Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]([O:16]C)[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:2].B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:2]
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc(OC)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCc1c(NC(=O)C(F)(F)F)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-ethyl-2-nitro-4-trifluoroacetamidoanisole (19.3 mmol) in dry methylene chloride (250 mL) at -78° C. under nitrogen atmosphere is treated dropwise with a solution of boron tribromide (96.9 mmol) in dry methylene chloride (50 mL). After complete addition, the mixture is allowed to warm to room temperature and stirring is maintained for one hour. The mixture is cooled to -78° C. and methanol (100 mL) is added dropwise. After complete addition, the solution is allowed to warm to room temperature. The reaction mixture is distributed between water (100 mL) and methylene chloride (200 mL). The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to yield 3-ethyl-2-nitro-4-trifluoroacetamidophenol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:18]([NH2:20])=O>CN(C)C=O.C(O)=O>[NH2:8][C:7]1[C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:2]=2[N:1]=[CH:18][N:20]=1
Reactant: NC=O
Reactant: Cc1c(C#N)c(N)n(-c2ccc(Cl)cc2)c1C
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1c(C)n(-c2ccc(Cl)cc2)c2ncnc(N)c12

Procedure:
15 g (0.06 mol) of 2-amino-1-(4-chlorophenyl)-3-cyano-4,5-dimethylpyrrole in 100 ml of formamide, 30 ml of dimethylformamide and 15 ml of concentrated formic acid are heated under reflux for 7 hours. The crystals which precipitate on cooling are washed with water and recrystallised from ethanolic potassium hydroxide solution. Melting point: 250° C., yield: 13 g (79% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Cu](C#N)[C:12]#[N:13].N1C=CC=CC=1.N>CN(C=O)C.O>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=1)[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc(Br)cc(Br)c1
Agent: N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(Br)cc(C#N)c1
Temperature: 150 °C

Procedure:
A mixture of 1,3-dibromo-5-ethylbenzene (2.7 g, 10.2 mmol), copper cyanide (0.916 g, 10.2 mmol), pyridine (1.65 mL, 20.5 mmol) in DMF (15 mL) was heated at 150° C. for 3 h. After cooling to r.t., the mixture was poured into a solution of H2O (30 mL) and ammonia (25% aq. Solution, 20 mL) and extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo. The product was purified using flash chromatography on silica gel, gradient elution of 0-60% EtOAc in n-heptane. GCMS (CI) m/z 210 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 45 °C
Yield: 60.9 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 3.2 mmol) in n-butyl alcohol (12 mL) was added 6-aminoindazole (0.47 g, 3.52 mol) and DIPEA (0.86 mL, 4.80 mmol). After heating at 45° C. for 15 h, the mixture was cooled to room temperature, and the resulting precipitates were collected by filtration to give 2-chloro-N-(1H-indazol-6-yl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CON(C)C(=O)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.7 %

Procedure:
Step AI (1): To a solution of 2-bromo-5-methylbenzoic acid (1000.0 mg, 4.65 mmol) in DMF (100 mL) were added N,O-dimethylhydroxylamine hydrochloride (454 mg, 4.65 mmol), EDC (891 mg, 4.65 mmol), and HOBT (628 mg, 4.65 mmol). The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 2-bromo-N-methoxy-N,5-dimethylbenzamide (656 mg, 55%) as a colorless oil. LC-MS (M+H)+=258.21.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].[NH2:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][C:14](Cl)=[CH:15][CH:16]=2)[CH:11]=1.O>CO>[NH2:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CC(C)CS
Reactant: Nc1cc2cc(Cl)ccc2cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CSc1ccc2cc([N+](=O)[O-])c(N)cc2c1
Reaction time: 0.17 h

