Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediamine hydrochloride (100 mg) was dissolved in pyridine (3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to separate an organic layer. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol 100:1) to obtain the title compound (79 mg) as a pale yellow foamy substance.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:32])([F:31])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:11]>C(Cl)Cl>[F:32][C:9]([F:8])([F:31])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(N2CCNCC2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.0 mL TFA were added to a solution of 267 mg (0.75 mmol) tert. butyl 4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazin-1-carboxylate in 30 mL DCM cooled to 0° C. and the reaction mixture was stirred for 24 h, while warming up to RT. It was evaporated down i.vac.; the crude product was further reacted without purification.
Reaction SMILES: [OH:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.OS(O)(=O)=O.[CH3:30]CN(CC)CC>CO>[CH3:30][O:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC1(O)OC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC1(C)OC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution of 5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone (Example 4) (1.0 g) in 120 mL of MeOH was added 0.1 mL of concentrated H2SO4. The mixture was heated to reflux for 3 days and then treated with 2 mL of Et3N. Methanol was removed under reduced pressure and the residue was purified by silica gel flash chromatography eluted with 4:1 toluene/EtOAc. After a swish from 2:1 hexane/EtOAc, 0.8 g of the title compound was obtained as a white solid.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH:19]([F:21])[F:20])[C:15](OC)=[O:16])[CH:8]=[CH:7]2.C[O-].[Na+].Cl.[NH2:27][OH:28]>CO>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH:19]([F:21])[F:20])[C:15]([NH:27][OH:28])=[O:16])[CH:8]=[CH:7]2
Reactant: NO
Reactant: COC(=O)C(c1ccc2cc(OC(F)F)ccc2c1)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)C(c1ccc2cc(OC(F)F)ccc2c1)C(F)F
Reaction time: 16 h

Procedure:
A mixture of 32 g. of methyl 6-difluoromethoxy-2-naphthyl-α-difluoromethylacetate, 10 g. of sodium methoxide, 14 g. of hydroxylamine hydrochloride, and 500 ml. of methanol are allowed to stand for 16 hours. The mixture is then filtered and evaporated. The residue is neutralized by the addition of aqueous 1N hydrochloric acid and extracted by ether. The ether solution is then washed with water, dried, and evaporated to afford 6-difluoromethoxy-2-naphthyl-α-difluoromethyl acethydroxamic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:17][CH:16]3[CH:14]([CH2:15]3)[CH2:13][CH:12]2[C:18]([O-:20])=[O:19])=[CH:5][CH:4]=1.CO.[OH-].[Li+]>COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:17][CH:16]3[CH:14]([CH2:15]3)[CH2:13][CH:12]2[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: CSc1ccc(SCC2CC3CC3CC2C(=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: CSc1ccc(SCC2CC3CC3CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Methyl(1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]-sulfanyl}-methyl)bicyclo[4.1.0]heptane-3-carboxylate was dissolved in ethylene glycol dimethyl ether (3.0 mL) and methanol (1 mL) in a 25 mL round bottom flask. Aqueous solution of lithium hydroxide (3.0 mL, 6.0 mmol, 2 M) was added and the reaction mixture was stirred at ambient temperature for 36 h. After acidification with 2 M aqueous hydrochloric acid to pH 3, the product was extracted into ether. The combined ether extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give (1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]sulfanyl}-methyl)bicyclo[4.1.0]heptane-3-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22](=[O:23])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
In a 250 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (1 g, 3.51 mmol), 4-nitrophenyl chloroformate (708 mg, 3.51 mmol) and N,N-diisopropylethylamine (1.36 g, 1.84 mL, 10.5 mmol) were combined with CH2Cl2 (30 mL). The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was concentrated to dryness to afford (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamic acid 4-nitro-phenyl ester (1.6 g, 100%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].BrBr.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>O1CCOCC1.C(#N)C>[CH3:14][C:15]1[N:16]([CH2:2][C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:3])[CH:17]=[CH:18][N:19]=1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: Cc1ncc[nH]1
Agent: BrBr
