Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[CH:13][N:12]=[C:11]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: Cc1ccc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)cc1C
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)ncc2OCC(F)(F)F)cc1C

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BO) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 475.1211 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[F:20][C:21]1[C:22]([C:27]#[N:28])=[N:23][CH:24]=[CH:25][CH:26]=1.[Li+].CC([N-]C(C)C)C.[I:37]I>C1COCC1.C(Cl)Cl>[F:20][C:21]1[C:22]([C:27]#[N:28])=[N:23][CH:24]=[CH:25][C:26]=1[I:37]
Reactant: II
Reactant: N#Cc1ncccc1F
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#Cc1nccc(I)c1F
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 55.2 %

Procedure:
To a solution of diisopropylamine (2.80 ml, 19.66 mmol) in THF (Volume: 201 ml) cooled to −78° C. was added n-butyllithium (7.86 ml, 19.66 mmol) dropwise. The dry ice/acetone bath was replaced with an ice water bath and reaction mixture was stirred at 0° C. for 25 min, and then re-cooled to −78° C. In a separate flask, a solution of 3-fluoropicolinonitrile (1.5 g, 12.29 mmol) in THF (50 mL) was cooled to −78° C., and then LDA (130 mL, 1.0 equiv) was added. The solution turned dark red. After 35 min, iodine (3.43 g, 13.51 mmol) was added rapidly. The reaction mixture was stirred for 45 min, then quenched with H2O. Layers were separated and the aqueous phase extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-20% EtOAc in hexanes over 23 min, tr=18 min) gave the title compound (1.7 g, 6.79 mmol, 55.2% yield) as a brown solid.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>N1C=CC=CC=1>[Br:19][C:16]1[CH:17]=[CH:18]/[C:13](=[N:12]/[S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])/[NH:14][CH:15]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Br)c[nH]2)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Tosyl chloride (52.9 g, 277.4 mmol) is added slowly to a stirred solution of 2-amino-5-bromopyridine (40.0 g, 231 mmol) in dry pyridine (240 ml) at 0° C. The reaction is heated at 90° C. for 16 hours. The solvent is removed in vacuo and water (500 ml) is added and the mixture is stirred for 30 minutes at room temperature. The title compound is collected by filtration and dried in a vacuum oven at 50° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[C:15](O)(=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)N.NC1C=CC=C(C)C=1>CN(C)C=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:19][CH:17]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(CC(=O)Nc2ccccc2C(=O)O)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
N(chloroacetyl)anthranilic acid 6.4 g (15 mmol) (synthesized from anthranilic acid by the same procedures as those of Example 9) and m-toluidine 9.5 ml (0.09 mol) were dissolved in 60 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction mixture was poured into ice water and extracted with ether. The resulting ether solution was extracted with 10% sodium hydroxide and the resulting aqueous solution was neutralized with 10% HCl solution. The neutralized solution was extracted with ether, and the ether solution was washed with water and dried. The solvent of dried solution was distilled off and the residue was recrystallized from benzene-hexane to obtain N[(3-methylphenyl)acetyl]anthranilic acid 4.7 g (yield: 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.O[C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:27]([NH:26][C:25]1[CH:30]=[CH:31][C:22]([O:1][CH2:2][CH2:3][CH:4]2[CH2:10][CH2:9][C:8]3[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=3[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(NC(C)=O)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 62.4 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (101 mg), p-hydroxyacetanilide (166 mg), and triphenylphosphine (126 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (81 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 80 min and concentrated. The residue was purified successively by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) and by alumina column chromatography (eluent:ethyl acetate/hexane=1/1) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (93 mg).
Reaction SMILES: O[CH:2]([CH3:32])[CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1.OC1C=CC2N=C(C3N=CC(OC[C@@H](NC(=O)OC(C)(C)C)C)=CC=3)OC=2C=1.BrCC(=O)C.COCCN(S(F)(F)[F:76])CCOC.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:76][CH:2]([CH3:32])[CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(O)COc1ccc2nc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn3)oc2c1
Agent: CC(=O)CBr
Agent: C[C@@H](COc1ccc(-c2nc3ccc(O)cc3o2)nc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(F)COc1ccc2nc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn3)oc2c1

Procedure:
A mixture of tert-butyl [(1S)-2-({6-[6-(2-hydroxypropoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate (1.02 g) (obtained using tert-butyl [(1S)-2-{[6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.00 g) and 1-bromopropan-2-one (1.56 g) and in the same manner as in Example 2, step E and Example 24, step F), bis(2-methoxyethyl)aminosulfur trifluoride (0.848 mL) and toluene (10 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-({6-[6-(2-fluoropropoxy)-1,3-benzoxazol-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate. Using the obtained compound, and in the same manner as in Example 1, step D, the title compound was obtained (61.3 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH:7]=[CH:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([NH2:23])[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([NH2:23])[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc2nc3ccccc3c(N)c2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc2nc3ccccc3c(N)c2c1
Yield: 103.4 %

