Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C@@H:4]1[C:20](=[O:21])[N:6]2[CH:7]([C:17]([OH:19])=[O:18])[C:8]([CH2:11][C:12]3[S:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][S:10][C@H:5]12)=O.[ClH:22].O>O1CCOCC1>[ClH:22].[NH2:3][C@@H:4]1[C:20](=[O:21])[N:6]2[CH:7]([C:17]([OH:19])=[O:18])[C:8]([CH2:11][C:12]3[S:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 72 h

Procedure:
A solution of 0.975 g of 7β-formylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid in 10 ml of dioxane is treated with 1.2 ml of a 1:1-mixture of concentrated hydrochloric acid and water and left to stand for 3 days at room temperature. The faintly yellow reaction solution is lyophilised to yield the 7β-amino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid hydrochloride, which according to thin-layer chromatogram which contains only traces of the starting material; thin-layer chromatogram (silica gel; detection with iodine vapour); Rf = 0.40 (system: n-butanol/acetic acid/water 67:10:23; starting material Rf = 0.56), Rf = 0.51 (system: n-butanol/pyridine/acetic acid/water 40:24:6:30; starting material Rf = 0.60), and Rf = 0.43 (system: ethyl acetate/n-butanol/pyridine/acetic acid/water 42:21:21:6:10; starting material Rf = 0.64).
Reaction SMILES: [N:1]1([C:52](OC(C)(C)C)=O)[CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([N:31]([CH3:48])[C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([N:31]([CH3:48])[C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O
Yield: 36 %

Procedure:
Condensation of BocPro-Phe-Phe-GlyOH (2.8 g.) and MeLeu-MetNH2 (1.6 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-Phe-Phe-Gly-MeLeu-MetNH2 in 49% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-GlyMeLeu-MetNH2 using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-MeLeu-MetNH2, which was isolated as the amorphous white solid free base in 36% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-])=O.Cl.[CH2:15](O)[CH3:16]>[Pd].C(O)C>[CH2:15]([O:13][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)Cc1ccccc1N

