Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, MsCl (13.9 mL) was dropwise added to a suspension of 2-(4-nitrophenyl)ethanol (25.0 g) and Et3N (31.3 mL) in CHCl3 (including amylene, 625 mL) over 10 minutes under ice cooling, followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4, and then the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to yield the title compound (41.8 g, light yellow solid).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:11]([C:10]1[C:5]2[C:4]([NH:23][CH:24]3[CH2:25][CH2:26]3)=[N:3][C:2]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=3)=[N:7][C:6]=2[NH:8][CH:9]=1)#[N:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc(C(N)=O)cc3)nc(NC3CC3)c12
Temperature: 135 °C
Reaction time: 20 h
Yield: 28.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (175 mg, 0.451 mmol), 4-aminobenzamide (122 mg, 0.897 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 334.3 (M+H); UV 204.6, 230.2, 308.1 nm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].O.[O-:27]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[O:27])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(SCc3ccc(Cl)cc3Cl)ccc12
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1csc2cc(S(=O)Cc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)sulfanyl)-1-benzothiophen-3-yl)acetate (315 mg), water (3.00 mL) and CH3CN (3.00 mL) was added NaIO4 (164 mg) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added NaIO4 (164 mg), and the mixture was stirred for further 1 day. To the mixture was added saturated aqueous Na2S2O3 at room temperature, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (204 mg). The residue was recrystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH:11](NCC2C=CC=CC=2)[CH:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:4][C:2]([CH3:1])([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:11]([O:21]2)[CH2:12]1)=[O:7])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(NCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Yield: 92.3 %

Procedure:
A solution of [trans-(+/-)]-3-hydroxy-4-[(phenylmethyl)amino]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (1.1 g, 3.76 mmol) in ethanol (150 ml) was hydrogenated over 10% palladium-on-carbon (0.05 g) for 3.5h. The catalyst was removed by filtration, washed with ethanol (50 ml) and the combined ethanolic solution was evaporated to leave an oil which was taken up in ethyl acetate (75 ml). The solution was filtered and the filtrate evaporated to leave a solid which was crystallised from ethyl acetate/cyclohexane to give the title compound (0.643 g), nmr(δ,CDCl3) 1.45(s, 9H), 1.6-2.2(bm, 3H), 3.1(m,1H), 3.3(m,2H), 3.68(m,2H), 3.98(m,1H).
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:52]=[N+:53]=[N-:54])=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:12][CH:13]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoic acid (217 mg, 0.54 mmol) in isopropanol (5.4 mL) was added triethylamine (0.09 mL, 0.65 mmol) and diphenyl phosphorazidate (0.13 mL, 0.60 mmol) and the reaction was stirred at room temperature for 16 hours. The white precipitate that had formed was filtered and dried in a vacuum oven to provide 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoyl azide as a white solid (145 mg, 63%): mp 140° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 8.32 (m, 4H), 8.24-8.17 (m, 2H), 7.68 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −85.25, −86.89; ESIMS m/z 426 ([M+H]+).
Reaction SMILES: [BH4-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][C:12](=[N:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].O>O1CCCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) is slowly added to a solution of 0.12 mole of 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (starting compound A7) in 100 ml of dry tetrahydrofurane. After complete addition, the mixture is stirred for another 30 min after which a 100 ml of water is added to destroy the excess of borohydride. Subsequently the tetrahydrofurane is evaporated and the resulting aqeous solution extracted with diethyl ether. After drying the solvent over magnesium sulfate, the ether is evaporated. M. p.112-115° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+].O.[Cl:9][CH2:10][C:11]([N:13]([CH2:22]Cl)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12]>C1(C)C=CC=CC=1>[Cl:9][CH2:10][C:11]([N:13]([CH2:22][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12]
Reactant: c1cn[nH]c1
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(Cn1cccn1)C(=O)CCl
Reaction time: 4 h

