Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[C:4]([F:11])[CH:5]=1)#[N:8]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CCOP(=O)(Cc1ccc(C#N)cc1F)OCC
Temperature: 150 °C
Yield: 103.8 %

Procedure:
A mixture of 1.5 g (7.0 mmol) of 4-(bromomethyl)-3-fluorobenzonitrile [ref J.Med.Chem., 40, 2064 (1997)] and 1.4 g (8.4 mmol) of triethyl phosphite was heated at 150° C. for 2 hours. At the end of this time, the reaction mixture was concentrated under reduced pressure. Volatile materials in the residue thus obtained were removed by heating said residue at 100° C. in vacuo for 1 hour to afford 1.97 g (quantitative yield) of the title compound as an oil which solidified in the freezer. This oily product was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O:12]=[C:13]1[N:18]2[C:19]3[C:24]([NH:25][CH2:26][C:17]2=[N:16][CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=[CH:21][CH:20]=3>O>[O:12]=[C:13]1[N:18]2[C:19]3[C:24]([N:25]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:26][C:17]2=[N:16][CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1NC2
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1N(C(=O)OCC)C2
Reaction time: 8 h
Yield: 39.5 %

Procedure:
4 ml of dry dimethylformamide were saturated with nitrogen for 10 minutes before 150 mg of ethyl chloroformate and 280 mg of ethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate were added thereto. The solution obtained was left at room temperature overnight and then was poured into water. The mixture was extracted with ethyl acetate and the organic phase was dried over MgSO4 and evaporated to dryness. The residue was chromatographed over silica gel and eluted with ethyl acetate to obtain 140 mg (41% yield) of diethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2,6-dicarboxylate melting at 140°-2° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[F:28])[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N3CCOCC3)ccc1F)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(N2CCOCC2)ccc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 35.9 %

Procedure:
A mixture of 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.12 g, 0.29 mmol), lithium hydroxide hydrate (0.12 g, 0.29 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (40 mg, 36%) as a white solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.5, observed: 385.3.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:29]=[O:30])C.[OH-].[Na+]>C(OCC)C>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]=2[CH:29]=[O:30])[CH2:9][CH2:10]1
Reactant: CN(C)C=O
Reactant: CN1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN1CCN(Cc2ccc(-c3ccccc3)cc2C=O)CC1
Yield: 28 %

Procedure:
A solution of 1-biphenyl-4-ylmethyl-4-methyl-piperazine (26 mmol) in diethyl ether (50 mL) was added n-BuLi (38 mmol) and DMF (15 mL) and was refluxed for 6 h. The reaction was cooled and added 2 N NaOH (50 mL) and extracted with diethyl ether. Evaporation in vacuo gave a black oil that was purified by flash chromatography. Yield: 28% as black oil.
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:34][CH3:35])[C:32]=1[CH3:33])[C:27](Cl)=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C@H:5]([N:9]([C:27](=[O:28])[C:26]1[CH:30]=[C:31]([O:34][CH3:35])[C:32]([CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1)[NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Reactant: CCC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC[C@@H](N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C
Temperature: 25 °C

