Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-])=O.Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([Cl:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 70.3 %

Procedure:
To a stirred mixture of 3-amino-6-chloro-4-nitrobenzotrifluoride (300 mg, 1.25 mmol) in ethanol (5 mL) was added SnCl2.2 H2O (1.40 g, 6.20 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath, 90° C.) for 1 h and the solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 185 mg (71%) of 3,4-diamino-6-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.404 (s, 2H); 3.717 (s, 2H); 6.754 (s, 1H); 6.974 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>C1COCC1.O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:13][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ncc(Br)c(OC)n1
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (0.6 g, 2.69 mmol) in THF (10 mL) was treated with ethylamine (2.0M in THF, 6.71 mL, 13.43 mmol) was heated at 60° C. for 1 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (EtOAc/Hex) to afford 5-bromo-N-ethyl-4-methoxypyrimidin-2-amine as a white solid (0.54 g, 87%). MS (ESI) m/z: 232.03 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12](CC#N)=[C:11]([CH3:19])[C:10]=1[OH:20])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH-:21].[Na+].[CH2:23]([OH:26])[CH2:24]O>>[C:1]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:24][C:23]([OH:26])=[O:21])=[C:11]([CH3:19])[C:10]=1[OH:20])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1CC#N
Reactant: OCCO
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1CC(=O)O

Procedure:
This compound was made in a similar manner to the method disclosed in Example 5 by hydrolyzing 4-tert.-octyl-2,6-dimethyl-3-hydroxyphenylacetonitrile with sodium hydroxide in aqueous ethylene glycol. After crystallization from toluene 4-tert.-octyl-2,6-dimethyl-3-hydroxyphenylacetic acid melted at 157° to 159° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(Br)c1F
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol 5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).
Reaction SMILES: ClCC1C=CC(C(C(O)=O)C(O)=O)=CC=1.[CH2:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17].[CH3:23][C:24]([O:26][CH2:27][C:28]1[CH2:37][S:36][C@@H:31]2[C@H:32]([NH2:35])[C:33](=[O:34])[N:30]2[C:29]=1[C:38]([OH:40])=[O:39])=[O:25]>C(Cl)Cl.C(O)CC>[CH2:16]([NH+:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17].[C:24]([O:26][CH2:27][C:28]1[CH2:37][S:36][CH:31]2[N:30]([C:33](=[O:34])[CH:32]2[NH2:35])[C:29]=1[C:38]([O-:40])=[O:39])(=[O:25])[CH3:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCN(CC)CC
Agent: O=C(O)C(C(=O)O)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCCO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Product: CC[NH+](CC)CC

Procedure:
α-Carboxy-p-chloromethylphenylacetyl nitrophenyl polymer, prepared according to the procedure described in Canadian Patent No. 892,580, carrying 4 m. mole of p-chloromethylphenylmalonic acid is suspended for about 8 hours in 20 ml of dry methylene chloride solution containing 1 m. mole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylammonium salt, which is prepared from 544 mg of 7-aminocepahlosporanic acid (1 m. mole) and 0.56 ml of triethylamine (1 m. mole) at room temperature. After only traces of 7-aminocephalosporanic acid remain in solution, which is determined by thin layer chromatography on cellulose in 70% aqueous propanol, the polymer is filtered off and washed with 3 portions of 50 ml each of methylene chloride. The combined filtrates are evaporated and the residue is dissolved in 20 ml or distilled water. This solution is acidified to pH 2 by adding 0.2N hydrochloric acid and extracted twice with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated at room temperature. The remaining solid is dried overnight over phosphorus pentoxide under vacuum to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(chloromethyl)phenyl[-2-carboxyacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])[N:10]=2)[N:7]=1.[Cl-].[NH4+].C([N:21](CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([NH2:21])=[O:13])[N:10]=2)[N:7]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.20 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 8 ml of N,N-dimethylformamide; 0.892 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.321 g of ammonium chloride and 0.832 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.697 g of the title compound.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].[CH:27](N1CCOCC1)=[O:28]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:27]=[O:28])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 ml (35.3 mmol) of TMP are initially introduced at −20° C. in 30 ml of THF, and 21.5 ml (34.2 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 11.8 g (34.0 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 70 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 90 min. The solution is cooled to −60° C., and 3.6 ml (36.0 mmol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 2 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is recrystallised from toluene. 5-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cccc(Cl)c1

