Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[CH3:44][NH:45][CH3:46].C([BH3-])#N.[Na+].CC(O)=O>C(#N)C.CC(O)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH2:12][N:45]([CH3:46])[CH3:44])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (40.0 mg, 0.063 mmol)and DIMETHYLAMINE (0.040 mL, 0.316 mmol) in Acetonitrile (1.5 mL) at 0° C. was added SODIUM CYANOBOROHYDRIDE (3.98 mg, 0.063 mmol). To this was added 1 drop of HOAc, and a second drop of HOAc after 5 min. The reaction was then stirred at R.T. for another hour. LC/MS showed reaction complete. It was concentrated, diluted with ether and washed with 0.5M NaOH, then loaded onto an SCX cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded, and eluted with 2M NH3 in MeOH, the solvent was concentrated to give the title product (27 mg, 0.041 mmol, 64.5% yield). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H),), 7.48 (d, J=1.83 Hz, 1H), 7.29 (m, 2H), 7.03 (m, 2H), 6.61 (d, J=19.8 Hz, 1H), 5.64 (m, 2H), 5.05 (m, 1H), 3.63 (m, 2H), 3.60 (t, c), 3.4 (m, 1H), 3.31 (m, 1H), 3.04 (m, 2H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m,2H), 2.25 (d, J=2.44 Hz, 6H), 2.2 (m, 1H), 2.05 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.43 (s, 9H), 0.9 (t, J=8.55 Hz, 2H), 0.06 (s, 9H). LC/MS (HPLC method 3): tR=3.53 min, 661.5(MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4].[N+:20]([O-])([OH:22])=[O:21].CCCCCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.6 %

Procedure:
5-Hydroxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (46.0 g, 169.63 mmol) is dissolved in 200 ml of concentrated (97%) sulphuric acid at 0-5° C. To this cooled solution is added drop wise fuming (100%) nitric acid (7 ml, 10.69 g, 169.63 mmol). After the addition is complete, the reaction mixture is allowed to warm to room temperature. TLC analysis (4:1 hexane:ethyl acetate) after 30 min shows reaction completion. The reaction mixture is slowly poured onto an ice/water mixture (ca. 2 l), and the crystals then filtered at the pump, thoroughly washed with water, and dried in vacuo. This affords the title compound (47.0 g, 87.6%) as pale yellow crystals.
Reaction SMILES: CO.[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:7]=[C:6]([CH2:19][C:20]2[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][N:24]3S(C2C=CC(C)=CC=2)(=O)=O)[N:5]=1.C([O-])([O-])=O.[K+].[K+]>O>[NH2:3][C:4]1[N:5]=[C:6]([CH2:19][C:20]2[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc(N)nc(Nc5ccc(C#N)cc5)n4)c(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)ccc4[nH]ccc34)n2)cc1
Yield: 45 %

Procedure:
Methanol (120 ml) was added to a mixture of intermediate (5) (2.35 g) and K2CO3 (9.19 g) in water (40 ml). The resulting reaction mixture was stirred and refluxed for 19 hours under argon. Water (120 ml) was added, the precipitate was filtered off and purified by column chromatography over silica gel (eluent: DCM/2-propanone 90/10). Two desired fractions were collected and their solvent was evaporated. The first fraction group was slurried in ACN, cooled, filtered off and dried, yielding 0.75 g (45%, white solid) of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 8, mp. 267-268° C.). The second column fraction group yielded 0.15 g of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide (compound 9). After 24 hours at RT the aqueous filtrate was filtered to give 0.25 g of compound (9). The two fractions of compound 9 were combined, dissolved in 500 ml of refluxing methanol, hot filtered, the filtrate concentrated to 50 ml, cooled and filtered, then dried, yielding 0.25 g (14%) of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide (compound 9, mp. 204-205° C.).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:48])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]C)=[O:45]>>[C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:48])=[O:17])([OH:46])=[O:45]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-(methylsulfonyl)oxyhexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 79% overall yield. The product was a colorless solid, mp 86°-88° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:8][N:9]=1)[CH3:3].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:8][N:9]=1)[CH3:3]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CN(C)Cc1ncc(C2(O)CCC(=O)CC2)s1
Product: CN(C)Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(2-dimethylaminomethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][C:40](F)=[C:39](F)[CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[N:33](C)[CH3:34])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC=CC=3)C=C(C(=O)NC[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])C=2)C=1CCC(=O)NOCC)C.[OH-].[Na+]>C1COCC1.CCO>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CCONC(=O)CCc1c(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)cccc1OCCCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)c1CCC(=O)O
Yield: 80 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-bi phenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbamoyl-ethyl)-phenoxy]-butyric acid ethyl ester (176 mg, 0.23 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (129 mg, 80%) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.CN(C)C=O.[Cl:24]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:7]([Cl:24])=[N:6][C:5]([O:8][CH:9]([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(OC(C(F)(F)F)C(F)(F)F)ncc1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC(C(F)(F)F)C(F)(F)F)nc(Cl)c1N
Reaction time: 1 h
Yield: 44.4 %