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-butyl)-hydrazide (100 mg, 0.34 mmol) and 3,5-dimethoxy-4-methyl-benzoyl chloride (90 mg, 0.41 mmol) were dissolved in 1 mL methylene chloride. 1.5 eq. of ca. 25% K2CO3 was added, and the reaction mixture was stirred at room temperature and monitored by TLC. Upon completion, the phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 phase was dried over MgSO4 or Na2SO4, and solvent was removed in vacuo to provide an oily solid. This was triturated with 1:1 hexane:ether and allowed to dry in air to yield (R)-3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. Rf=0.29 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.1 (t, 1H), 7.0 (s, NH 1H), 6.9 (d, 1H), 6.7 (s, 2H), 6.3 (d, 1H), 4.78 (m, 1H), 3.95 (s, 3H), 3.85 (2s, 6H), 2.2 (s, 3H), 2.05 (m, 1H), 1.95 (s, 3H), 1.8 (m, 1H), 1.6 (m, 2H), 1.2+1.1+1.05 (3s, 9H), 1.05 (m, 3H); HRMS (ESI) m/z calcd for C27H39N2O5 [M+H]+ 471.2859. found 471.2850, calcd for C27H38NaN2O5 [M+Na]+ 493.2670. found 493.2678.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]=[C:29]=[O:30])=[C:18]([F:31])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([F:31])[CH:17]=1
Reactant: Cc1nnc(-c2cc(N=C=O)c(F)cc2Cl)o1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.04 g of sodium hydride (oil, purity: 55%) in 75 ml of dimethylformamide, a solution of 4.3 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 58 ml of toluene was added dropwise of 0° C. over a period of 15 minutes. Thereafter, the solution was stirred at 0° C. for 15 minutes and then cooled to -30° C., followed by dropwise addition of a solution of 5.7 g of 4-chloro -2-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl isocyanate in 60 ml of toluene. The resulting mixed solution was stirred at room temperature for 3 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8]
Reactant: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCNc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a tetrahydrofuran solution (20 mL) of 3-nitro-4-n-propylaminobenzoic acid (see Working Example 82-1) (1.94 g, 10.8 mmol) was added 10% palladium-carbon (200 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 6 hours. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (1.68 g, quant.).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:21][C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)[O:24][N:23]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13]
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(Br)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C
Yield: 138 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.100 g, 0.385 mmol), Cs2CO3 (0.188 g, 0.578 mmol), and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.152 g, 0.578 mmol) were combined in DMF (10 mL) and heated to 90° C. for 30 min. The reaction mixture was partitioned between Et2O and water. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) provided the title compound 0.258 g: MS (ESI) m/z 487 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.891 g, 5.16 mmol) and thionyl chloride (15 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.0 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.354 g, 3.49 mmol, 88%).
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH3:19])[O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH3:19])[O:18][C:14]=2[C:13]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC1Cc2c(ccc(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CC1Cc2c(c(C(C)(C)C)cc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 112.3 %

Procedure:
Under ice-cooling, 3 ml of methanesulfonic acid was added dropwise to a solution of 0.77 g of 4-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran in 1.5 g of t-butyl alcohol and 6 ml of chloroform. After stirring at 0° C. for 10 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in chloroform) to give 0.55 g of 4,7-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white crystal (yield 57%).
Reaction SMILES: C(OC([NH:11][CH:12]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=1)=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl.O>[C:21]([C:16]1[CH:15]=[C:14]([CH2:13][CH:12]([NH2:11])[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:19]=[CH:18][C:17]=1[OH:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nccs2)ccc1O
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-2-(3-tert-butyl-4-hydroxylphenyl)-1-(thiazol-2-yl)ethylamine (15.28 g, 37.27 mmol) in methylene chloride (1.1 l), thioanisole (8.75 ml, 74.54 mmol) was added. To the mixture, a solution of 1.0M boron tribromide in methylene chloride (186 ml, 186.34 mmol) was added dropwise under cooling with ice and stirred for 1 hour. The reaction mixture was mixed with water and alkalinized by 2N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving the titled compound (9.46 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>CC#N.CN(C1C=CN=CC=1)C>[C:17]([O:16][C:14]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CSc1ccc2cc(C)[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CSc1ccc2cc(C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
2-Methyl-6-methylthioindole (13.9 g) prepared according to Allais A. et al. Eur. J. Med. Chem.—Chim. Ther. (1975), 10(2), 187-99, was dissolved in CH3CN (150 mL) followed by the addition of (BOC)2O (18 g) with 480 mg DMAP. After 5 h the mixture was evaporated to dryness and the resulting 2-methyl-6-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester was purified by chromatography over silica gel.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22](O)=[O:23])[CH:4]=[N:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:16][N:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23])=[O:21]
Reactant: Cn1ncc(C(=O)O)c1C(=O)NCCc1nc2ccccc2n1C
Reactant: C1CCNC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (25 mg, 76.4 μmol) and pyrrolidine (6.52 mg, 7.58 μL, 91.6 μmol) according to the method described in example 37, step 3 as light red solid (15 mg, 39.4 μmol, 51.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=C[C:20]([C:23](F)([F:25])F)=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:27])=[O:9])[CH:7]=1.ClC1C=C(NC2C=CC=C(F)C=2)C=CC=1C(C1C=C([N+]([O-])=O)C=CC=1C)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:23]([F:25])[CH:22]=3)=[CH:12][C:11]=2[Cl:27])=[O:9])[CH:7]=1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl
Product: Cc1ccc(N)cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 457 (2.25 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.[OH-].[Na+].Cl>>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-Methyl 6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinate (Stage 170.2, 640 mg, 4.26 mmol) was added to 2 M NaOH (2 mL) and stirred 30 min at RT until complete dissolution. The RM was acidified (pH=2) with 2 M HCl and the solid which precipitated was filtered to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=2.19 min, UPLC-MS (Condition 7) m/z=287.1 [M+H]+.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]([F:27])([F:26])[CH2:10][O:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>>[ClH:1].[F:27][C:9]([F:8])([F:26])[CH2:10][O:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)COCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 4M hydrogen chloride in 1,4-dioxane (2.48 mL, 9.93 mmol) was added to tert-butyl 4-[(2,2,2-trifluoroethoxy)methyl]piperidine-1-carboxylate (Intermediate 180, 0.289 g, 0.993 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (0.136 g, 59%). Method B HPLC-MS: MH+ (HCl salt) requires m/z=198 Found: m/z=198, Rt=0.72 min.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]4[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=4[Cl:44])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:45][C:46]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:60])=[CH:53][C:47]=1[CH2:48][NH:49][CH:50]1[CH2:52][CH2:51]1>>[Cl:45][C:46]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:60])=[CH:53][C:47]=1[CH2:48][N:49]([CH:50]1[CH2:51][CH2:52]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]3[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=3[Cl:44])=[CH:29][CH:28]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: Cc1cc(Cl)c(OCCc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCc1ccc(Cl)c(CNC2CC2)c1
Product: COCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(CCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
From (rac.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester, as for compound L1, but using N-[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropanamine instead of N-[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropanamine, then as for Example 1, the desired compound was obtained. MS (M+1) ESI 668.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(OC)c4)c3)csc12