Procedure:
In 15% hydrogen chloride-ethanol, m- or o-nitrophenylacetic acid was ethyl-esterified and the resulting ethyl ester was hydrogenated with palladium catalyst in ethanol to give m- or o-aminophenylacetic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].O>O1CCCC1>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (60%, 2.87 g, 71.87 mmol) was added to anhydrous tetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethyl malonate (12.12 ml, 79.86 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. 1-Iodo-4,4,5,5,5-pentafluoropentane (11.5 g, 39.93 mmol) dissolved in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the reaction mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (11.2 g, Yield 88%).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[S:46][CH:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[S:46][CH:47]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1csc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (64 mg, 0.33 mmol) in CH2Cl2 (3.0 mL) was treated at rt with DMAP (10 mg, 0.08 mmol), HOBt (55 mg, 0.39 mmol), EDC (157 mg, 0.82 mmol) and DIPEA (0.25 mL, 1.48 mmol) and the resulting mixture was stirred for 15 min at rt. A solution of 2-((4-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (74 mg, 0.33 mmol) in CH2Cl2 (3.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (15.0 mL), the layers were separated and the org. phase was washed with 1N HCl (15.0 mL), water (10.0 mL), followed by brine (10.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 90:10 hept-EA to 60:40 hept-EA) gave the title compound as a white solid. TLC: rf (7:3 hept-EA)=0.15. LC-MS-conditions 07: tR=0.83 min, [M+H]+=397.21
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of quinoline-8-carboxylic acid (421 mg, 2.43 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.43 mmol), HATU (1.39 g, 3.65 mmol) in anhydrous DMF (15 mL) is added DIPEA (603 μL, 3.65 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (47) as white solid (281 mg, 32%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1([CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=O)[CH2:23]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([CH3:32])([CH3:21])[CH2:23]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)c4ccccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 3,3-dimethyl-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=423.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.Cl([O-])=O.[Na+].OP([O-])(O)=O.[Na+].CC(=CC)C.C[C:25]([OH:28])(C)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:28][CH3:25])=[O:8])[S:5][CH:6]=1
Reactant: CC(C)(C)O
Reactant: O=Cc1cc(Br)cs1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cs1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A biphasic mixture of 4-bromothiophene-2-carbaldehyde (13.2 g, 69.1 mmol, 1 equiv), sodium chlorite (9.40 g, 104 mmol, 1.50 equiv), sodium phosphate monobasic (9.53 g, 69.1 mmol, 1.00 equiv) in a mixture of t-BuOH (120 mL), 2-methyl-2-butene (20 mL), and water (50 mL) was stirred at 23° C. for 1 hour. More sodium chlorite 3.00 g, 33.2 mmol, 0.480 equiv) and a solution of sodium phosphate monobasic (3.00 g, 21.7 mmol, 0.315 equiv) in water (25 mL) were added. The resulting mixture was stirred for 1 hour, then concentrated. The residue was diluted with aqueous 0.1 N sodium hydroxide solution, and the resulting aqueous mixture was extracted with ethyl acetate (200 mL). The aqueous layer was then acidified to pH 2 with aqueous 1 N HCl solution and extracted with dichloromethane (3×100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in anhydrous methanol (600 mL) and concentrated sulfuric acid (4 mL) was added. The resulting solution was heated at reflux for 48 hours. The reaction mixture was concentrated, then carefully partitioned between aqueous saturated sodium bicarbonate solution (400 mL) and ethyl acetate (2×200 mL). The organic layer was dried over sodium sulfate and concentrated to give methyl 4-bromothiophene-2-carboxylate (5-1) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=1.5 Hz), 3.90 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]([CH2:33][CH2:34]O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([O:1][CH2:34][CH2:33][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:4]=2[O:8][CH2:7]1
Reactant: OCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2OCC3=O)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol), 2-phenoxyethanol (0.0475 g, 0.344 mmol) and triphenylphosphine (0.113 g, 0.431 mmol) in THF (2 mL) was added with a solution of a 40% solution of diethyl azodicarboxylate in toluene (0.225 g, 0.517 mmol) in THF (0.5 mL), and the mixture was stirred at 70° C. for 3 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0720 g, 53%).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.N(OCCC(C)C)=O.[ClH:37]>C(#N)C.[Cu]Cl>[Cl:37][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Agent: Cl[Cu]
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 16 h

Procedure:
400 mg (1.08 mmol) of 2-amino-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 1) are dissolved in 10 ml of acetonitrile. 759 mg (0.87 ml, 6.48 mmol) of isoamyl nitrite and 871 mg (6.48 mmol) of copper(I) chloride are then added, and the mixture is stirred at 40° C. for about 16 h. The reaction solution is then diluted with 1N hydrochloric acid and extracted three times with in each case 50 ml of dichloromethane. The combined organic phases are dried with sodium sulfate and concentrated under reduced pressure. The concentration residue is crystallized from dichloromethane/methanol.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:11]#[N:12])[NH:8][C:9]=1[CH3:10])([OH:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:32](O)([CH3:34])[CH3:33]>>[C:11]([C:7]1[NH:8][C:9]([CH3:10])=[C:4]([C:1]([O:3][CH:32]([CH3:34])[CH3:33])=[O:2])[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])#[N:12]
Reactant: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 97.6 %

Procedure:
Methyl (-)-5-carboxy-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (4.47 g) is reacted with phosphorus pentachloride (3.62 g) and isopropyl alcohol (2.5 g) in the same manner as in Example 7 to provide 5-isopropyl 3-methyl (-)-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Br[CH2:18][C:19]([O:21]CC)=[O:20]>>[C:19]([CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)([OH:21])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Product: O=C(O)COc1ccc2sc3ccccc3c(=O)c2c1
Yield: 75 %

