Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:7]2[C:12]([C:13](=[O:27])[C:14]=1[CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:17]1=[O:26])=[CH:11][CH:10]=[C:9]([Cl:28])[CH:8]=2)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:7]2[C:12]([C:13](=[O:27])[C:14]=1[CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]1=[O:26])=[CH:11][CH:10]=[C:9]([Cl:28])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1ccn(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1c(Cn2ccc(C(=O)O)cc2=O)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-chloro-3-(4-methoxycarbonyl-2-oxo-2H-pyridin-1-ylmethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (0.22 g, 459 μmol) in tetrahydrofuran (10 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (0.7 mL, 459 μmol). The reaction was stirred at 25° C. for 2 h. At this time, the reaction was acidified with a 1N aqueous hydrochloric acid solution and then concentrated in vacuo to afford 3-(4-carboxy-2-oxo-2H-pyridin-1-ylmethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester. The material was used without further purification.
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl.N1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCl)Nc1ccccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a solution of 2-anilinoaniline (4.0 g) in a mixture of dichloromethane (20 ml) and pyridine (6.87 g) was dropwise added 4-chlorobutyryl chloride (4.29 g) at 8° C. during a period of 16 minutes. The mixture was stirred at the same temperature for 40 minutes and then diluted with ice-water. The mixture was extracted twice with dichloromethane. The combined extract was washed with 1 N hydrochloric acid and water in turn and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crystalline residue of 4-chloro-N-(2-anilinophenyl)butyramide (4.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[CH2:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:20]#[C:21][CH3:22]>>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:19][C:20]#[C:21][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OCC)cc1
Yield: 70.1 %

Procedure:
According to the procedure of Example 51, 1.55 g (5.99 mmol) of the product of Example 50 and 1.61 g (6.59 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 1.96 g (72%) of the sulfonamide as a white solid. Electrospray Mass Spec 467.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].CS(O[CH2:28][CH2:29][O:30][CH3:31])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:28][CH2:29][O:30][CH3:31])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCOC)cc23)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-ol (2.9 g, 0.01 mol), 2-methoxyethyl methane sulfonate (4.6 g, 0.03 mol, 3 equiv), and cesium carbonate (9.9 g, 0.03 mol, 3 equiv) in DMF (100 ml) was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into cold water, the solid was filtrated and dried to give 1.5 g product. MS (ESI) m/z: 350 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41](=O)[NH2:42])[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.CCOC(C)=O>C1COCC1>[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:31]([C:41]#[N:42])[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C#N
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Pyridine (2 mL) was added to a solution of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoylpiperidine-1-carboxylate (1.0 g, 1.87 mmol) in dry THF (40 mL). Then, Tf2O (1.0 mL) was slowly added over 5 minutes. The mixture was stiffed at 0° C. for 1 h and then EtOAc (30 mL) was added. The mixture was washed with saturated sodium chloride (4×), dried overNa2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜40% petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-cyanopiperidine-1-carboxylate (0.76 g, 79%) as a yellow solid ESI-MS (EI+, m/z): 539.0 [M+Na]+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22]Br)[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22][N:25]=[N+:26]=[N-:27])[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC1C2CC(CBr)(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC1C2CC(CN=[N+]=[N-])(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Reaction time: 8 h

Procedure:
6,7,8-Triacetoxy-1-bromomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (as described in Example 1 of the Japanese Patent Application No. 144309/1981, pp. 37) (4.1 g) is dissolved in dimethylformamide (15 ml), and sodium azide (1.0 g) is added to the solution, followed by stirring under heating on a bath of the temperature of 130° to 140° C. for 7 hours. The reaction mixture is concentrated under reduced pressure and further freed of the dimethylformamide azeotropically with toluene, under reduced pressure. 20% Aqueous methanol (100 ml) is added to the residue, which is then allowed to stand overnight in a refrigerator. The resultant crystals are recovered by filtration, washed with 20% aqueous methanol cooled with ice, and dried to produce 6,7,8-triacetoxy-1-azidomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (2.7 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17]1.NC[C@H]1CCN(C(OC(C)(C)C)=O)C1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCN(CCn2c(=O)ccc3ccc(F)cc32)C1)OCc1ccccc1
Reaction time: 16 h