Procedure:
To a refluxing solution containing 43.9 g (0.25 mole) of 3-chlorobenzoyl chloride in 120 ml. of dry benzene is added 30.0 g. (0.225 mole) of anhydrous aluminum chloride in several portions over a period of 10 minutes. When the reaction is complete, as indicated by vapor phase chromatographic (vpc) techniques, the mixture is cooled to 25° and diluted with ether. Extraction with dilute base is followed by thorough drying (magnesium sulfate) and concentration in vacuo. Final purification is effected by recrystallization from ether-hexane to afford 13.7 g (0.06 mole) of 3-chlorobenzophenone, m.p. 84°14 85°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C@H:7]1[CH2:9][C@H:8]1[C:10](O)=[O:11])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]3[CH:8]([C:10](=[O:11])[NH:17][N:18]=2)[CH2:9]3)[CH:13]=[CH:14][CH:15]=1
Reactant: NN
Reactant: Nc1cccc(C(=O)[C@H]2C[C@H]2C(=O)O)c1
Solvent: CCO
Solvent: O
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 60 %

Procedure:
600 mg (2.9 millimoles) of cis-2-(m-aminobenzoyl)-cyclopropanecarboxylic acid, 20 ml of ethanol and 0.16 g (3.2 millimoles) of hydrazine hydrate are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 0.35 g (60% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, which are identical with the compound from Example 33.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:3]1[C:20]([O:22]CC)=O.[ClH:25].[NH2:26][C:27]([NH2:29])=[NH:28].[CH3:30][O-].[Na+]>CO>[ClH:25].[CH3:30][NH:28][C:27]([NH2:29])=[N:26][C:20]([C:3]1[NH:2][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2cccc(NCCc3ccccc3)c2n1C
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2cccc(NCCc3ccccc3)c2[nH]1
Yield: 39.5 %

Procedure:
A mixture of 0.16 g (0.51 mmol) of ethyl 1-methyl-7-(2-phenylethylamino)-2-indolecarboxylate, 0.49 g (5.09 mmol) of guanidine hydrochloride and 0.28 g (5.09 mmol) of sodium methoxide in 10 ml of methanol was reacted in a manner similar to Example 1 to give 0.075 g (39.5%) of 1-methyl-7-(2-phenylethylamino)-2-indoloylguanidine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O-:19])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1)=[O:36]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C([O-])N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-chloro-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 616 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])=[N:15][NH:16][C:17]=1[CH3:18])[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:16]1[C:17]([CH3:18])=[C:13]([CH2:11][CH3:12])[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])=[N:15]1)=[O:10]
Reactant: CCc1c(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]c1C
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4-ethyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.13 g, 3.6 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of N-methyl-4-ethyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.71 g, yield: 63.6%). mp: 96-97° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.08 (t, J=7.6 Hz, 3H), 2.35 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.94 (d, J=5.0 Hz, 3H), 6.70-6.90 (m, 1H), 7.48 (d, J=9.2 Hz, 1H), 8.40 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8].[OH-].[Na+]>C1COCC1.CO>[C:14]([O:13][C:11]([NH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[C@@H:5]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:4][C:3]([OH:26])=[O:2])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 47 (500 mg, 1.28 mmol) in 25 mL of THF/MeOH (1:1), cooled to 0° C., 1N NaOH solution (25 mL) was added. The reaction was stirred at 0° C. for 2 h and then overnight at rt. The reaction mixture was concentrated and diluted with H2O (20 mL), cooled to 0° C., acidified to pH 2 with 1N KHSO4 solution, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with NaCl (50 mL, sat), dried (Na2SO4), filtered and evaporated. The resulting acid 48 was obtained as a colorless oil (1.76 g, 86%) and used directly in the next step. 1H-NMR (500 MHz, CDCl3): 0.06 (s, 6H), 0.84-0.95 (m, 15H), 1.43 (s, 9H), 2.01-2.11 (m, 1H), 2.53 (m, 1H), 2.64 (m, 1H), 3.53-3.58 (m, 1H), 4.10-4.14 (m, 1H), 3.65 (s, 3H), 4.17-4.19 (m, 1H), 4.51-4.54 and 6.29-6.31 (m, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[NH2:15][C:16]1[N:21]=[C:20]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29](F)[C:30]=3[Cl:32])[C:25](=[O:35])[CH:24]([C:36]([OH:38])=[O:37])[C:23]2=[O:39])[C:19]([C:40]#[N:41])=[CH:18][C:17]=1[F:42].C(O)C>CN(C)C=O>[NH2:3][CH:4]1[CH2:7][N:6]([C:29]2[C:30]([Cl:32])=[C:31]3[C:26]([C:25](=[O:35])[CH:24]([C:36]([OH:38])=[O:37])[C:23](=[O:39])[N:22]3[C:20]3[C:19]([C:40]#[N:41])=[CH:18][C:17]([F:42])=[C:16]([NH2:15])[N:21]=3)=[CH:27][C:28]=2[F:34])[CH2:5]1
Reactant: NC1CNC1
Reactant: N#Cc1cc(F)c(N)nc1N1C(=O)C(C(=O)O)C(=O)c2cc(F)c(F)c(Cl)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(N)nc1N1C(=O)C(C(=O)O)C(=O)c2cc(F)c(N3CC(N)C3)c(Cl)c21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
A solution in 300 mg of N,N-dimethylformamide of 40 mg of 3-aminoazetidine dihydrochloride and 80 mg of triethylamine was stirred at 90° C., and 50 mg of 1-(6-amino-3-cyano-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylic acid was added to the solution, and stirred at 90° C. for 10 minutes. To the reaction solution was added 1 ml of ethanol, and the solid precipitate was collected and dried to obtain 36 mg of the title compound as a pale yellow powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[CH2:10][C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1>CO>[CH3:16][C:14]1[O:13][N:12]=[C:11]([CH2:10][S:5][CH2:4][CH2:3][NH2:2])[N:15]=1
Reactant: NCCS
Reactant: Cc1nc(CCl)no1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(CSCCN)no1
Reaction time: 1.17 h
Yield: 121.9 %