Procedure:
3-(9-Amino-acridin-2-yl)-acrylic acid tert-butyl ester 6 (40 mg, 0.06 mmol) was dissolved in ethanol (25 mL). 10% Pd/C (15 mg) was added and the solution was put under hydrogenation at 3 bar for 1 h30. The mixture was filtered through Celite and the solvent was evaporated. The residue was purified by Flashmaster II using a gradient elution (DCM→DCM:MeOH 40:60) afforded pure 3-(9-amino-acridin-2-yl)-propionic acid tert-butyl ester 7 as an orange oil (20 mg, 52%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=[CH:9][CH:8]=1>C1COCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17]2=[O:18])[C:1]#[C:2][CH3:3])=[CH:22][CH:23]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-propynyl magnesium bromide in THF (0.5 N, 322 mL, 161.28 mmol) is added a solution of 5-(4-hydroxy-benzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (20 g, 80.64 mmol) in THF (200 mL) by cannula under a nitrogen atmosphere. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After addition is compete, the reaction mixture is stirred for 15 minutes at 50° C., quenched with aqueous NH4Cl, and acidified to pH ˜2 with 2 N HCl. The mixture is extracted with EtOAc (2×300 mL) and the combined extracts are washed with saturated brine, dried over MgSO4, filtered, and concentrated to a yellow solid (20 g, 86%). The product is carried on crude.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[I:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(N(CC)CC)C.CCOCC>CCOC(C)=O.C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[I:21])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)c2ccccc2I)N=C(c2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, o-iodo-benzoylchloride and triethylamine were mixed at room temperature and stirred 1 hour. Flash chromatography of the reaction solution on silica gel (5% Et2O in (CH2Cl2) provided the title compound as a crystalline solid from EtOAc: m.p. 115°-120° C. (physical change), 173°-175° C. (melt).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH2:6]1>CCOCC>[O:4]=[C:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:3])=[O:12])[CH:8]=[CH:7][CH2:6]1
Reactant: O=C1CC=CC(C(=O)O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1C=CCC(=O)C1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 0.7M diazomethane in ether was slowly added to a solution of 6.0 g (42.8 mmol) of 5-oxocyclohex-2-ene-1-carboxylic acid in 100 mL of ether at 0 degrees centigrade, with swirling. The addition of diazomethane was continued until the bubbling ceased and a yellow color persisted. The solution was treated with a rapid stream of nitrogen until the yellow color was discharged. The solvent was removed by evaporation. Benzene (100 mL) was added and evaporated at room temperature using an aspirator. The residue was placed on a vacuum line for 2 hours to produce 6.5 g (42.4 mmol, 99 percent) of methyl 5-oxocyclohex-2-ene-1-carboxylate (oil).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:30])([F:29])[CH:13]([OH:28])[CH2:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([S:25][CH3:26])[CH:23]=2)[O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[F:30][C:12]([F:11])([F:29])[C:13](=[O:28])[CH2:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([S:25][CH3:26])[CH:23]=2)[O:18][CH2:17][CH2:16]1
Reactant: CSc1ccc2c(c1)C(C)(CC(O)C(F)(F)F)CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSc1ccc2c(c1)C(C)(CC(=O)C(F)(F)F)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a chilled (−60° C.) solution of 0.254 mL (2.9 mmol) of oxalyl chloride in 5 mL of methylene chloride was added a solution of 0.414 mL (7 mmol) of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of 450 mg (1.46 mmol) of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-ol in 2.5 mL of dichloromethane was added. The mixture stirred for 15 minuets and then 1.2 mL (8.7 mmol) of triethylamine was added. The reaction was warmed to room temperature for 30 minutes and then concentrated in vacuo. The residue was diluted with water and extracted with diethyl ether. The combined organic fractions were washed with four portions of water, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 340 mg (94%) of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-one as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21]I.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(Cl)c(Br)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.0 g (44.2 mmol) of (+/−)-tert-butyl 1-[(3-bromo-4-chlorophenyl)(hydroxy)methyl]cyclopropanecarboxylate were dissolved in 80 ml of DMF, and 4.1 ml (66.6 mmol) of methyl iodide were added at RT. The reaction mixture was cooled to +10° C., and 1.95 g (60% in mineral oil, 48.7 mmol) of sodium hydride were added in several portions. Ten minutes after the addition had ended, the mixture was warmed to RT and stirred at RT for a further 1.5 h. The reaction mixture was then added to water and extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 15.3 g of the target compound (92.2% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](Cl)=[O:13])[CH:5]=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:22])=[O:13])[CH:5]=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: N
Reactant: O=C(Cl)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Into a 3 neck round bottom flask fitted with condenser and dropping funnel was added 3-(2-chloro-α,α,α-trifluoro-4-tolyloxy) benzoyl chloride (19.8 g 0.059 mol) and toluene (80 ml). The mixture was cooled in an ice bath to about 5° C. then ammonia solution 32% (15.6 g, 0.29 mol) was added dropwise. A yellow/orange precipitate formed and the mixture was stirred vigorously for 3 hours. The mixture was then extracted with toluene (200 ml) and washed with water (80 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting solid was then triturated with hexane to afford the product as a white solid (16.5 g, 91%). IR 1652 cm-1 (amide C=O), 3376 and 3191 cm-1 (N--H str);
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCc1cccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CCc1cccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 47-5 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using General Procedure II-C, the title compound was prepared from 3,5-difluorophenylacetyl chloride (General Procedure II-B) and L-alanine (Aldrich).
Reaction SMILES: [NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>CN(C)C=O>[NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: S
Reactant: CN(C)C(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(N)=C(C#N)C(N)=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 5.4 g of 3-amino-2-cyano-3-(dimethylamino)propenenitrile and 4.0 g of triethylamine in 25 ml of dimethylformamide at 50° were added 11.6 g of aqueous hydrogen sulfide. Upon complete addition of hydrogen sulfide, the reaction mixture was heated at 65° for 1 hour. Since comparison by thin-layer chromatography of the reaction mixture with the starting material indicated that no reaction had taken place, the reaction temperature was increased to 80°, where it was maintained for two hours, but again no reaction occurred. A small amount of triethylamine and 1 g of hydrogen sulfide were added to the solution. Heating was then continued at 85°. After 30 minutes reaction (as determined by thin-layer chromatography) was 40% complete. Small increments of triethylamine and hydrogen sulfide were added as heating continued until, after 21/2 hours at 85°, reaction was 95% complete. The solution was poured onto 150 ml of ice-water, and was purged with nitrogen gas to remove excess hydrogen sulfide. After 30 minutes, a solid formed, and was collected by filtration. The solid filter cake was washed with cold water and air-dried overnight to give 4.6 g of white solid 3-amino-2-cyano-3-(dimethylamino)propenethioamide, m.p. 186°-187° . The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11])([O-:3])=[O:2].O.[NH2:14][NH2:15].O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:14][NH2:15])[CH3:11])([O-:3])=[O:2]
Reactant: NN
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CC(=NN)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 120 h
Yield: 46.9 %

