Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing a solution of 29 (0.21 g, 0.59 mmol), Et3N (0.18 g, 1.78 mmol) and DMAP (0.034 g, 0.28 mmol) in CH2Cl2 (5 mL) was added ethanesulfonyl chloride (0.19 g, 1.48 mmol), dropwise, at RT and the reaction allowed to stir overnight at RT.
Reaction SMILES: [CH3:1][C:2]([C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19])([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].CC(C(NC1C2CC3CC(CC1C3)C2)=O)(CC1C2C(=CC=CC=2)NC=1)C(O)=O.[K+].[Br-]>>[CH3:1][C:2]([C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19])([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1c[nH]c2ccccc12)C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: [Br-]
Agent: [K+]
Product: CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)NCC12CC3CC(CC(C3)C1)C2

Procedure:
Compound 10 was prepared from Compound 9 according to the procedure for Compound 6. The product was obtained as a white solid. 1.95 g (71%) IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 746 cm-1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2cc1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
3-(1-Benzylpiperidin-4-yl)quinolin-2(1H)-one (1.72 g, 5.40 mmol) was suspended in methanol (70 mL). A catalytic amount of palladium hydroxide (20% on carbon) was added to the mixture. The reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen. The reaction was shaken at room temperature for 5 h. The mixture was removed from the apparatus and filtered. The filtrate was concentrated to give the title compound as white solid in 90% yield. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.64 (d, J=10.61, 1H), 7.41 (t, J=7.50, 1H), 7.26 (d, J=8.05, 1H), 7.13 (t, J=7.32, 1H), 3.02 (d, J=11.71, 2H), 2.82 (t, J=11.89, 2H), 2.58 (t, J=11.71, 2H), 1.73 (t, J=11.71, 2H), 1.42 (m, 2H). Mass spec.: 229.4 (MH)+.
Reaction SMILES: C#C.[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:28].[Li+]>>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][I:28])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: [I-]
Agent: C#C
Agent: [Li+]
Product: ICC1CN(Cc2ccccc2)CCO1

Procedure:
The starting material for use in processes (a), (b) and (h) in which A is a vinylene radical may be prepared, as described in Example 1, by reaction of 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine and lithium iodide to give 4-benzyl-2-iodomethylmorpholine. This compound is then reacted with triphenyl phosphine to give 4-benzylmorpholine-2-ylmethyl triphenyl phosphonium iodide which is subsequently reacted with a base to form the corresponding phosphorane. This intermediate is reacted in situ with the appropriate substituted benzaldehyde to give 4-benzyl-2-(β-substituted phenylvinyl)morpholine as a mixture of cis and trans isomers. These isomers are, if necessary, separated by chromatography, or by fractional crystallisation of an acid-addition salt, and if required this N-benzyl derivative is used to form other N-substituted starting materials. Thus reaction with an aryl or optionally substituted alkyl chloroformate gives the corresponding phenoxy- or alkoxy-carbonyl derivative, or reaction with cyanogen bromide gives the corresponding N-cyano derivative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[C:14]3[N:15]=[C:16]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 2.6 %

Procedure:
A mixture of the product of Example 7, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.280 g, 10.75 mmol), and 4-aminopyridine (0.5 g, 15.3 mmol) was placed in a small round bottom flask and immersed in an oil bath at 180° C. for 5 minutes with stirring. The reaction mixture was cooled to 20° C. and the mixture triturated with water (10 mL). The insoluble product was filtered and dried in air on the filter. The crude product was purified by column chromatography eluting with a solvent gradient starting with pure chloroform and finishing with methanol/chloroform (1:20). The product was crystallized by suspending it in methanol (10 mL) and adding methylene chloride (30 mL) until a solution resulted. The solution was concentrated on a steam bath to approximately 8 mL in volume. The precipitated product was filtered and washed with methanol (0.5 mL) to afford 112 mg of the titled compound. mp 305–307° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[CH2:10]Br.[P:12]([O:19][CH2:20][CH3:21])([O:16]CC)[O:13][CH2:14][CH3:15]>>[Br:1][C:2]1([P:12]([O:13][CH2:14][CH3:15])(=[O:16])[O:19][CH2:20][CH3:21])[C:7]([P:12]([O:19][CH2:20][CH3:21])(=[O:16])[O:13][CH2:14][CH3:15])=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[CH3:10]
Reactant: BrCc1ccc(CBr)c(Br)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1=C(C)C=CC(C)C1(Br)P(=O)(OCC)OCC
Temperature: 180 °C