Procedure:
A solution of 7.5 parts by weight of pyrazole and 4.0 parts by weight of sodium hydroxide in 20 parts by volume of water was added dropwise at 20°-25° C., with vigorous stirring, to a solution of 24.6 parts by weight of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide and M parts by weight of phase transfer catalyst in 70 parts by volume of toluene, and stirring was continued for 3-5 hours at the same temperature. After complete conversion (checked by thin layer chromatography), the organic phase was washed three times with water, dried and concentrated under reduced pressure at 70° to give G parts by weight of 2-chloro-2',6'-dimethyl-N-(pyrazol-1-yl-methyl)-acetanilide, as shown in the Table which follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[CH3:29][S:26]([C:23]1[N:22]=[CH:21][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:30])=[CH:25][CH:24]=1)(=[O:27])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)nc3)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of (S)-tert-butyl-4-(3-(6-(methylsulfonyl)pyridine-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (259 mg, 0.59 mmol) in DCM (10 mL) was added excess 4N HCl in dioxane (3 mL). The reaction was stirred for 4 hours, then concentrated in vacuo to yield (S)-3-(6-(methylsulfonyl)pyridin-3-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride salt (210 mg, 94%) as an off white solid, which was used without any further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[S:55]([NH:58][CH2:59][C:60]([NH2:62])=[O:61])(=[O:57])=[O:56])([O-:48])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:58]([S:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[N+:46]([O-:48])=[O:47])(=[O:57])=[O:56])[CH2:59][C:60](=[O:61])[NH2:62])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CC(N)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (98 mg) in tetrahydrofuran (2 mL) were added 2-(2-nitrobenzenesulfonylamino)acetoamide (40 mg), triphenylphosphine (45 mg) and diethyl azodicarboxylate (40% toluene solution, 0.1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-[(4-(3-[N-(2-nitrobenzenesulfonyl)-N-(carbamoylmethyl)amino]propoxy)-2-methylphenyl)methyl]-1H-pyrazole (92 mg). This material was dissolved in acetonitrile (1 mL). To the solution were added cesium carbonate (0.14 g) and thiophenol (0.012 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (57 mg).
Reaction SMILES: [CH:1]1([S:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH:1]1([S:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cccc(CS(=O)(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1-[(cyclopentylsulfonyl)methyl]-3-nitrobenzene (4.9 g) in ethanol (37 mL) and water (11.1 mL) was treated with ammonium chloride (4.9 g) at 0° C. Then zinc powder (5.9 g) was cautiously added in portions and stirred for 3 hours at room temperature. Then the mixture was filtered over cellite, washed with ethanol, condensed to dryness, treated with ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness. Crystallization of the crude product (4.5 g) from diethyl ether furnished the pure title compound (3.6 g).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+:10]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][C:16]3[CH:27]=[CH:28][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc([N+](=O)[O-])cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.48 g) and ethyl 2-(4-nitrobenzyl)acetoacetate (1.00 g) in ethanol (150 ml) was treated with dry HCl at 0° C. for 7.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 0.63 g (51%). Melting point 280-285° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC([O-])(C)C.[K+].[CH2:22]([O:24][C:25](=O)[O:26]CC)[CH3:23]>CCOCC>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH2:1][C:25]([O:24][CH2:22][CH3:23])=[O:26]
Reactant: CCOC(=O)OCC
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)Cc1cc2ccccc2[nH]1

Procedure:
2-Methylindole (1.7 g, 13 mmol) in 130 mL Et2O was treated with nBuLi (1.6M in hexane, 24.4 mL, 39 mmol) and KOtBu (1.0M in THF, 26 mL, 26 mmol) at RT for 40 min, then diethylcarbonate (3.15 mL, 26 mmol) was added. After 1 h the reaction was quenched with water, adjusted to pH 7 with 6N HCl, extracted with EtOAc, then the organic layer was washed with water and brine, dried (MgSO4), and concentrated. Flash chromatography (silica 10% then 20% EtOAc/hexane) provided 4-1 as a brown oil. Rf 0.33 (silica, 20% EtOAc/hexane).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 6′-methyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) 325 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(C(C)(C)C)cc3)CC2)CS1