Procedure:
An example of a conventional synthetic route to 2-carboxymethoxythioxanthone involves three stages. Firstly, phenol is reacted with dithiobisbenzoic acid to produce 2-hydroxythioxanthone in a 60% yield. Secondly, the 2-hydroxythioxanthone is reacted with ethyl bromoacetate to produce the ethyl ester of 2-carboxymethoxythioxanthone in 75% yield. Thirdly, the ester is hydrolysed by acidification to produce the desired product in 90% yield. These three stages form an inefficient and time-consuming process to provide a product that is a dark colour, contains impurities and by-products and is produced with only an overall yield of 40% from the starting material.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][C:14]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[NH2:16]
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccncc2)c(F)c1
Yield: 80.3 %

Procedure:
A solution of 4-mercaptopyridine (4.2 g, 35.6 mmol), 3,4-difluoronitrobenzene (5.7 g, 35.7 mmol), and potassium carbonate (12.4 g, 89.7 mmol) in anhydrous DMF (40 mL) was stirred at 40° C. and under argon for 3 h. TLC showed complete reaction. The mixture was diluted with ethyl acetate (100 mL) and water (100 mL) and the aqueous layer was back-extracted with ethylacetate (2×100 mL). The organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude product was purified by column chromatography with 50% ethyl acetate/50% hexanes. It afforded the desired product as a yellow solid (6.3 g, 71%). TLC (50% EtOAc/50% hexane) Rf 0.53; 1H-NMR (DMSO-d6) δ 7.27 (dd, J=0.76, 4.2 Hz, 2H), 7.78 (dt, J=0.76, 7.2 Hz, 1H), 8.11-8.11 (m, 1H), 8.28-8.33 (m, 1H), 8.5 (dd, J=1.4, 4.6 Hz, 2H), MS [M+H]+=251. Step 2. Preparation of 3-fluoro-4-(4-pyridinylsulfanyl)aniline.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@:7]23[O:13][C@H:12]2[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:5][CH:4]=[N:3]1>[Ni].C(O)(C)C>[CH3:1][N:2]1[C:6]([C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]2[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@@]12CCCC[C@@H]1O2
Agent: [Ni]
Solvent: CC(C)O
Product: Cn1nccc1[C@H]1CCCC[C@@H]1O
Yield: 28.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 102c by using the 1-methyl-5-[(1S,6S)-7-oxabicyclo[4.1.0]hept-1-yl]-1H-pyrazole (0.21 g, 1.17 mmol) prepared in Example 123d, Raney nickel (2.0 g) and isopropanol (5.9 mL), to yield the title compound (0.060 g, 28%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:34])[NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=4)[N:21]=[C:20]([NH2:33])[N:19]=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][NH2:36]>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:34])[NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]5[C:27]([C:30]([NH2:31])=[N:35][NH:36]5)=[CH:28][CH:29]=4)[N:21]=[C:20]([NH2:33])[N:19]=3)[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
To phenylmethyl{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}carbamate (57 mg, 0.124 mmol) in ethanol (3 mL) was added hydrazine (0.182 mL, 3.71 mmol) into a 5 mL sealable vial. The solution was then capped and heated at 100° C. overnight. The reaction was then concentrated, re-dissolved in 2 mL of DMSO, and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (30 ml/min, 33% CH3CN/H2O, 0.1% TFA to 58% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined, and the volume was reduced to remove the CH3CN. To the resulting aqueous mixture was added 5 mL of saturated aqueous NaHCO3, and then extracted 3× with EtOAc. The organics were then combined, washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (37 