Procedure:
3-[3-(3-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and m-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=O)[CH3:26].C([BH3-])#N.[Na+].CO.C(O)(=O)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH3:26])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: CC(=O)c1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccncc1)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a small sample of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g, 0.1 mmol) weighed out in a 1 mL sealable vial, excess 4-acetylpyridine was added (100 μL, ca. 1 mmol) followed by sodium cyanoborohydride (360 μL of a 1 M solution in tetrahydrofuran) and methanol-acetic acid (95:5). The vial was capped and placed in a shaker at 50° C. for several days until reasonable conversion by TLC was evident. The reaction mixture was then diluted with methanol, shaken well for several minutes, and allowed to stand for 0.5 h before applying it to a 2 g SCX column. After washing well with methanol, the product was gravity-eluted from the column with 2 M ammonia in methanol. The product fractions were combined and concentrated in vacuo to a residue which was triturated in acetonitrile, giving rise to the title compound as a powdery solid (0.03 g, 74%) in >98% purity by HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24].C(OO)(=[O:29])C.CCCCCCC.C(OCC)(=O)C.O>ClC(Cl)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[S:22]([C:23]([F:26])([F:25])[F:24])=[O:29]
Reactant: CC(=O)OO
Reactant: COc1cc(C(F)(F)F)cc(Cl)c1-n1nc(C#N)c(SC(F)(F)F)c1N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(Cl)Cl
Product: COc1cc(C(F)(F)F)cc(Cl)c1-n1nc(C#N)c(S(=O)C(F)(F)F)c1N
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-amino-1-(2-chloro-6-methoxy-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (Compound number 8-04, 1.04 g, 2.4 mmol) in dichloroethane (10 ml) was added peroxyacetic acid (acetic acid solution 35%, 0.62 g, 2.9 mmol). The mixture was stirred at 20° C. for 20 hours. After extractive workup (heptane-ethyl acetate, water) and column chromatography the title product was obtained (0.55 g). Two diastereomers were observed in NMR and HPLC (46% and 49%), mp 195° C., 1H-NMR: 3.94 (3H), 5.04 (2H), 7.24 and 7.49; 19F-NMR: −63.9, −75.3 and −75.4.