Procedure:
Compound 202 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=188-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d, J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73 (m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25 (s, 9H). LCMS: 538 [M+H].
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl.[C:9]([C:11]1[C:16](=[S:17])[NH:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:13]([C:26]([O:28]CC)=O)[C:12]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=O)#[N:10].[CH2:40](O)C>>[OH:39][N:37]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:12]2[C:11]([C:9]#[N:10])=[C:16]([S:17][CH3:40])[N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]=2[C:26]1=[O:28]
Reactant: CCO
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)n(O)c2ccccc32)cc1
Reaction time: 4 h
Yield: 80 %

Procedure:
12.05 g (53.4 mmol) of tin chloride dihydrate and 14 ml of concentrated hydrochloric acid are added to 4 g (8.9 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate dissolved in 160 ml of ethanol. The reaction medium is carried at 65° C. for 4 hours. The precipitate obtained is filtered, rinsed with isopropanol and then dried to yield 2.78 g (80%) of 6-hydroxy-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carbonitrile in the form of a yellow solid.
Reaction SMILES: [Li]CCCC.C1COCC1.[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]3[C:25](=[CH:26][C:12]1=2)[CH:24]=[C:23]1[C:19]([S:20][CH:21]=[CH:22]1)=[CH:18]3.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29]>O>[CH3:27][Sn:28]([CH3:30])([CH3:29])[C:15]1[S:11][C:12]2[CH:26]=[C:25]3[C:17](=[CH:16][C:13]=2[CH:14]=1)[CH:18]=[C:19]1[S:20][C:21]([Sn:28]([CH3:30])([CH3:29])[CH3:27])=[CH:22][C:23]1=[CH:24]3
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2cc3cc4sccc4cc3cc2s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc3cc4sc([Sn](C)(C)C)cc4cc3cc2s1
Temperature: -78 °C
Reaction time: 11 h
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (1.57N hexane solution, 5.7 ml, 8.9 mmol) was slowly added to an anhydrous THF (80 mL) solution of naphtho[2,3-b:6,7-b′]dithiophene (a compound of formula (2)) (675 mg, 2.8 mmol) at −78° C. The reaction solution was heated and refluxed. After the reaction for 1.5 hours, the reaction solution was cooled to −78° C. To the reaction solution, trimethyltin chloride (2.24 g, 11.2 mmol) was added. After the mixture was stirred at room temperature for 11 hours, and water (100 mL) was added thereto. The resultant mixture was separated into phases. The water layer was extracted with methylene chloride (100 mL×3). The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. The resultant residue was recrystallized with acetone to obtain 2,7-bis(trimethylstannyl)naphtho[2,3-b:6,7-b′]dithiophene (861 mg, yield 54%) as a yellow solid substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12](OC)[CH:11]=1.[CH3:26][NH2:27].CS(C)=O.Cl>O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:27][CH3:26])[CH:11]=1
Reactant: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 mL) and DMSO (2 mL) in a sealed tube was heated at 110° C. for 4 hours, cooled and then poured into water (25 mL). The dilution was treated with 3M aqueous hydrochloric acid to give an orange solid. The solid was isolated by filtration to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m/e calc 345.35; found 346 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH2:11].Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:11]
Reactant: Nc1c(Br)cccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(Br)c1N
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A suspension of 2-bromo-6-nitrobenzenamine (2.0 g, 9 mmol) and SnCl2 (10.2 g, 54 mmol) in EtOH (20 mL) was heated at reflux for 2 h, then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (200 mL). The resulting slurry was filtered through a pad of Celite® and washed with EtOAc (50 ml, ×3). The filtrate was washed with saturated NaHCO3, water, and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 3-bromobenzene-1,2-diamine as a brown oil (1.5 g, 90%). MS (ESI): m/z=186.9 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.C1C=CC=CC=1>C(O)(=O)C>[CH:14]1([C:17]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[C:5]=3[N:7]=2)[CH2:15][CH2:16]1
Reactant: Cc1cc(N)n(-c2ccncc2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2-c1ccncc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), benzene (50 mL), and acetic acid (25 mL). The final product was collected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.64-2.69 (m, 4 H), 4.47 (q, J=7.07 Hz, 2 H), 7.74 (s, 1 H), 8.27-8.36 (m, 2 H), 8.66-8.71 (m, 2 H).