Procedure:
To 1 mole of isobutylmercaptan in 500 ml of methanol stirring at room temperature is added 1.1 mol of sodium methoxide. The mixture is stirred for 10 minutes and the solvent is evaporated under vacuum. The residue is taken up in 500 ml of dimethylformamide. To this mixture, stirring at room temperature, is added 1 mole of 2-amino-7-chloro-3-nitronaphthalene. The mixture is refluxed for 2 hours, then cooled and poured into 2 liters of water. After stirring for 30 minutes the resulting precipitate is filtered off and recrystallized from methanol or ethanol to yield the title compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=O)C.[BrH:21]>O>[BrH:21].[BrH:21].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Agent: Br
Solvent: O
Product: c1ccc2sc(NCC3CCNCC3)nc2c1
Yield: 79 %

Procedure:
A mixture of 140 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine and 1500 parts of a hydrobromic acid solution 24% in water was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was suspended in boiling ethanol. After cooling, the product was filtered off and dried, yielding 122 parts (79%) of N-(4-piperidinylmethyl)-2-benzothiazolamine dihydrobromide. hemihydrate; mp. >300° C. (intermediate 53).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]O)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2].P(Br)(Br)[Br:21]>CCOCC>[Br:13][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=1[CH2:11][Br:21]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CO
Solvent: CCOCC
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CBr
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of ethyl-5-bromo-4-(hydroxymethyl)-1-phenyl-1H-pyrazole-3-carboxylate (2.91 g, 8.98 mmol, 1 eq) in Et2O cooled at −10° C. is added phosphorus tribromide (1.02 mL, 10.77 mmol, 1.2 eq) and the reaction mixture is stirred at Rt for 1 h. The reaction mixture is poured over ice and extracted with MTBE. The organic layer is washed with brine, dried over Na2SO4 and concentrated to afford 2.1 g (60%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.65-7.57 (m, 5H), 4.77 (s, 2H), 4.35 (q, J=6.0 Hz, 2H), 1.32 (t, J=6.6 Hz, 3H). HPLC (max plot) 83.30%; Rt 5.33 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH:7]([O:41]C(=O)C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[NH:21][C:22]=2[CH2:23][CH2:24][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)=[O:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:45])[CH:7]([OH:41])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[NH:21][C:22]=2[CH2:23][CH2:24][C:25]23[CH2:32][CH:31]4[CH2:33][CH:27]([CH2:28][CH:29]([CH2:30]4)[CH2:34]2)[CH2:26]3)=[O:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C(O)Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Yield: 63.1 %

Procedure:
A solution of the product of step c (282 mg, 0.46 mmol) and potassium carbonate (96 mg, 0.70 mmol) in methanol (3 ml) and water (0.3 ml) was stirred at room temperature for 3 h. The reaction was quenched with 10% aqueous citric acid (1 ml), then diluted with ethyl acetate (20 ml). The organic phase was washed with water (20 ml), brine (20 ml), dried (MgSO4) and the solvent was evaporated. The residue was purified by flash chromatography (silica, hexane/ethyl acetate 2:1) to afford colourless foam (167 mg, 63%). 1H NMR (300 MHz, CDCl3) 9.05 (1H, br s), 8.62 (1H, br s), 7.60 (2H, m), 7.25 (1H, m), 6.98 (1H, d), 4.34 (1H, m), 3.13-3.02 (4H, m), 2.93 (1H, m), 2.85 (1H, d), 2.68 (1H, m), 2.05-1.35 (36H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of methyl 6-chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylate (360 mg, 0.973 mmol) in methanol (10 mL) was added sodium hydroxide (1M, 4.0 mL, 4 mmol) and the reaction was heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure. The crude reaction was diluted with methanol (9 mL) to which was added additional sodium hydroxide (1M, 6.0 mL, 6 mmol) and heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure and acidified using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the Biotage Isolera One (SNAP 50 g silica gel column) and eluting with a gradient of 0-20% methanol/dichloromethane yielding 215 mg of the title compound as a solid. To a round bottom flask containing the title compound was added methanol (10 mL) and the reaction was heated to reflux. Additional methanol (5 mL) was added and the solution was allowed to cool to room temperature and stirred overnight at room temperature. The resulting precipitate was filtered and washed with 1 mL of methanol and dried by pulling high vacuum yielding 119 mg of the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]1=[O:25].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:57][C:58]1[C:63]([C:64]([F:67])([F:66])[F:65])=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:68][NH2:69]>ClCCl>[ClH:57].[Cl:57][C:58]1[C:63]([C:64]([F:66])([F:67])[F:65])=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:68][NH:69][C:14]([CH:13]1[CH2:12][N:11]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10](=[O:25])[N:9]1[CH3:8])=[O:16]
Reactant: CN1C(=O)N(CCN2CCOCC2)CC1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(CCN2CCOCC2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A mixture of 3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (186 mg, 0.5 mmol), N-ethyl morpholine (0.383 ml, 3 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (105 mg, 0.5 mmol) in dichloromethane (1 ml) was added and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and was washed with saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The product from mass-directed automated HPLC was dissolved in methanol (2 ml) and an excess of 1M hydrogen chloride in ether (0.5 ml) was added. The solvent was evaporated, the residue was triturated with ether and the solid collected and dried to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxamide hydrochloride (73 mg, 30%). LC/MS [M+H]+=449, retention time=1.80 minutes.
Reaction SMILES: Cl.[Br:2][C:3]1[O:4][C:5]2[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=2[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[CH2:10]1>Br>[BrH:2].[Br:2][C:3]1[O:4][C:5]2[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=2[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10]1
Reactant: COc1cccc(C2CCCN(Cc3c(Br)oc4ccccc34)C2)c1
Agent: Br
Agent: Cl
Product: Oc1cccc(C2CCCN(Cc3c(Br)oc4ccccc34)C2)c1
Yield: 172.6 %

