Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:23]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:23])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred suspension of 4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}benzaldehyde (3.3 g, 10.98 mmol) and methyl(triphenyl)phosphonium bromide (3.92 g, 10.98 mmol) in dry THF (30 mL) was added NaH (1.536 g, 38.4 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 2 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.63 g, 8.81 mmol, 80% yield) as a light green oil. LCMS: rt=4.45 min, [M+H+]=324
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]([N:12]1[C@H:16]([C:17]([N:19]([CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH3:21])=[O:18])[CH2:15][Si:14]([CH3:41])([CH3:40])[CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:46]>C(Cl)Cl>[NH2:8][C@@H:9]([C:42]([CH3:43])([CH3:45])[CH3:44])[C:10]([N:12]1[C@H:16]([C:17]([N:19]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH3:21])=[O:18])[CH2:15][Si:14]([CH3:41])([CH3:40])[CH2:13]1)=[O:11].[ClH:46]
Reactant: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H](C)c2ccccc2F)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2C(=O)[C@@H](N)C(C)(C)C)[C@H](C)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a crude solution of methyl 4-(((R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-N—((R)-1-(2-fluorophenyl)ethyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxamido)methyl)benzoate (100 mg, 0.16 mmol) in DCM (4 mL) was added HCl (4.0 M solution in dioxane, 1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo to give the title compound as a HCl salt. MS(ESI+) m/z 542.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:16][C:12]=2[CH:11]=1)=[O:9])=[O:4].Br.C(S[C:30](=[NH:32])[NH2:31])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:30]([N:20]1[CH2:21][CH2:22][CH:17]([C:15]2[N:14]([CH3:23])[C:13]3[CH:24]=[CH:25][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:9])=[CH:11][C:12]=3[N:16]=2)[CH2:18][CH2:19]1)(=[NH:31])[NH2:32]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(C1CCNCC1)n2C
Reactant: CCSC(=N)N
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(C1CCN(C(=N)N)CC1)n2C

Procedure:
Prepared from 5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-2-(4-piperidinyl)-benzimidazole and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(N(CC)CC)C.[Cu]I>[OH:29][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(c2ccc(C#CCO)cc2)c2ccccc2C)ccn1
Reaction time: 3 h
Yield: 70 %

Procedure:
To 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one ((example 74, step 5), 400 mg) in triethylamine (4.1 mL) tetrakis(triphenylphosphine)palladium (59 mg) and CuI (10 mg) were added. At 80° C. 2-propyn-1-ol (0.12 mL) was added slowly, and the solution was stirred at that temperature for 3 hours. The solution was concentrated in vacuo and redissolved in EtOAc and a saturated solution of NH4Cl. The phases were separated and the inorganic one extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1) to yield the title compound (264 mg, 70%) as a yellow oil, MS (ESI+): m/z=370.1 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40].[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[O:17][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: Oc1cnccc1OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a mixture of 57 mg of sodium hydride and N,N-dimethylformamide, 0.286 g of 4-benzyloxy-3-hydroxypyridine was added and stirred at room temperature for 30 minutes. Then 0.5 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene was added to the mixture, and stirred for 1 hour at room temperature, then for 1 hour at 50-60° C. The mixture was poured into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.548 g of 4-benzyloxy-3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1N1CCCCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1N1CCCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-bromo-3-nitro-2-(piperidin-1-yl)pyridine (5.88 g, 20.5 mmol) in EtOAc (50 mL) was added tin(II) chloride dihydrate (23.5 g, 104 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 1 h, the reaction was cooled in an ice bath, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (0-15% EtOAc in hexanes) to provide a white solid as 5-bromo-2-(piperidin-1-yl)pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (1H, d, J=2.2 Hz), 7.09 (1H, d, J=2.3 Hz), 5.04 (2H, s), 2.98 (4H, m), 1.73 (4H, m), 1.58 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[CH3:16][O:17][C:18]([C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19].C(N(CC)CC)C>O1CCOCC1>[CH3:16][O:17][C:18]([C@H:20]1[N:25]([C:8]2[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)nc1C(F)(F)F
Yield: 61 %

Procedure:
Combine 2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (240 mg, 1.70 mmol), (S)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.04 mmol) and triethylamine (5.11 mmol) in a 0.85 M solution of dioxane. Microwave reaction mixture for 30 min at 150° C. Filter reaction mixture and rinse with acetonitrile. Purify filtrate by column chromatography in a 0-70% ethyl acetate/heptane gradient to give (S)-4-(5-Methoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl-ester contaminated with approximately 15% of the mono hydrolysis product. The mixture is carried on to next step without further purification. (61% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(3-(benzyloxy)phenyl)acetate (Step A, 5.00 g, 18.5 mmol) in absolute ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.O>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a stirred mixture of 6-chloropyridine-3-sulfonyl chloride (1 g, 4.717 mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (790 μl, 5.66 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (945 mg, 4.717 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration to yield 1.7 g (99%) of tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate as a white solid. 1H-NMR (CDCl3, 300 MHz): δ 9.82 (s, 1H), 8.11 (dd, 1H), 7.43 (d, 1H), 4.62 (d, 1H), 3.91 (m, 2H), 3.36 (m, 1H), 2.80 (m, 2H), 3.97 (m, 1H), 1.81 (m, 2H), 1.40 (s, 9H), 1.18 (m, 2H); LCMS: MS (m/z): 376 (MH+).
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][OH:69])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCO
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32b was prepared as described hereinabove for Compound 32a, using Compound 29b (0.023 gram, 0.043 mmol), methanesulfonyl chloride (0.014 gram, 0.12 mmol) and triethylamine (0.021 gram, 0.021 mmol) in dichloromethane (2.3 ml), yielding 0.015 gram of the product (55% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].O.[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47]Br)[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]>CC(C)=O>[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47][O:15][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 80.5 %