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1nccn1CC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetylbenzonitrile (50 g, 0.345 mol) is dissolved in dioxane (600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol) is added in and the mixture is stirred for 30 minutes. The dioxane is removed in vacuo to give a solid which is dissolved in acetonitrile (300 ml). 2-Methylimidazole (28.3 g, 0.345 mol) is added to the solution and the mixture is stirred for 1 hour, the temperature of the mixture rising to 45° C. The precipated solid is filtered off, washed with acetonitrile, and slurried with methanol for 1 hour. After filtering to remove undissolved solid, the filtrate is evaporated in vacuo to leave a solid which is dried in vacuo at 40° C. to give the title compound, m.s. 369 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccc(Cl)cc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 7.22 g (0.0287 m) of N-methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 5.9 g of a white solid, m.p. 74°-76° C.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].[K+]>CN1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][C:14]=1[S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Brc1ccccc1-c1ccccn1
Reactant: Sc1nc2ccccc2o1
Agent: CN1CCCC1
Agent: [K+]
Agent: [OH-]
Product: c1ccc(-c2ccccc2Sc2nc3ccccc3o2)nc1
Yield: 4.3 %

Procedure:
2-Mercapto benzoxazole (604 mg; 4 mmole) was reacted with 2-(2-bromophenyl)pyridine (936 mg; 4 mmole) in the presence of KOH (224 mg; 4 mmole) in N-methyl pyrrolidine (16 ml). The mixture was heated under reflux for 6 hours, worked up and flash chromatographed (silica), using ethyl acetate/petroleum ether (2/3) eluant to give the sub-title compound as a pale brown oil (52 mg; 4.3%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[NH:15]([C:17](OC)=[O:18])[NH2:16]>CO.C(O)C>[CH2:10]([O:9][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[CH2:4][CH2:3][CH2:2][NH:1][C:17](=[O:18])[NH:15][NH2:16])[CH3:11]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: COC(=O)NN
Solvent: CCO
Solvent: CO
Product: CCO[Si](CCCNC(=O)NN)(OCC)OCC
Reaction time: 2 h

Procedure:
A mixture of 44.2 g (0.20 mole) 3-aminopropyltriethoxysilane and 18.0 g (0.20 mole) methyl hydrazinocarboxylate under nitrogen was gradually heated to 150° C. with a slow distillation of the evolved methanol/ethanol from the reaction. After 2 hours at 150° C., 9.1 g. of distillate had been collected, and the reaction mass was cooled to ambient. The pale yellow oil was decanted from the small amount of white solid; yield 51 g (91%). IR (neat) 3320, 1640 (br), 1540 (br), 1070 (br), 940, 790 cm-1. NMR (CDCl3) 0.4-1.0 (m; 2H), 1.2 (t; 9H), 1.3-2.0 (m; 2H), 2.9-3.5 (m; 2H), 3.5-4.1 (m; 8H), 6.3 (br; 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12](CC2C=CC(OC)=CC=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][CH:35]([Cl:37])[CH3:36])=[O:33]>C(Cl)Cl>[Cl:37][CH:35]([O:34][C:32]([N:12]1[CH2:13][CH2:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:33])[CH3:36]
Reactant: COc1ccc(CN2CCC(CNC(=O)OC(C)(C)C)(c3ccccc3)CC2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [1-(4-methoxy-benzyl)-4-phenylpiperidin-4-ylmethyl]carbamic acid tert-butyl ester (3.2 mmol) in CH2Cl2 is added 1-chloroethyl chloroformate (4.7 mmol), then the mixture is stirred at room temperature for 2.5 h. After the bulk of solvent is concentrated in vacuo, the residue suspended in ether and filtered. After the filtrate is concentrated in vacuo, the residue is suspended in hexane and filtered. The filtrate is concentrated in vacuo to give the 4-(tert-butoxycarbonylaminomethyl)-4-phenylpiperidine-1-carboxylic acid 1-chloroethyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:12]([C:10]1[CH:9]=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[C:6]([NH2:5])[CH:11]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide (prepared in Example OO-1; 9.4 g, 34 mmol) was dissolved in MeOH (30 mL) and treated with 7% aqueous potassium carbonate solution. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated. The crude product was used further without any purification. MS(APCI): 181 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]([CH3:30])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]([CH3:30])[CH3:27])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 14.4 g of N-(5-(3-aminophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. After the extraction solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=2/3) to give N-(5-(3-isopropylamino-phenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, as an intermediate. This intermediate was dissolved in 200 ml of methanol, followed by addition of 2.02 g of 10% palladium-carbon, and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, the catalyst was filtered, and the solvent was distilled off to give the title compound (12.0 g, 81% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][N:13]([CH2:29][C:24]2[C:23]([CH3:22])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CNCC1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)CC1CN(C(=O)OC(C)(C)C)C1