Procedure:
1.0 g of 5-amino-4-methyl-2-(2,2,2-trifluoro-1-trifluoromethylethoxy)pyridine was introduced to 10 ml of N,N-dimethyl formamide, and 0.56 g of N-chlorosuccinimide was added at room temperature. The temperature was elevated to 60° C., and the mixture was stirred for 1 hour and poured into water. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thus obtained residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=10:1) to give 0.50 g (yield 44%) of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Ag]=O.CC(C)=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(C2CCCN(Cc3ccccc3)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
2.2 g of silver oxide were added to a mixture of 4.6 g of 3-(m-trifluoromethylphenyl)-piperidine and 22 ml of acetone and the mixture was cooled on an ice water bath while 2.55 ml (≃3.6 g) of benzyl bromide was added dropwise over 10 minutes at a temperature less than 10° C. The mixture was stirred at 0° C. for one hour and was filtered. The filtrate was evaporated to dryness under reduced presssure to obtain 7 g of raw product which was chromatographed over silica gel. Elution with an 85-10-5 cyclohexane-chloroformtriethylamine mixture and evaporation to dryness under reduced pressure yielded 4.99 g of N-benzyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S([CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])(=O)=O)=CC=1>>[CH3:19][N:20]([CH2:28][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[O:7][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH3:21]
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)cc1
Product: CN(C)Cc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
The following compounds were similarly prepared from the corresponding phenol (A) and 2-[2-(4-methylbenzenesulphonyl)ethyl]-1H-isoindole-1,3(2H)-dione (C).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([F:28])=[CH:21]2)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1COCC1.C(Cl)Cl>[F:28][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:16]1[S:49][C:12]([CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[N:14][N:15]=1)=[CH:27][CH:26]=2
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc2cnc(F)cc2c1)Cc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 84.7 %

Procedure:
A mixture of (R)—N′-(4-(tert-butyloxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanoyl)-3-fluoroisoquinoline-6-carbohydrazide (108 mg, 207 μmol) and Lawesson's reagent (101 mg, 249 μmol) in THF (2 mL) was heated in a Biotage® microwave reactor at 100° C. for 10 minutes. The mixture was diluted with DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 2-8% MeOH/DCM) providing tert-butyl (R)-4-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (96 mg, 88%) as a white solid. LCMS (API-ES) m/z: 548.1 (M+H+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:11]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])(=[O:13])[CH3:12]
Reactant: CCCCOC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: C=C(OC(C)=O)C(=O)OCCCC
Temperature: 120 °C
Reaction time: 25 h
Yield: 67.1 %

Procedure:
Next, in a mixture of the obtained butyl pyruvate (235 g, 1.6 mol) and acetic anhydride (333 g, 3.3 mol), p-toluenesulfonic acid monohydrate (5 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 25 hours to obtain a second reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (5 mmHg) was removed from the second reaction solution. Thereafter, the residue was purified by reduced pressure distillation (2 mmHg, 56 to 63° C.) to obtain butyl α-acetoxyacrylate (200 g, yield 67%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([NH:28][CH2:27][CH2:26][NH:25][C:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:16][C:17]3[CH:21]=[C:20]([CH:22]4[CH2:23][CH2:24]4)[NH:19][N:18]=3)[C:2]([Br:1])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:31])[CH3:30]
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 23 °C
Reaction time: 12 h
Yield: 68.1 %

