Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12]N=CC=1)=[O:7].[C:19]([C:21]1C=CC=CN=1)#[N:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:21]=[CH:19][N:20]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Reactant: N#Cc1ccccn1
Product: COc1ccc(C(=O)c2ccccn2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crude mixture was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford after drying in vacuo (60° C., 1 mm) 1.67 g (34%) of the product: mp 91.5-93° C.; 1H NMR (CDCl3) δ8.76-8.70 (m, 1 H), 8.05-7.71 (m, 4 H), 7.55-7.45 (m, 1 H), 7.00-6.89 (m, 1 H), 3.96 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ192.1, 155.7, 153.3, 148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0, 55.9; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.47; N, 5.66.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([F:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[F:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[C:14]2[CH3:15]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Product: Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 5-fluoro-3-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.1 ([M−H]−).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:41])[CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[C:26]([CH3:36])=[C:25]1[CH3:37]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:19][CH2:18][C:17]([O:16][CH3:15])=[O:41])[C:25]([CH3:37])=[C:26]3[CH3:36])=[O:34])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[O:9])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][Mg]Cl>C1COCC1>[CH2:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C@:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:11]1)([OH:9])[CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])[CH3:2]
Reactant: COCCCC[Mg]Cl
Reactant: CCc1ccccc1Oc1ccccc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-(2-ethylphenoxy)benzoyl)piperidine-1-carboxylate (2.25 g, 4.09 mmol) in THF (7 mL) at −20° C., 4-methoxybutylmagnesium chloride in THF (1.63 M, 5.0 mL, 8.15 mmol) was added dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with satd aq NH4Cl (8 mL) and extracted with ether (4×10 mL). The combined organic layers were washed with water and brine, and solvent was removed under vacuum to give a crude product, which was purified by flash column chromatography to give (R)-tert-butyl 3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (1.52 g, 75%). 1H NMR (CDCl3, 400 MHz) δ: 7.52 (d, 1H), 7.26 (dd, 1H), 7.20-7.00 (m, 4H), 6.78 (d, 1H), 6.60 (d, 1H), 4.34 (d, 1H), 4.00 (d, 1H), 3.30 (t, 2H), 3.24 (s, 3H), 2.78 (dd, 1H), 2.64 (q, 2H), 2.62 (m, 1H), 2.40 (m, 1H), 2.26 (m, 1H), 1.92 (m, 1H), 1.56 (m, 4H), 1.40 (s, 9H), 1.30 (m, 3H), 1.22 (t, 3H); MS m/z 520 (M+Na+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10]N1C(=O)CCC1=O>ClCCl>[Cl:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cc2[nH]ccc2cn1
Solvent: ClCCl
Product: Clc1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A solution of 1H-pyrrolo[3,2-c]pyridine (200 mg, 1.69 mmol) in dichloromethane (10 ml) was treated with N-chlorosuccinimide (339 mg, 2.5 mmol) and stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution, brine, dried over anhydrous sodium sulfate and concentrated. Purification from silica gel column chromatography using methanol and dichloromethane gradient afforded 3-chloro-1H-pyrrolo[3,2-c]pyridine (98 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH:25]2OCC[O:26]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH:25]=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(CCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Solvent: CC(=O)O
Product: COc1cc(CCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 86.2 %

Procedure:
A mixture of 2-[2-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1.3-dioxolane (2.73 g) and an aqueous solution of acetic acid (50%, 75 ml) was stirred for 3 hours at 80° C. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and made alkaline with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent to yield 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionaldehyde (2.09 g, 86%). The product was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.85-86° C.
Reaction SMILES: [Sb](F)(F)(F)(F)[F:2].FC(O[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])=O>>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[F:2]
Reactant: Cc1cccc(C)c1OC(=O)F
Reactant: F[Sb](F)(F)(F)F
Product: Cc1cccc(C)c1F
Temperature: 200 °C
Yield: 40 %