Procedure:
To a solution of (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (1.17 g, 5.71 mmol) and phenylmethyl [(3R)-3-pyrrolidinylmethyl]carbamate (may be prepared analogously to the 3R isomer of Preparation 23(b) in WO2006002047, from (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine) (1.34 g, 5.71 mmol) in 1:1 CH2Cl2:MeOH (80 mL) were added 8 eq. Na2SO4 (6.5 g, 46 mmol) and the reaction was stirred at ambient temperature for 18 h. The intermediate imine was treated with sodium triacetoxyborohydride (3.63 g, 17.0 mmol) and stirred for an additional 16 h. The solvents were removed under reduced pressure; the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3, and the organic layer was dried over Na2SO4. Purification by column chromatography on silica gel, (1% to 20% methanol:dichloromethane gradient) yielded a light amber oil. (820 mg, 34%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C(=O)C.[CH:32]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([S:38][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
The N-[(4-flourophenyl)sulphonyl]glycine, 1,1-dimethylethyl ester from Example 5a (4.5 mmol, 1.30 g) was combined with dried 325 mesh K2CO3 (5.0 mmol, 0.69 g) and N,N-dimethylacetamide (4.5 mL). Cyclohexyl mercaptan (5 mmol, 0.61 mL) was added, and the mixture was stirred under argon at 60° C. for 40 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (125 mL). The organic phase was dried using magnesium sulphate, filtered through silica, and concentrated. The N-[[4-(cyclohexyl-thio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, a white solid (528 mg), was obtained following chromatography eluting with hexane:ethyl acetate (4:1). NMR indicated the presence of about 20% starting material after chromatography, but the mixture was used as is in the next step. The structure was confirmed spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>CC(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(Cl)nnc1Cl
Solvent: CC(C)O
Product: COc1ccc(CNc2cc(C)c(Cl)nn2)c(OC)c1
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 3,6-dichloro-4-methylpyridazine (1.35 g, 8.28 mmol) and 2,4-dimethoxybenzylamine (11.1 g, 66.3 mmol) in i-PrOH (5 ml) was heated in a microwave at 100° C. for 50 min. (30+20 min.). The mixture was concentrated and the residue was subjected to ISCO (120 g column, hexane 5 min., 0-55% EtOAc in hexane over 90 min. to give (6-chloro-5-methyl-pyridazin-3-yl)-(2,4-dimethoxy-benzyl)-amine (680 mg) plus the 6-methyl analog (320 mg).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=NC=N1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: c1nc[nH]n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A solution of methyl 4-(4-biphenylylmethoxy)phenylacetate (60.0 g), N,N-dimethylethylenediamine (47.7 g), and 1H-1,2,4-triazole (12.6 g) in toluene (120 ml) was stirred under nitrogen at 100° C. for 8 hr and cooled until the temperature of the reaction mixture was reached to 60±2° C., to which ethyl acetate (240 ml) was added for 20 min. The reaction mixture was further heated under reflux for additional 30 min, left to stand at room temperature over night and stirred in an ice bath for 2 hr. The precipitate was collected by filtration and washed with ethyl acetate (120 ml) to obtain the titled compound (71.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9](O)([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1(/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(C)(O)C1(C(=O)OCC)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)/C=C(\C)C1(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A 90.31 g (0.37 mol) portion of ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanepropanoate was dissolved in 182 ml of pyridine to which was subsequently added dropwise thionyl chloride at -10° C. to -5° C. After completion of the dropwise addition, this was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction solution was poured into 1 liter of ice water and extracted with dichloromethane (300 ml×3). The organic layers were combined, washed with 1N hydrochloric acid (1 liter×1) and saturated brine (1 liter×1) in that order and then dried on anhydrous sodium sulfate. To the resulting dichloromethane solution was added dropwise 58 ml of 1,8-diazabicyclo[5,4,0]-7-undecene at 0° C., followed by 18 hours of stirring at room temperature. After completion of the reaction, the reaction solution was washed with 1N hydrochloric acid (1 liter×1) and saturated brine (1 liter×1) in that order, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was applied to a silica gel column chromatography to yield 56.57 g (68%) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=9:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:29][C:4]=1[O:5][C:6]1[C:7]([N+:26]([O-])=O)=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(OC(C)(C)C)=O)[C:10]([C:22]([F:25])([F:24])[F:23])=[CH:9]2>CO.[Pd]>[NH2:26][C:7]1[C:6]([O:5][C:4]2[CH:29]=[CH:30][C:31]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:3]=2[O:2][CH3:1])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:22]([F:25])([F:23])[F:24])[NH:11]2
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(cc(C(F)(F)F)n3C(=O)OC(C)(C)C)c2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C(F)(F)F)cc3c2N)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 14.4 (0.020 g, 0.047 mmol) in methanol (2 mL), was added 10% Pd/C (0.006 g, 0.005 mmol). The mixture was stirred under hydrogen at room temperature for 1 h. Solvent was removed after filtration to give a residue. MS ESI (pos.) m/z: 395.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:7][C:8](=[S:11])[NH:9][N:10]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: BrCc1ccccn1
Reactant: COc1ccc(Cc2n[nH]c(=S)[nH]2)c(OC)c1
Agent: Br
Product: COc1ccc(Cc2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Yield: 34 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,4-dimethoxybenzyl)-2H-1,2,4-triazole-3(4H)-thione (example 9a) and 2-(bromomethyl)pyridine hydrobromide. Yield 34%. 1H NMR (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.79 (s, 3H), 4.0 (s, 2H), 4.34 (s, 2H), 6.35-6.45 (m, 2H), 7.1 (d, 1H), 7.15 (t, 1H), 7.3 (d, 1H), 7.7 (t, 1H), 8.5 (s, 1H). MS (M+H, 343).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16][C@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[C:22]#[N:23])=[CH:11][CH:10]=1>O1CCCC1.C(OCC)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][S:16][C@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[CH2:22][NH2:23])=[CH:11][CH:10]=1
Reactant: COc1ccc(CS[C@H]2COC[C@H]2C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CS[C@H]2COC[C@H]2CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A room temperature solution, under argon, of 4.22 ml of 1.0M lithium aluminum hydride in tetrahydrofuran is treated, dropwise, with 0.876 g of product from Example 199 in 3 ml of diethyl ether; during which time the reaction refluxes gently. After complete addition, the reaction is stirred at room temperature for 2 hour. The reaction mixture is quenched with 1 ml of water, 10.5 ml of 1.0N sodium hydroxide and 2.0 ml of water. The solid white precipitate formed is collected and washed with large volumes of diethyl ether. The diethyl ether layer is concentrated in vacuo to give 0.889 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](C)[C:9]=2C=CC(O)CC(O)CC(OCC)=O)=[CH:4][CH:3]=1>C(O)COCCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)CC(O)C=Cc1c(-c2ccc(F)cc2)c2cccnc2n1C
Solvent: OCCOCCO
Product: Fc1ccc(-c2c[nH]c3ncccc23)cc1