Procedure:
A 100 mL round bottomed flask was charged with 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (332.5 mg, 0.82 mmol, 1 eq), N-(2-aminoethyl)acetamide (125.3 mg, 1.23 mol, 1.5 eq), EDCI (313.0 mg, 1.6 mmol, 2 eq), HOBt (221.1 mg, 1.6 mmol, 2 eq) and DIPEA (635.4 mg, 4.9 mmol, 6 equiv) in DMF (5 mL). The mixture was stirred for 12 h at 23° C. and extracted with THF (3×70 mL). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA/MeOH=1:1:0.05 as eluant) to give pale-yellow solid N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 68.3%). LC-MS (m/z)=491.1 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](O)=[O:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)=[O:27]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCc1ccc(CCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(CCO)cc1)c1c(Cl)cncc1Cl
Yield: 44.1 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of 2-(4-Aminomethyl-phenyl)-ethanol (306 mg, 2.03 mmol), 3,5-dichloroisonicotinic acid (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methyl morpholine (0.50 mL, 4.45 mmol), and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 mL) overnight at room temperature and overnight at 40° C. followed by column chromatography on silica gel (2:2:96 MeOH—NH4OH—CH2Cl2) gave the title compound (291 mg, 44%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:49][C:50]1([F:54])[CH2:53][NH:52][CH2:51]1.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]([F:47])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22]([N:52]4[CH2:53][C:50]([F:54])([F:49])[CH2:51]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 54, 200 mg, 0.280 mmol) in THF (5 mL) was added 3,3-difluoroazetidine (129.5 mg, 0.840 mmol) and DIEA (0.244 mL, 1.399 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with 10%-100% acetonitrile in water, to give title compound as a slightly yellow solid. LCMS (M+H)+: 728.1. 1H NMR (CDCl3, 500 MHz): δ 8.37 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.78 (s, 2H), 5.79 (d, J=8.5 Hz, 1H), 4.78 (d, J=17.0 Hz, 1H), 4.58 (m, 4H), 4.42 (m, 3H), 4.08 (d, J=17.0 Hz, 1H), 2.72 (s, 3H), 2.43 (s, 3H), 0.80 (d, J=7.0 Hz, 3H). RTA IC50: 61 nM.
Reaction SMILES: [Si]([O:8][CH:9]1[C@H:22]([CH:23]=[CH:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@@H:12]([CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[C:11](=[O:32])[CH2:10]1)(C(C)(C)C)(C)C.F.[C:34](=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]([OH:31])/[CH:24]=[CH:23]/[C@@H:22]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:34])=[O:20])[C:11](=[O:32])[CH2:10][C@H:9]1[OH:8]
Reactant: CCCCCC(O)C=C[C@H]1C(O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CC=CCCCC(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: F
Agent: [Na+]
Solvent: CC#N
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C/CCCC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
(−)-methyl(11R, 15S, 5Z, 13E)-11-tert-butyldimethylsilyloxy-15-hydroxy-9-oxoprost-5,13-dien1-oate (518 mg, 1.08 mmol) and acetonitrile (10 ml) were placed into a Teflon container and cooled to 0° C., whereby 46% hydrofluoric acid (1.0 ml) was added and stirred for 2 h. The reaction mixture was poured into a saturated aqueous sodium carbonate cooled with ice and extracted with ethyl acetate (150 ml) two times. The combined organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (2/1)] to give 345 mg (88% yield) of prostaglandin E2 methyl ester;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[C:15]([O:18][CH2:19]Br)(=[O:17])[CH3:16].Cl>CN(C)C=O.O>[C:15]([O:18][CH2:19][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1H-Indole-3-carboxylic acid (400 mg) was dissolved in N,N-dimethylformamide (6 ml) and cooled to 0° C. Sodium hydride (500 mg) was added to the solution in two divided portions, and the mixture was stirred as such for 30 minutes. Bromomethyl acetate (0.32 ml) was added slowly dropwise thereto, and the mixture was stirred for 15 minutes at 0° C., warmed to room temperature and stirred for 45 minutes. The mixture was cooled to 0° C., and water was added to the mixture which was then acidified by 2 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (354 mg, Y.:61%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[BH3-][C:15]#N.[Na+].C=O.Cl>CO.O>[CH3:15][N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCc2c([nH]c3ccccc23)C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-β-carboline (0.50 g, 2.9 mmol) and NaCNBH3 (0.44 g, 7.0 mmol) were added to a round bottomed flask, dissolved in MeOH (35 mL), and treated with 3.23 mL of a 27% solution of formaldehyde in water. This mixture was stirred for 2 h, after which, 2N HCl (50 mL) was added, followed by stirring for 15 min. The mixture was taken to pH=11 by addition of concentrated, aqueous NaOH and extracted with methylene chloride (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The product was purified by MPCC (0-10% gradient of MeOH in CH2Cl2), giving the title compound (511 mg, 95%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.39 (d, 1H, J=7.7 Hz), 7.27 (d, 1H, J=8.0 Hz), 7.05 (t, 1H, J=7.5 Hz), 6.96 (t, 1H, J=7.7 Hz), 3.68 (s, 2H), 2.86 (m, 4H), 2.53 (s, 3H). 13C NMR APT (100 MHz, CD3OD): δ 136.1 (up), 131.7 (up), 127.2 (up), 121.2 (down), 119.2 (down), 117.9 (down), 110.8 (down), 107.8 (up), 53.0 (up), 52.1 (up), 45.5 (down), 21.4 (up). ESI-HRMS (m/z): [M+H]+ calcd. for C12H14N2, 187.1230. found, 187.1233