Procedure:
1-(2-Bromo-3-benzofurylmethyl)-3-(3-methoxyphenyl) piperidine hydrochloride (1) (0.65 g) in 48% hydrobromic acid (200 ml) was heated at 110°-115° C. for 1.5 hours under nitrogen, and evaporated to dryness in vacuo. The residue crystallised from ethanol-ether to afford 3-[1-(2-bromo-3-benzofurylmethyl)-3-piperidyl]phenol hydrobromide (11) (0.6 g), m.p. 134°-140° C. (Found: M+ 385.0665. C20H20NO2Br requires M 385.0677).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[S:13]1(=[O:35])[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:19]=[C:20]([C:24]2[N:32]3[C:27]([CH:28]=[N:29][C:30]([S:33][CH3:34])=[N:31]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.C(Cl)Cl>>[O:35]=[S:13]1(=[O:12])[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[CH:19]=[C:20]([C:24]2[N:32]3[C:27]([CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:9])=[N:31]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ncc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)n2n1
Yield: 90.1 %

Procedure:
m-Chloroperbenzoic acid (0.380 g, 1.54 mmol) was added to a solution of 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfanyl)pyrrolo[2,1-f][1,2,4]triazine (0.515 g, 1.43 mmol) in Methylene chloride (30.0 mL, 468 mmol). The reaction was quenched at 30 min by the addition of satd. NaHCO3 (50 mL). The mixture was stirred vigorously, sept. and ext. with DCM (3×15 mL). The comb. org. was washed with 1:1 brine:satd. NaHCO3 (50 mL) and dried over sodium sulfate. After conc. in vacuo, the residue was purified on the ISCO (load onto 3.4 g silica, 40 g column, 20-100% EtOAc:Hex, then to 10% MeOH:EtOAc, then 10% MeOH:DCM) to afford 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfinyl)pyrrolo[2,1-f][1,2,4]triazine (0.485 g, 90%). 1H-NMR (DMSO-d6): 9.34 (s, 1H), 8.16 (s, 1H), 7.95 (d, 1H, J=7.9 Hz), 7.72 (d, 1H, J=4.9 Hz), 7.55 (m, 1H), 7.34 (m, 2H), 3.87 (t, 2H, J=6.5 Hz), 3.57 (t, 2H, J=7.4 Hz), 2.99 (s, 3H), 2.44 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:2]=2[O:1][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: COc1cccc(CNc2ccc(C(C)=O)cc2)c1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1c(CNc2ccc(C(C)=O)cc2)cccc1OC
Yield: 95.9 %