Procedure:
The mixture of 2-bromo-α,α′-dibromo-p-xylene (68) (14.43 g, 0.042 mol) and triethyl phosphite (145 ml) was refluxed at 180° C. overnight. The excess triethyl phosphite was removed under reduced pressure, 60 ml of hexanes was added, the mixture was cooled at −78 ° C. and white solid was formed on vigorous stirring. The solid was collected by rapid filtration, washed three times with 20 ml of cool hexanes, dried in vacuo and isolated in 14.0 g (72.7%) yield as light yellow oil.1H NMR (CDCl3, 500 MHz) δppm: 7.51 (s, br, 1H), 7.40 (dd, 3J=7.7 Hz, 4J=2.2 Hz, 1H), 7.21 (d, 3J=8.0 Hz, 1H) 4.04 (m, 8H, CH2), 3.38 (d, J=21.5 Hz, 2H, CH2), 3.09 (d, J=21.5 Hz, 2H, CH2), 1.25 (m, 12H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CO[C:25](OC)([CH3:27])[CH3:26]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:25]1([CH3:27])[O:12][CH2:11][CH:10]([NH:9][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][O:14]1
Reactant: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-{[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-1,3-propanediol (53.93 g, 228.7 mmol) was stirred in 2,2-dimethoxypropane (900 ml) under argon and p-toluenesulphonic acid monohydrate (1.00 g) was added. The mixture was stirred at room temperature overnight to give a clear yellow solution. This was with diluted with DCM (1 L) and the resulting solution was treated with saturated aqueous NaHCO3 (20 ml) and solid NaHCO3 (20 g) with vigorous stirring (effervescence). The mixture was vigorously stirred for 20 minutes, then the remaining water was absorbed by addition of anhydrous Na2SO4. The mixture was filtered with suction and the solids were washed with DCM (500 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a yellow solid which was stirred with petroleum ether (40-60°) over the weekend. The solid was isolated by filtration with suction, washed with petroleum ether (40-60°) and air-dried to give the title compound as a bright yellow solid (57.83 g, 92%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:14][CH:15]([F:18])[CH2:16][NH2:17].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][C:11]([CH3:13])=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH2:16][CH:15]([F:18])[F:14]
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cn1
Reactant: NCC(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NCC(F)F)c(Cl)nc2cn1
Yield: 94.7 %