Procedure:
In 40 ml of acetone is dissolved 1.2 g of N-t-butoxycarbonylleucine, and 1.2 g of potassium t-butoxide and 8 ml of water are added, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (1:3, 400 ml and 5:2, 750 ml), elution is carried out with 1000 ml of a 4:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: NC1C=C([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)C=CC=1.BrC1N2N=C(N)N=C2C=CC=1.[N+](C1C=C(B(O)O)C=CC=1)([O-])=O.C1(Br)C=CC=CC=1.O1C=CC(C2N3N=C(NC4C=CC=CC=4)N=C3C=CC=2)=C1.[N+](C1C=C(C2N3N=C(NC4C=CC=CC=4)N=C3C=CC=2)C=CC=1)([O-])=O.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[C:18]1([NH:17][C:15]2[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][N:13]3[N:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2cccc3nc(Nc4ccccc4)nn23)c1
Agent: Nc1nc2cccc(Br)n2n1
Agent: O=[N+]([O-])c1cccc(-c2cccc3nc(Nc4ccccc4)nn23)c1
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: Brc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(Nc2nc3ccccn3n2)cc1

Procedure:
5-(3-Aminophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 543-Nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 3-nitro-phenylboronic acid and phenyl bromide according to the procedure described for the synthesis of 5-(furan-3-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. A mixture of 5-(3-nitrophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (170 mg, 0.51 mmol), zinc dust (338 mg, 5.1 mmol), and ammonium chloride (270 mg, 5.1 mmol) in a mixture of methanol and tetrahydrofuran (v/v, 1:1, 8 mL) at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the crude product, which was washed with ethyl ether to give 5-(3-aminophenyl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (79 mg, 51% yield). 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 7.62-7.59 (m, 3H), 7.44 (m, 1H), 7.37 (m, 1H), 7.30-7.24 (m, 4H), 7.08 (m, 1H), 6.89 (m, 2H); MS (ESI): m/z 302.1 [M+1]+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:30])=[N:11][O:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[C:10]([CH3:30])=[N:11][O:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1N

Procedure:
[4′-(4-tert-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-acetic acid (1.0 mmol) was treated with trifluoroacetic acid (5 mL) for 1 hour. Work-up provided the title compound. Mass spec. data (M+H)=309.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:12]([C:10]1[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Reaction time: 0.67 h

Procedure:
1248 mg (6.03 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 1000 mg (5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2291 mg (6.03 mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure. The reaction mixture is taken up in methanol and stirred together with acidic ion exchange resin (Dowex WX2-200) for about 40 min. The loaded ion exchanger is washed six times with in each case 100 ml of methanol. It is then eluted using methanol/triethylamine 99:1 to 90:10. The solvent is removed under reduced pressure. The product is taken up in 1N aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The extract is dried on magnesium sulfate. 1100 mg (69% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:18])[CH2:15][N:16]=1)=[CH:8]2)[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22]
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C(=O)N4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a mixture of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.25 g), morpholine (0.10 g), 1H-1,2,3-benzotriazol-1-ol (0.10 g) and N,N-dimethylformamide (4 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) at room temperature, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to basic silica gel column chromatography to give the title compound (0.25 g, yield 86%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran. melting point 238-239° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[ClH:43].O1CCOCC1>C(OCC)(=O)C>[NH:31]1[CH2:30][CH2:29][CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:42])[F:41])=[O:6])[CH:13]=[CH:12][CH:11]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)[CH:24]=[N:25]2)[CH2:33][CH2:32]1.[ClH:43]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (130 mg, 0.22 mmol) in ethyl acetate (2 mL) was added 4.0 M hydrogen chloride in dioxane (0.22 mL, 0.89 mmol). The suspension was stirred at r.t. 2 h. and then concentrated under reduced pressure to afford the desired compound as HCl salt. LCMS (M+H)+: m/z=484.2.
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:14])[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:18]>O>[NH:9]1[C:8]2[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:18]
Reactant: CC(=O)O
Reactant: CCSc1nc2c(c(=O)[nH]1)SCCC2
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)SCCC2
Reaction time: 8 h
Yield: 72 %

Procedure:
To a suspension of 2-(ethylthio)-7,8-dihydro-3H-thiopyrano[3,2-d]pyrimidin-4(6H)-one (4.5 g, 19.7 mmol) in water (20 mL) was added 3.0 mL of conc. HCl and 6.0 mL of AcOH. The mixture was heated to reflux and stirred overnight. The reaction was cooled and the solid that formed was collected by filtration, washed with water and methanol, evaporated and dried to obtain 7,8-dihydro-1H-thiopyrano[3,2-d]pyrimidine-2,4(3H,6H)-dione as a white solid (2.6 g, 72%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:41][C:42]([N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]1([CH3:53])[CH3:52])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]2([CH3:53])[CH3:52])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.4 mg) was obtained.