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.8 Hz, 3H), 1.66 (m, 4H), 2.67 (dt, J=3.7, 1.8 Hz, 1H), 3.38 (bs, 1H), 4.50 (bs, 1H), 4.73 (bs, 1H), 5.06 (d, J=5.3 Hz, 2H), 5.39 (s, 2H), 6.04-6.20 (bs, 2H), 6.58 (bs, 1H), 7.30-7.46 (m, 6H), 7.55 (d, J=8.3 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 11.52 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:22][C:23]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(O)(=O)C>O>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([NH:22][C:2]2[C:3]([NH:12][S:13]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:32]=1
Reactant: Cn1cnc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COC(=O)c1ccc(OC)cc1N
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)c1cn(C)cn1
Temperature: 170 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (2 g; 6.2 mmol; 1 eq) and methyl 2-amino-4-methoxybenzoate (1.2 g; 6.8 mmol; 1.1 eq) are taken up in water (60 mL) and acetic acid (160 μL; 3.65 mmol; 0.6 eq) is added. The suspension is heated up to 170° C. in the microwave under normal absorption for 20 min. The reaction is stopped by filtration of the solid and washing with water until neutral. The orange powder obtained is dried under vacuum at 40° C. overnight then taken up in DCM. Triethylamine (1.72 mL) is added. After sonication, the solvents are removed under reduced pressure and the residue obtained is washed with water then dried under vacuum at 40° C. overnight. The powder is taken up in MeOH and refluxed then the suspension is left at 4° C. for 1 h. The precipitate is filtered and washed with MeOH then dried under vacuum at 40° C. for 2 days, to afford 1.68 g (58%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 11.77 (s, 1H), 9.05 (d, J=2.3 Hz, 1H), 8.10-7.95 (m, 2H), 7.90 (s, 1H), 7.85-7.76 (m, 1H), 7.73-7.60 (m, 1H), 7.55-7.35 (m, 2H), 6.73 (dd, J=8.6, 2.2 Hz, 1H), 3.91 (s, 6H), 3.72 (s, 3H). HPLC (max plot) 100%; Rt 4.12 min. LC/MS: (ES+): 469.0, (ES−): 467.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[CH:22]=3)[N:17](C3CCCCO3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3ccco3)c1)nn2C1CCCCO1
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4ccco4)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
3-[3-(2-Furylcarbonylamino)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide was suspended in 10 mL of toluene and HCl gas was bubbled through for 15 min. The reaction mixture was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.111 g, 54% yield): 1H NMR (DMSO d6) δ 13.5 (br s, 1H), 10.3 (s, 1H), 8.64 (s, 1H), 8.4 (s, 1H), 8.11 (br s, 1H), 7.97 (s, 1H), 7.92 (t, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.52 (t, 1H), 7.39 (d, 1H), 7.36 (s, 1H), 6.7 (t, 1H); ES-MS (m/z) 347 [M+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C2C=CC=C3C=2C=C(S(O)(=O)=O)C=C3)[CH2:18][CH2:17]1>>[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:11]2[CH:2]=[CH:3][CH:4]=[C:5]3[C:10]=2[CH:9]=[C:8]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6]3)[CH2:18][CH2:17]1
Reactant: NS(=O)(=O)c1ccc2ccc(I)cc2c1
Reactant: O=S(=O)(O)c1ccc2cccc(OCCN3CCOCC3)c2c1
Product: NS(=O)(=O)c1ccc2cccc(OCCN3CCOCC3)c2c1
Yield: 27 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 11, 8-(2-morpholinoethoxy)naphthalene-2-sulfonic acid (100 mg, 0.30 mmol) was converted to the title compound (27 mg, 27%). 1H NMR (CD3OD) δ 8.82 (d, J=1.8 Hz, 1H), 8.05-8.01 (m, 1H), 7.99-7.94 (m, 1H), 7.63-7.60 (m, 2H), 7.16 (dd, J=5.3, 3.3 Hz, 1H), 4.70-4.65 (m, 2H), 4.00 (t, J=4.7 Hz, 4H), 3.79-3.74 (m, 2H), 3.49 (d, J=4.2 Hz, 2H), 3.33 (ddd, J=3.2, 1.8, 1.7 Hz, 2H); MS(ESI−) m/z 335.3 (M−H)−.