Procedure:
To a solution of 2′-nitroacetophenone (8.26 g, 50.00 mmol) in ethanol (50 ml) was added hydrazine monohydrate (4.85 ml, 100 mmol) and the reaction mixture was heated at 70 ° C. for 5 h. The reaction mixture was cooled to room temperature and water (100 nml) was added. After 5 d, the reaction mixture was concentrated in vacuo to ca. 100 ml and diethyl ether (100 ml) was added. The layers were separated and the aqueous layer was extracted with diethyl ether (100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford ca. 8.0 g of a crude yellow oil. This was purified by chromatography in two batches Iusing a Biotage Flash 40M™ cartridge packed with silica gel (90 g) eluting with dichloromethane:diethyl ether (19:1) to afford the title compound as viscous yellow oil (4.20 g, 45%).
Reaction SMILES: Br[C:2]1[CH:6]=CS[C:3]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=[O:8].NC(C1N=NC(NC2C=C[C:40]([O:43]C)=[CH:39]C=2)=NC=1)C.O1CCC(C(O)=O)CC1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:15]2[N:16]=[N:17][C:12]([CH:10]([NH:9][C:7]([CH:3]3[CH2:2][CH2:6][O:43][CH2:40][CH2:39]3)=[O:8])[CH3:11])=[CH:13][N:14]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: O=C(O)C1CCOCC1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Reaction time: 16.5 h

Procedure:
In a similar manner as described for Intermediate 49, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and tetrahydropyran-4-yl-carboxylic acid (58 mg, 0.45 mmol), except the reaction was stirred for 16.5 h and a 10 g SCX cartridge was used, to give N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (81 mg) as a yellow solid. MS m/z 358 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:54]2[CH2:55][CH2:56][CH:51]([OH:50])[CH2:52][CH2:53]2)=[O:17])=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.17 h

Procedure:
Route A: To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 1.4 g, 3.87 mmol) in DMF (35 mL) was added HATU (1.77 g, 4.64 mmol) and the reaction stirred for 10 min. 4-Hydroxypiperidine (0.43 g, 4.26 mmol) was added, followed by DIPEA (0.8 mL, 4.64 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were washed with sodium bicarbonate (2×30 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 96:4 dichloromethane/methanol) gave the title compound. m/z (ES+)=445.15 [M+H]+; RT=3.24 min. Route B: The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (Preparation 20). The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a pale yellow solid. δH (CD3OD): 1.08-1.19 (0.5H, m), 1.29-1.51 (1.5H, m), 1.54-1.62 (0.5H, m), 1.73-1.84 (1.5H, m), 3.06-3.36 (4H, m), 3.67-3.95 (2.5H, m), 4.03-4.10 (0.5H, m), 5.32 (1H, t), 6.97-7.04 (2H, m), 7.14 (1H, s), 7.26-7.33 (2H, m), 7.66 (1H, s), 8.55 (1H, s); m/z (ES+)=445 [M+H]+; RT=3.27 min.