.02 mmol) and AlMe3 (100 μl; 0.94 mmol) were added. The mixture was reflux for 5 hours. The mixture was evaporated to dryness. The crude product was dissolved in methanol (30 mL) in the presence of ammonium chloride. The mixture was evaporated to dryness and the residue was purified on silica gel reverse-phase (C18) using water/acetonitrile (from 9/1 to 6/4) as eluant to give the title compound (35 mg) as a yellow powder.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH2:28]([S:30][Si](C)(C)C)[CH3:29].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[C:25]([O:24][C@@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@H:10]1[S:30][CH2:28][CH3:29])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: CCS[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of galactose pentaacetate (38.00 g, 97.43 mmol), (ethylthio)trimethylsilane (19.60 g, 146.15 mmol) and trimethylsilyl trifluoromethanesulfonate (23.60 g, 106.20 mmol) in CH2Cl2 (150 ml) was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2 (150 ml) and washed with 1M Na2CO3 solution (300 ml), water (300 ml), dried over MgSO4 and concentrated. The residue was crystallised from hexane/diisopropyl ether 1:1 (v/v) to give ethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (34.00 g, 89%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH3:10])[CH3:2].[C:11](=O)([O-:13])[O-:12].[K+].[K+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[C:6]([OH:9])=[CH:5][C:4]=1[CH3:10])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(O)cc1C
Agent: [K+]
Solvent: O
Product: CCc1cc(C(=O)O)c(O)cc1C

Procedure:
A mixture of 4-ethyl-3-methylphenol (31.51 g) and anhydrous potassium carbonate (91.25 g) was heated at 175° for 4 hours under a carbon dioxide pressure of 1,300 p.s.i. The cooled reaction products were dissolved in water (2 l). Acidification with hydrochloric acid, filtration and recrystallisation of the solid from ethanol-water gave 5-ethyl-4-methylsalicylic acid, m.p. 152.5°-154° C. (Found; C, 66.55; H, 6.71; C10H12O3 requires; C, 66.65; H, 6.71.)
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>CCO.CC#N>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Solvent: CC#N
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in analogous fashion to that described in Example 8 using (S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 34.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=4.42 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent:EtOH/MeCN (98:2), 0.5 mL/min, UV 210 nm) tR=28.27 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.88 (m, 2H) 2.92 (d, J=11.73 Hz, 1H) 3.19-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.18 (br. s, 1H) 4.80 (d, J=3.13 Hz, 1H) 6.37 (s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.16 (s, 1H) 12.85-13.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:27])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:21][CH:22]=2)=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (710 mg), 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg), triethylamine (1.26 ml) and powdered 4 Å molecular sieves (700 mg) in dichloromethane (18 ml) was added copper(II) acetate (330 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (600 mg).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]=1[CH3:18])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccccc2)c1C

Procedure:
Similar to Example 1, phenyl hydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum and the oil resuspended in chloroform. The resulting suspension was washed with 5% sodium bicarbonate, 5% hydrochloric acid, and then brine. The organic layer was dried over NaSO4, the solids filtered, and the solvents removed under vacuum. The crude material was purified over silica gel to yield the named product as an oil. 1H-NMR (CDCl3, ppm): 1.37 t (3H); 2.51 s (6H); 4.32 q (2H); 7.42 bs (5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([OH:23])=O)(=[O:19])=[O:18])=[CH:7]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:23])(=[O:18])=[O:19])=[CH:7]1
Reactant: Nc1ccccn1
Reactant: O=C(O)CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12)Nc1ccccn1

Procedure:
2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)acetic acid (30 mg, 0.68 mmol) from Step D, 2-amino-pyridine (13 mg, 0.135 mmol), PyClu (45 mg, 0.135 mmol), and DIEA (29 μL, 0.169 mmol) were added to dichloroethane (3 mL) and microwave irradiated at 110° C. for 30 minutes. The solvent was removed in vacuo and the remaining residue was purified on a Gilson reverse phase HPLC system with a Phenomenex, Luna 50×21.2 mm, 5 uM C18 column (5%-95% water:acetonitrile over 6 min) to yield the desired product. LCMS>99% 215 nm, RT=0.78 min, m/z=520 ([79Br]m+1), 522 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 10.89 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.66 (s, 1H) 7.59 (d, J=8.4 Hz, 2H), 7.38-7.34 (m, 2H), 5.61 (s, 2H), 4.64 (s, 2H), 2.16 (s, 3H). HRMS found 520.0142; calculated for C22H17N3O3SBrF2, 520.0142.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.Cl.[NH2:20][CH2:21][C:22]([CH3:25])([SH:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:20][CH2:21][C:22]([S:24][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1)([CH3:25])[CH3:23]
Reactant: CC(C)(S)CN
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SC(C)(C)CN)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 80 mg of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione, 90 mg of 1-amino-2-methyl-2-propanethiol hydrochloride, 2 ml of DMF and 200 mg of cesium carbonate was stirred at 70° C. for 5 hours.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH2:19][O:20][CH3:21].[C-:22]#[N:23].[Na+].CCOC(C)=O>CN(C=O)C.O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:22]#[N:23])=[C:4]([O:18][CH2:19][O:20][CH3:21])[CH:5]=1
Reactant: COCOc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(-c2nc3ccccc3o2)ccc1CC#N