Procedure:
Cysteamine hydrochloride (3.03 g; 26.7 mmoles) was added in several portions over a period of 10 minutes to a stirred solution of sodium methylate (2.89 g; 53.4 mmoles) in 50 ml of methanol at 0°. After stirring for 70 minutes at 0° , a solution of 3-chloromethyl-5-methyl-1,2,4-oxadiazole (3.54 g; 26.7 mmoles) in 15 ml of methanol was added dropwise over a period of 15 minutes, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The mixture was filtered, evaporated and redissolved in isopropyl alcohol, then filtered and evaporated under reduced pressure to give the title compound (5.64 g) as a yellow oil. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 3.77 (s, 2H); 2.77 (m, 4H); 2.63 (s, 3H).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:9]=[N:10][C:11]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](SC)[CH:26]=2)=[C:12]([CH:23]=1)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22])=[O:14].O.[CH:34](O)(C)C>>[F:7][C:8]1[CH:9]=[N:10][C:11]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([S:3]([CH3:34])(=[O:5])=[O:2])[CH:30]=2)=[C:12]([CH:23]=1)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22])=[O:14]
Reactant: CC(C)O
Reactant: O=S([O-])OO
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxone™ (245 mg, 0.40 mmol) was added to a solution of 5-fluoro-N-[(1S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (50 mg, 0.13 mmol) in a mixture of isopropanol (2 ml), tetrahydrofurann (1 ml) and water (1 ml) at 0° C. The mixture was warmed to ambient temperature and stirred for 18 h then partitioned between water (2 ml) and dichloromethane (10 ml) using a Chemelute™ cartridge. The organic phase was evaporated and the residue purified by flash column chromatography using dichloromethane:methanol (98:2) as eluant to give 5-fluoro-N-[(1S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfonyl)phenoxy]nicotinamide (39 mg) as a colourless glass.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:42])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:33]2)=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:26]=1)#[N:24]
Reactant: CC(C)C[C@H](N)CO
Reactant: N#Cc1ccc(N=C=S)c(C(F)(F)F)c1
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2ccc(C#N)cc2C(F)(F)F)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1c to give (4S)-2-(4-cyano-2-(trifluoromethyl)phenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(4-cyano-2-(trifluoromethyl)phenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.
Reaction SMILES: C[N:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][CH2:4][CH2:5][NH:6]C.[C:13]1([C:19]#[C:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:23])[C:20]#[C:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNCCCN(C)c1nccs1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C#Cc1ccccc1)NCCCNc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
440 mg (2.37 mmol) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine was dissolved, together with 347 mg (2.37 mmol) 3-phenyl propiolic acid, 412 μl (2.37 mmol) DIPEA and 761 mg (2.37 mmol) TBTU, in THF (30 ml), and stirred for 2 h at RT. The reaction solution was concentrated in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. CC (DCE/EtOH 10:1) was carried out on the residue, yielding 314 mg (1.00 mmol, 42%) N-(3-((thiazol-2-yl)amino)propyl)-3-phenylpropiolamide. MS [MH+] 314.1
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Li]CCCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccccn1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 2-ethynyl-pyridine (309 mg, 3 mmol) in THF (6 mL) was added BuLi (1.6 M in hexane, 1.88 mL, 3 mmol) dropwise at −75° C. and the reaction mixture was stirred at −75° C. for 30 min, then ethyl chloroformate (286 μL, 3 mmol) was added dropwise at −75° C. and the reaction mixture was stirred at −75° C. for 1 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (349 mg, 66%) as a brown solid. MS: m/e=176.2 [M+H]+.