Procedure:
Using General Procedure B: Reaction of 3-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester in CH2Cl2 with 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a sticky colorless oil. 1H NMR (CDCl3) δ 1.36 (s, 9H), 2.06 (s, 6H), 2.64-2.75 (m, 3H), 3.22-3.26 (m, 2H), 3.72 (s, 4H), 3.80 (t, 2H, J=7.5 Hz), 7.08-7.12 (m, 2H), 7.39 (d, 2H, J=6.0 Hz), 8.36 (d, 2H, J=3.0 Hz). Deprotection with TFA using General Procedure F gave azetidin-3-ylmethyl-bis-(3-methyl-pyridin-2-ylmethyl)-amine as a pale yellow sticky oil. 1H NMR (CDCl3) δ 1.85 (s, 1H), 2.10 (s, 6H), 2.73 (d, 2H, J=9.0 Hz), 2.94-2.99 (m, 1H), 3.09-3.12 (m, 2H), 3.49-3.54 (m, 2H), 3.70 (s, 4H), 7.08-7.12 (m, 2H), 7.39 (d, 2H, J=6.0 Hz), 8.37 (d, 2H, J=6.0 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M48) (0.35 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (211 mg, 78%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([O:23][CH3:24])[CH:7]=1)=[O:5].[CH3:26][Li].Cl>C1COCC1>[CH3:24][O:23][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH3:26])[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=1
Reactant: [Li]C
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)N(C)OC)c3o2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 121 (0.6 g, 1.7 mmol) in THF (10 ml) was added Methyl lithium (3.4 ml of 1.0 M in THF) and the reaction was stirred for 1 hr. The solution was then poured into 2 N HCl and extracted with EtOAc which was separated, dried over MgSO4, and concentrated to give a solid which was triturated with MeOH and collected by filtration to give 122 as a white solid (0.35 g, 67%); 1H NMR (CDCl3) δ 7.78(d, 2 H, J=8.7 Hz), 7.44 (d, 1 H, 2.6 Hz), 7.24 (s, 1 H), 6.99 (d, 2 H, J=8.7 Hz), 6.89 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.96 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O1CCCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1ccc(N)cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (1.00 g, 8.06 mmol) and pyridine (1.96 ml, 24.2 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.67 ml, 12.1 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (2.30 g, 95.4%) as a solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([NH:25][CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20].N1C=CC=CC=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>O1CCCC1>[Cl:3][C:4]1[CH:24]=[C:23]([N:25]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CNc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate dihydrochloride (418 mg), pyridine (396 mg) and tetrahydrofuran (4.2 ml) was added dropwise ethyl chlorocarbonate (0.115 ml) under ice-cooling and the mixture was stirred at room temperature for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was pulverized in diethyl ether to give methyl 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (340 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:32]([CH2:35][CH3:36])=[C:33]=[O:34]>C1COCC1.O>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([CH:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([NH:32][CH2:35][CH3:36])=[O:34])[CH:7]=4)=[CH:10][CH:11]=3)[CH2:16]2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.183 g, 0.044 mmol) in THF (4.5 mL) under an atmosphere of nitrogen at 0° C. was added isocyanatoethane (0.035 mL, 0.44 mmol) in THF (0.2 mL) dropwise. The reaction mixture was allowed to warm to rt. After 3 h, additional isocyanatoethane (0.104 mL, 1.32 mmol) was added, and after 4 h isocyanatoethane (0.104 mL, 1.32 mmol) was added again. The reaction mixture was heated at 50° C. for 4 h and then diluted with water. The mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, and dried over Na2SO4. The solution was filtered and concentrated. The residue was purified by column chromatography and then the product dissolved in DCM/MeOH. 2M HCl in Et2O was added and the mixture was concentrated to give N-(3-tert-butylphenyl)-7-[(2-{[(ethylamino)carbonyl]amino}-pyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-370 as its HCl salt (143 mg, 62%). 1H NMR (300 MHz, d6-DMSO; HCl salt) δ: 10.02 (s, 1H), 8.16 (d, 1H), 7.65 (dd, 1H), 7.49 (d, 2H), 7.17-7.28 (m, 2H), 6.95-7.09 (m, 2H), 6.87 (d, 1H), 6.70 (s, 1H), 3.10-3.20 (, 2H), 2.72-2.97 (m, 5H), 2.09 (d, 1H), 1.71-1.81 (m, 1H), 1.26 (s, 9H), and 1.06 (dd, 3H). LCMS: (FA) ES+ 487.4, ES− 485.3.