Procedure:
2-[4-(Bromomethyl)-3-(methoxymethoxy)phenyl]-1,3-benzoxazole (250 mg, 0.72 mmol) was treated with sodium cyanide (150 mg, 2.2 mmol) in DMF/H2O (15 mL/1.5 mL) at 90° C. for 3 h and EtOAc (150 mL) was added. The EtOAc solution was washed with H2O (2×20 mL), brine (2×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was eluted with flash column (silica gel, hexanes:EtOAc 4:1) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-(methoxymethoxy)phenyl]acetonitrile as a yellow solid. 1H NMR (CD3OD, 300 MHz), δ 8.02 (d, 2H), 7.95 (m, 1H), 7.80 (m, 1H), 7.63 (m, 1H), 7.57 (d, 2H), 7.40 (m, 2H). MS (ESI) 295 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCC(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-hydroxymethyl-cyclohexane carboxylic acid methyl ester (300 mg, 1.74 mmol; CAS Reg. No. 13380-85-3) in dichloromethane (10 ml) under nitrogen was added triethylamine (0.5 ml, 3.48 mmol) and p-toluenesulfonyl chloride (664 mg, 3.48 mmol; CAS Reg. No. 98-59-9) at 25° C. and the mixture was stirred for 16 h. The reaction mixture was evaporated under reduced pressure, and the crude product was purified by column chromatography over silica gel (ethyl acetate/n-hexane) to give the desired compound. Colorless powder (62%). MS (Turbo Spray): m/z=327.1 (M+H).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.O.[S:19](=O)(=O)(O)O>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11]([OH:17])=[S:19]
Reactant: O=S(=O)(O)O
Reactant: Sc1nc2ccccc2s1
Reactant: O=C1C=CC(=O)O1
Solvent: O
Product: O=C(O)CC(C(O)=S)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
16.8 g of finely powdered 2-mercaptobenzothiazole are suspended in 40 ml of 70% sulfuric acid, and 10.2 g of powdered maleic anhydride are added at 48°-51° in the course of 1 hour, with stirring. After a further hour at 50°, the reaction mixture is cooled to room temperature and is diluted by dropwise addition of 250 ml of water at 25°-35°. After 1 hour, the precipitated product is filtered off and dissolved in dilute sodium hydroxide solution. The solution is filtered and the filtrate is acidified with hydrochloric acid. The precipitate is filtered off and dried at 60° in vacuo. 24.7 g (87% of theory) of benzothiazol-2-ylthiosuccinic acid of melting point 175°-176°, with decomposition, are thus obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[CH2:14][C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:15](=[O:16])[C:14](=[C:14]3[C:15](=[O:16])[C:7]4[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=4[O:10]3)[O:10][C:6]=2[CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc2c(c1)OC(=C1Oc3cc(N(CC)CC)ccc3C1=O)C2=O
Temperature: 65 °C
Yield: 32.8 %

Procedure:
1 g (6 mmol) of 3-diethylamino-phenol is dissolved is 20 ml of chloroform with exclusion of moisture. 1 g (9 mmol) of chloroacetyl chloride is added dropwise in the course of 30 minutes. Silica gel (about 10 g in total) is then introduced until the entire reaction solution has been absorbed, and the mixture is heated at 60-70° C. for 6 days. Finally, the silica gel is filtered off with suction through a G4 frit and washed with chloroform until the wash solution remains colourless. The dark red organic phases are combined and the solvent is stripped off on a rotary evaporator. 0.4 g of a dark red solid is obtained and is subsequently separated into the isomers by column chromatography over silica gel using chloroform as the solvent. The cis-isomer is obtained in the first runnings as a blue fraction, and the trans-isomer is obtained as a red-violet fraction. After the solvents have been stripped off, the resulting colorant isomers are dried at 95° C. under an oil pump vacuum for 7 hours.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:10][O:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3,5-xylenol (10 g, 0.082 mol) and anhydrous potassium carbonate (34 g, 0.25 mol) were added into DMF (150 mL) and then iodomethane (12.8 g, 0.090 mmol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 10 g of the product (90%) by column chromatography.