Procedure:
A solution of 2,3-dichloro-7-methylpyrido[3,4-b]pyrazine (125 mg, 0.584 mmol), 2,2-difluoroethanamine (53.6 μL, 0.701 mmol), and DIPEA (306 μL, 1.752 mmol) in DCM (1.17 mL) was stirred at room temperature for 48 h, then poured into a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The extracts were combined, filtered through MgSO4, and concentrated to give 3-chloro-N-(2,2-difluoroethyl)-7-methylpyrido[3,4-b]pyrazin-2-amine (143 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11](C)[CH:10]=2)[N:5]=[C:4]([C:17]([NH:19][OH:20])=[NH:18])[N:3]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][N:26]=1>N1C=CC=CC=1>[CH3:16][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:17]2[N:18]=[C:29]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:21])[F:34])=[CH:33][CH:32]=3)[O:20][N:19]=2)[N:5]=1
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Reactant: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
In a sealed tube under nitrogen was placed 4-amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidine (Intermediate 1, 100 mg, 380 μmol). Then 5 mL anhydrous pyridine was added followed by 6-(2,2,2-trifluoroethoxy)-nicotinoyl chloride (prepared in an analogous manner to Intermediate 57, 91 mg, 380 μmol). The mixture was stirred at room temperature for 48 hrs. After this time the mixture was heated at 115 C for 18 h, allowed to cool and concentrated in vacuo. The crude residue was loaded onto a 2 g isolute silica column in a minimal amount of DCM and eluted with ethyl acetate-heptane 20-50% to give the title compound (54 mg, 32%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=O)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CCN(CC)CC.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][NH:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(Cc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-ethyl-carbamic acid tert-butyl ester (240 mg, 0.806 mmol), cyclopropylamine (0.085 mL, 1.2 mmol) and Et3N (0.169 mL, 1.21 mmol) in MeOH (2.7 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (76.2 mg, 2.01 mmol) was added. The mixture was stirred for 1 h at rt, and aq. sat. NaHCO3 was added. The mixture was extracted several times with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (125 mg, 46%). LC-MS: tR=0.78 min; ES+: 380.20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([NH:53][NH2:54])(=[O:52])[CH3:51].CCN(C(C)C)C(C)C>ClCCl>[C:50]([NH:53][NH:54][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:23])[F:25])=[CH:16][N:15]=2)=[CH:4][C:5]=1[O:11][CH3:12])(=[O:52])[CH3:51]
Reactant: CC(=O)NN
Reactant: CNc1nc(Nc2cc(OC)c(C(=O)O)cc2Cl)ncc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2cc(OC)c(C(=O)NNC(C)=O)cc2Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A suspension of 5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoic acid (144 mg, 50% pure material, 0.19 mmol), HATU (85 mg, 0.22 mmol), acetic hydrazide (16 mg, 0.22 mmol) and DIPEA (81 uL, 0.46 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). A solid persisted in the aqueous layer; this was filtered, washed with water and then suspended in methanol. The solid was collected by filtration and dried in a vacuum oven to afford N′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide as a white solid (68 mg, 85%). This was taken through to the next step without further purification.
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.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(O)C>[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]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloropyridine hydrochloride (87 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL), sealed, and placed in a 120° C. bath. After 24 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 10% 2 N ammonia in methanol:methylene chloride) affording 70 mg (57%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:54])[C:7]([O:10]/[N:11]=[C:12](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][C:26]1[N:27]=[N:28][N:29]([CH2:31][CH2:32][NH:33]C(OC(C)(C)C)=O)[CH:30]=1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][N:29]1[CH:30]=[C:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:54])=[O:5])/[C:41]3[N:42]=[C:43]([NH2:46])[S:44][CH:45]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[N:27]=[N:28]1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cc1cn(CCN)nn1)c1csc(N)n1)C(=O)O
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection, using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-oxoazetidine-1-sulfonic acid (7.22 mg, 9.00 μmol), DCM (200 μl) and TFA (50 μl, 649 μmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (1.2 mg, 24%). LCMS: Rt=0.487 min, m/z=546.2 (M+1). Method 2m_acidic.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[C:11]=3[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1c(F)cc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (S)-1-(4-fluorophenyl)ethylamine (0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as an orange solid (0.30 g, 71%). 1H NMR (400 MHz) 11.89 (s, 1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6 Hz), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.81 (d, 1H, 7.6 Hz), 5.39 (s, 1H), 5.00 (m, 1H), 1.80 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417; Found: [M+H]+ 418.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30]([OH:32])=O)[CH3:26].C(N(C(C)C)C(C)C)C.[C:43]([C:47]1[O:51][C:50]([C:52]2[C:53]([NH2:71])=[N:54][CH:55]=[C:56]([C:58]3[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]4[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]4)[N:59]=3)[N:57]=2)=[N:49][N:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:71][C:53]1[N:54]=[CH:55][C:56]([C:58]2[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]3[CH2:66][CH2:67][N:68]([C:30](=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:69][CH2:70]3)[N:59]=2)=[N:57][C:52]=1[C:50]1[O:51][C:47]([C:43]([CH3:44])([CH3:45])[CH3:46])=[N:48][N:49]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
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: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(CC)n2)CC1
Temperature: 25 °C
Yield: 147 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (474 mg, 1.25 mmol) was added over 30 seconds in portions to a stirred solution of 3-ethoxy-3-oxopropanoic acid (150 mg, 1.13 mmol), N-ethyl-N-isopropylpropan-2-amine (0.394 mL, 2.26 mmol) and 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (450 mg, 1.13 mmol) dissolved in DMF (20 mL) at 50° C. The resulting solution was sampled after 1 min (complete reaction) and immediately allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude ethyl 3-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (850 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][CH3:19])[CH:9]=1)[CH3:6])[CH3:2].[CH:22]1([C:25]2[C:30]([CH2:31][C:32](O)=[O:33])=[CH:29][N:28]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[N:26]=2)[CH2:24][CH2:23]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([N:18]([C:32](=[O:33])[CH2:31][C:30]2[C:25]([CH:22]3[CH2:23][CH2:24]3)=[N:26][C:27]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=3)=[N:28][CH:29]=2)[CH3:19])[CH:9]=1)([CH3:20])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(NC)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cc(N(C)C(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(C(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26]Cl)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CNCC(F)(F)F)OC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
(R)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (6.80 g, 16.7 mmol) in acetonitrile (70.0 ml, 1340 mmol) was added 2,2,2-trifluoroethylamine (8.27 g, 84 mmol). After 20 min, potassium carbonate (2.308 g, 16.70 mmol) was added and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the crude product was dissolved in a mixture of dichloromethane and chloroform. A thick emulsion formed and addition of methanol provided a clear organic phase. The organic layer was dried (Na2SO4), the solvent was removed and the crude product was used as such for the next step. MS (ESI) 470 (M+H); Rf=1.56.