Procedure:
3.9 g of antimony pentafluoride were added to 100 g of 2,6-dimethylphenyl fluoroformate and the mixture was heated at 200° C. for 5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,6-Dimethylfluorobenzene was obtained in a yield of 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24](=[O:33])[C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=1>>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)/[C:25](=[C:26](\[C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[Cl:1])/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)/[C:24]2=[O:33])[CH:17]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(C(F)(F)F)ccc3Cl)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-2-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.63-7.67 (m, 2H), 7.33-7.52 (m, 7H), 7.10 (t, 1H), 6.64-6.71 (m, 2H), 5.98 (d, 1H), 4.87-5.04 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[O:29]=[S:30]1(=[O:36])[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:29]=[S:30]1(=[O:36])[CH2:34][CH2:33][CH:32]([NH:35][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:31]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NC1CCS(=O)(=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCS(=O)(=O)C3)ccc21
Yield: 73.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amide (39 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine (30 mg), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 527; and 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (br, 1H), 8.09 (d, 1H), 7.92 (d, 1H), 7.78-7.63 (m, 2H), 7.48 (d, 1H), 7.34 (d, 1H), 4.72 (m, 1H), 3.62 (s, 3H), 3.52 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.08 (m, 1H), 2.43 (t, 2H), and 2.25 (m, 1H).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>O>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)c1ccco1)c1ccc(Cl)cc1
Yield: 98.1 %

Procedure:
To a mixture of 10 g of (2-furylcarbonyl)methylamine hydrochloride, 12.5 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water are dropwise added 12.0 g of 4-chlorobenzoyl chloride at a temperature below 10° C. under stirring. The mixture is stirred at room temperature for 3 hours. Then, the ethyl acetate layer is collected, washed with water and dried. Said ethyl acetate layer is evaporated under reduced pressure to remove solvent. 16.0 g of N-(4-chlorobenzoyl)-(2-furylcabonyl)methylamine are thereby obtained. Yield: 98.2%
Reaction SMILES: [C:1]1(=O)[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].N1C=CC=CC=1>CCO.O>[N:15](=[C:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1)[OH:16]
Reactant: NO
Reactant: O=C1CCn2c1cc1ccccc12
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCn2c1cc1ccccc12
Temperature: 80 °C

Procedure:
To a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (J. Med. Chem. 1965, 8, 700-2) (2.43 g, 14.2 mmol) and hydroxylamine hydrochloride (2.96 g, 42.6 mmol) in EtOH (60 mL) there was added pyridine (6 mL) and the mixture was heated at 80° C. for 10 minutes. After cooling to room temperature (r.t.), the mixture was diluted with H2O (150 mL) and filtered to afford the oxime as a fluffy white solid, m.p.>220° C.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CO>ClCCl>[CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: F[C@@H]1CNCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 93.7 %

Procedure:
To a solution of cis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (0.9087 g, 2.95 mmol) in anhydrous dichloromethane (5 mL) under argon was added trifluoroacetic acid (2.5 mL) and the solution was stirred at room temperature under argon for 140 min. Anhydrous methanol (1 mL) was added and the solvents were removed in vacuo. More methanol (2 mL) was added and removed in vacuo. The residue was partitioned between CH2Cl2 (30 mL) and dilute NaOH solution (20 mL). The aqueous layer was further extracted with CH2Cl (30 ml×2) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo to give 0.5756 g (94%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.54 (1H, qd, J=12.0 and 4.1 Hz), 1.83 (1H, m), 2.54-2.76 (3H, m), 3.11 (1H, m), 3.88 (2H, m), 4.73 (1H, m), 7.23-7.37 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)C.CO>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a stirring solution of 4-hydroxybenzylamine (0.5 g, 4.06 mmol) and TEA (2.26 mL, 16.24 mmol) in DCM (20 mL) at 0° C. was added 4-nitrobenzoyl chloride (1.66 g, 8.93 mmol) and left at room temperature for 1 h. The reaction mixture was diluted with DCM (100 mL), washed with NaHCO3 (50 mL), and the organic layer reduced to dryness. The resulting residue was diluted with MeOH (25 mL) and DCM (5 mL), to which NaOH (18.0 mL, 1.0 M) was added. After stirring at room temperature for 10 min, analysis showed the bis-acylated material was cleaved to give the desired mono-acylated product. The reaction mixture was acidified with acetic acid until neutral and the MeOH removed under vacuum. The product was extracted into DCM (50 mL) and washed with brine (50 mL). The organic residue was purified by chromatography (EA/hexanes), to afford 647 mg (58%) of N-(4-hydroxybenzyl)-4-nitrobenzamide INT-1. LCMS-ESI (m/z) calculated for C14H12N2O4: 272; found 273 [M+H]+, tR=1.84 min (Method 5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][NH2:13].[CH3:15][O:16][C:17](=[O:22])[C@H:18](Br)[CH2:19][CH3:20]>C(#N)C>[CH3:7][O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][NH:13][CH:18]([C:17]([O:16][CH3:15])=[O:22])[CH2:19][CH3:20]
Reactant: COC(=O)CCCN
Reactant: CC[C@@H](Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(NCCCC(=O)OC)C(=O)OC
Temperature: 40 °C
Reaction time: 19 h
Yield: 98.6 %