Procedure:
4'-(2-Hydroxy-3-methoxybenzylamino)acetophenone (500 mg, 1.84 mmol) is treated with 629 mg (3.22 mmol) of ethyl 4-bromobutyrate, 764 mg (5.53 mmol) of potassium carbonate and a catalytic amount (182 mg, 1.22 mmol) of sodium iodide in 2 mL N,N-dimethylformamide as described in Preparation 3 to give 680 mg of 4-[2-[[(4-acetylphenyl)amino]methyl]-6-methoxyphenoxy]butanoic acid, ethyl ester as a light brown oil (95%). The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1660, 1600 cm-1 ; MS (CI) m/e 386 (M+H), 115; Analysis calculated for C22 H27O5N: C, 68.55; H, 7.06; N, 3.63; found: C, 68.27; H, 6.81; N, 3.54.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:26][CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([F:25])[CH:11]=1)[N:8]=[C:7]([NH:26][CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(NC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nc2c(F)cc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-methylamino-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Light yellow solid. MS (ESI): 379 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[CH2:13]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:19]([N:18]([CH3:22])[CH3:17])=[O:20])[CH:3]=2)[O:12][N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCc1noc(-c2cccc(N)c2)n1
Solvent: c1ccncc1
Product: CCCCc1noc(-c2cccc(NC(=O)N(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.0 g (0.037 mol) of 5-(3-aminophenyl)-3-butyl-1,2,4-oxadiazole were dissolved in 15 ml pyridine and were reacted with 3.4 ml (0.037 mol) of dimethylcarbamoylchloride. The reaction was complete after stirring for 8 hours at room temperature. The mass was then reacted with about 100 ml ice water resulting in precipitation of the reaction product. The reaction produce was removed by suction, subjected to drying at 50° C. in a vacuum and recrystallized from diisopropylether. There were obtained 8.3 g=77.5% of the theoretical value of 3-butyl-5-[3-(3,3-dimethylureido)-phenyl]-1,2,4-oxadiazole; m.p. 108° to 110° C.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=[C:5]2[CH:4]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([NH:45][CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:50][CH2:51]3)=[O:14])[N:11]=[C:5]2[CH:4]=1
Reactant: O=C(O)c1cn2ccc(O)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(O)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a stirred mixture of 7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid hydrobromide salt (0.24 g, 0.93 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.22 g, 2.2 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.24 g, 1.2 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate as an off-white solid (0.27 g, 81%). 1H-NMR (CDCl3, 300 MHz): δ 7.93 (m, 2H), 7.31 (m, 1H), 7.25 (m, 1H), 6.85 (m, 1H), 6.65 (m, 1H), 4.08 (m, 3H), 3.13 (m, 2H), 2.93 (m, 2H), 1.97 (m, 2H), 1.44 (s, 9H) ppm; MS (ESI): 361.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]([PH:10](=[O:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCOCC1.O>[C:4]1([CH2:3][CH:2]([PH:10](=[O:11])[OH:12])[NH:1][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(Cc1ccccc1)[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Temperature: 20 °C
Yield: 83.7 %

Procedure:
To a solution of 7 g (37.8 mmol) of (1-amino-2-phenylethyl)phosphinic acid in 86 ml of a mixture of dioxane and water, in the presence of one equivalent of sodium hydroxide (1.51 g), are added dropwise, at 0° C and simultaneously, a solution of 7.55 g (44.26 mmol) of benzyl chloroformate in 21 ml of dioxane and, in order to keep the pH of the reaction at about 9, a solution of 2.42 g of sodium hydroxide in 21 ml of water. At the end of the addition, the mixture is maintained at a temperature in the region of 20° C. for 2 hours. The aqueous phase is then washed with 3 times 20 ml of diethyl ether. The aqueous phase is acidified, at 0° C., with vigorous stirring, using 27 ml of 6N hydrochloric acid solution. The abundant white precipitate formed is filtered off, washed with water and dried. 12.08 g of product are recovered (yield=83.7%).