Procedure:
In a vessel, under nitrogen, about 27 g of the crude product of Step 1, above, in about 300 ml of diethylene glycol is refluxed (at about 250°) for about 7 hours. The contents are cooled, and then quenched with water yielding a yellow precipitate. The precipitate is washed thoroughly with water, then once with petroleum ether. The product is dissolved in ethyl acetate, dried and then concentrated by evaporation until precipitation begins. The precipitate is recovered by filtration, and washed first with cold ethyl acetate, then with petroleum ether yielding the title product of this step as yellow solids (mp 190°-192°).
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[CH:26]=[CH:25][C:24]=1[C:30]1[C:35]([C:36]2[NH:37][CH:38]=[CH:39][N:40]=2)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44]C2C=CC([N+]([O-])=O)=CN=2)[N:31]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[C:35]([C:36]2[NH:40][CH:39]=[CH:38][N:37]=2)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[N:31]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3Cl)n2)nc1

Procedure:
[4-(2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 2-chlorobenzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:37]([C:30]3[C:29]([NH2:28])=[CH:34][C:33]([C:35]#[N:36])=[CH:32][N:31]=3)=[O:38])[N:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)n2)CO[C@@]1(C)C(F)(F)F
Reactant: N#Cc1cnc(C(=O)O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@]1(C)C(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of [(2R,5R)-5-(6-amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (80 mg, 0.206 mmol), 3-amino-5-cyano-pyridine-2-carboxylic acid (40.3 mg, 0.247 mmol, Acid-4, HOAt (50.5 mg, 0.371 mmol) in DMF (1 ml) and EDC.HCl (59.2 mg, 0,309 mmol) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 and brine, and dried with MgSO4.H2O. The title compound was obtained after chromatography on silica gel (toluene/1-3% EtOAc) to give 71 mg of the title compound as a pale yellow solid slightly contaminated with some starting material. HPLC: RtH1=3.608 min; ESIMS: 534 [(M+H)+]; 1H-NMR (600 MHz, CDCl3): 10.92 (s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.82 (t, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 6.33 (br, 1H), 4.39 (d, 1H), 4.12 (d, 1H), 1.66 (s, 3H), 1.60 (s, 9H), 1.59 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25]([C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[O:26])=[O:18]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccco2)C(C)C)c1C
Yield: 53.6 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (227 mg, 0.89 mmoles) and furan-2-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.89 mmoles) in DMF (8 mL) was treated with triethylamine (0.37 mL, 2.67 mmoles), HOBT (144 mg, 1.07 mmoles) and EDCI (205 mg, 1.07 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (193 mg, 54%). LC-MS m/e 405.46 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:18])[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: Cc1cccc2nc(CCl)n(-c3ccccc3Cl)c(=O)c12
Yield: 23.9 %

Procedure:
Prepared according to Procedure B with 1g (2.18 g, 8.36 mmol) and chloroacetyl chloride (2.0 mL, 25.1 mmol) in acetic acid (40 mL). Purified by two chromatographies in CH2Cl2 and EtOAc/hexanes, followed by recrystallization from isopropanol to afford 638 mg of an off-white crystalline solid (24%). 1H NMR (DMSO-d6) δ: 7.73-7.80 (m, 3H); 7.58-7.64 (m, 3H); 7.41 (d, J=7.4 Hz, 1H); 4.40 (d, J=12 Hz, 1H), 4.26 (d, J=12 Hz, 1H); 2.74 (s, 3H). MS (ES): m/z 319.0 (M+).