Procedure:
To a mixture of potassium carbonate (19 g, 138 mmol, 5 equiv.) and methyl-4-aminobutyrate (IVc) (8.5 g, 55.3 mmol, 2 equiv.) in acetonitrile (70 ml, 14 vol.) is added methyl-(R)-2-bromobutyrate (IIf) (5 g, 27.6 mmol, 1 equiv.). The suspension is stirred at 40° C. for 19 hours. The mixture is then filtered and the cake is rinsed with 50 ml of acetonitrile. The filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in isopropylactetate. The resulting organic layer is washed with 60 ml of water and is concentrated under vacuum to afford methyl-4-(1-methoxycarbonylpropylamino)butyrate (VIa) as a colourless oil (5.91 g, 27.2 mmol, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[Br:13].C(O)C.O>[Zn].C(O)(=O)C>[Br:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: Brc1cc(Br)c(-c2sc(Br)cc2Br)s1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Brc1ccsc1-c1sccc1Br
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 3,3′,5,5′-tetrabromo-2,2′-bithiophene (25 g, 52.3 mmol), ethanol (50 ml), water (50 ml) and glacial acetic acid (100 ml) was heated to reflux. Then the heating oil bath was removed, and zinc powder (13.1 g, 200 mmol) was added in portions at such a rate that the mixture continued to reflux. After the addition was complete, heating was continued, the mixture was refluxed for another 5 h and cooled down to room temperature. The unreacted zinc powder was filtered off and the filtrate was collected, diluted with diethyl ether and then washed twice with water. The ether solution was dried with anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The crude product was recrystallized from hexane to afford a greenish crystal in the yield of 91% (15.3 g). 1H-NMR (CDCl3, ppm): δ7.40 (d, 2H, J=5 Hz), 7.11 (d, 2H, J=5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[C:32]([F:33])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[F:33][C:32]1[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[N:26][CH:27]=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: N#Cc1cnc(Cl)c(F)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloro-5-fluoronicotinonitrile. ESI-MS (m/z): 435 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19]([O:21]CC)=O)[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19]([NH:29][CH2:28][CH:25]3[CH2:27][CH2:26]3)=[O:21])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
Ethyl 7-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was treated with cyclopropylmethyl amine in a manner similar to that described in Example 2. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.85 (1H, br), 10.85 (1H, br), 10.11 (1H, br),8.20 (1H, br m), 7.39-7.25 (6H, br m), 4.01 (2H, br s), 3.33-3.13 (2H, br m), 1.20-0.90 (1H, m), 0.44 (2H, m), 0.19 (2H, m); HRMS calcd for C20H19N3O3+H+: 350.1505. Found: 350.1517.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:19][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 148.2 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 20.4 g (0.2 mol, 2.0 eq.) of 1-hexanol were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 33.1 g of 4-hexyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.CON(C)[C:15](=[O:30])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(OCC)(=O)C>C(OCC)C.O1CCCC1.O>[C:23]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:15](=[O:30])[C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH2:22][CH2:21]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: Brc1nccs1
Reactant: CON(C)C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
n-Butyl lithium (1 M in hexanes, 12.2 mL, 12.2 mmol) was slowly added to a solution of 2-bromothiazole (2.0 g, 12.2 mmol) in diethyl ether (50 mL) at −78° C. The mixture stirred at −78° C. for 1 h. Then, a solution of N-methoxy-N-methyl-4-Boc-piperazin-1-ylacetamide (3.0 g, 10.4 mmol) in tetrahydrofuran was slowly added. The mixture was allowed to slowly warm to −20° C. and stirred for 4 h. The mixture was then diluted with water followed by ethyl acetate. The water layer was extracted with ethyl acetate and the organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography (Sio2, 20:1-6:1 CH2Cl2:CMA) to provide 1-Boc-4-(2-oxo-2-thiazol-2-ylethyl)piperazine (2.2 g, 68%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Yield: 82 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 206a) and 4-methoxybenzeneboronic acid resulting in an 82% yield of the final product, m.p. 1 94-1 96° C. The product was recrystallized using hexane/ethyl acetate.