Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:7](=O)[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4].[C:40]([O:44][C:45]([NH:47][C:48]1([C:51]([OH:53])=O)[CH2:50][CH2:49]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:40]([O:44][C:45](=[O:46])[NH:47][C:48]1([C:51](=[O:53])[NH:1][CH:2]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:7][CH:6]2[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[O:4])[CH2:49][CH2:50]1)([CH3:41])([CH3:42])[CH3:43]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)C(CC2CC2)C1
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (62 mg, 0.12 mmol) in DMF (2 mL) are added tert-butoxycarbonylamino-cyclopropanecarboxylic acid (28.5 mg, 0.14 mmol), 1-hydroxybenzotriazole (36 mg, 0.266 mmol), N-methylmorpholine (74 mg, 0.74 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (29 mg, 0.15 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.
Reaction SMILES: P([O-])([O-])(O)=O.[K+].[K+].[CH3:8][O:9][CH2:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].S(Cl)(O[CH2:23][Cl:24])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C.O>[Cl:24][CH2:23][O:15][C:14](=[O:16])[C:13]([CH3:18])([CH3:17])[CH2:12][O:11][CH2:10][O:9][CH3:8]
Reactant: O=S(=O)(Cl)OCCl
Reactant: COCOCC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Product: COCOCC(C)(C)C(=O)OCCl
Temperature: 0 °C

Procedure:
To a mixture of water (240 mL) and TBME (360 mL), dipotassium hydrogen phosphate (246 g), tetrabutylammonium hydrogen sulfate (9.65 g) and 3-methoxymethoxy-2,2-dimethylpropionic acid (45.8 g) were sequentially added. The mixture was cooled to 0° C., and chloromethyl chlorosulfate [CAS No. 49715-04-0] (42.1 mL) was added dropwise thereto with stirring, followed by stirring the resulting mixture overnight at room temperature. Water (1.3 L) and TBME (800 mL) were added to the mixture. After shaking the mixture, the organic layer was collected and washed twice with saturated aqueous sodium chloride solution (300 mL), followed by drying over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (41.7 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[CH2:14]([N:18]1[C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:22]=2C(=O)[O:20][C:19]1=O)[CH2:15][CH2:16][CH3:17]>CC(N(C)C)=O>[CH2:14]([N:18]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][N:24]=2)[C:5]([OH:7])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:19]1=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a slurry of NaH (95%, 0.44 g, 18.2 mmol) in 15 mL anhydrous DMA at 10° C. under N2 was added diethyl malonate (2.9 g, 18.2 mmol) dropwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes, treated with the product of Example 1B (2.0 g, 9.1 mmol) and heated at 120° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and cold water adjusting the pH to with 1 M HCl. The organic layer was washed 2×100 mL with water, 2×100 mL with saturated brine, dried (Na2SO4), filtered and the filtrate was concentrated under vacuum. The residue was recrystallized from hexane/ethyl acetate to give the desired compound as a white solid (1.84 g, 70% yield). MS (APCI+) m/z 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[NH2:8].Cl.[N:12]([O-])=O.[Na+]>O>[CH3:9][N:4]1[C:3](=[O:10])[C:2]2[N:1]=[N:12][NH:8][C:7]=2[CH:6]=[N:5]1
Reactant: Cn1ncc(N)c(N)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc2[nH]nnc2c1=O
Reaction time: 1 h

Procedure:
In water (10 ml) was dissolved 4,5-diamino-2-methyl-3(2H)-pyridazinone (280 mg) followed by addition of concentrated hydrochloric acid (0.5 ml) with ice-cooling. Then, sodium nitrite (290 mg)/water (5 ml) was added dropwise at a temperature not exceeding 10° C. and the mixture was stirred at that temperature for 1 hour and then at 100° C. for 1 hour. This reaction mixture was allowed to stand in the refrigerator for 16 hours and the resulting precipitate was collected by filtration, rinsed with water, and dried. White powder, 262 mg. 1H-NMR (DMSO-d6) δ: 3.76(3H,s), 8.71(1H,s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34]C2C=CC([N+]([O-])=O)=CN=2)[N:21]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[N:21]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl) (2-pyridyl)]amino}ethyl)amine (71480) was prepared from 2-chloro-5-(trifluoro-methyl)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]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC1>>[N:22]1([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH2:27][CH2:26][CH2:23]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and azetidine and isolated as white solid (9.8 mg, 52%). MS(m/e): 357.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1Br)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:19]1[CH2:21][CH2:20]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(N)cc3N21
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(N)cc3N21
Temperature: 130 °C
Yield: 53.7 %

Procedure:
A mixture of 6-amino-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.500 g, 1.607 mmol), cyclopropylboronic acid (1.38 g, 16.07 mmol), K2CO3 (0.888 g, 6.43 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.262 g, 0.321 mmol) in water (10 mL) and dioxane (60 mL) was heated at 130° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30-100% EtOAc in petroleum ether) to give 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.235 g, 0.863 mmol, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 10.71 (s 1H), 6.50 (s, 1H), 6.45 (s, 1H), 4.75 (brs, 2H), 4.45 (m, 3H), 1.60 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 0.83 (m, 2H), 0.46 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:22][Si:23]([CH3:37])([CH3:36])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C([O-])(O)=O.[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:32]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:37])([CH3:36])[CH3:22])[N:29]=[CH:30][CH:31]=3)[C:3]=2[N:11]=[N:10]1)([O-:21])=[O:20]
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2c1nnn2Cc1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
A soluition of 7-chloro-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (306 mg, 1 mmol), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-ylboronic acid (2 mmol), Pd(PPh3)4 (100 mg) and saturated NaHCO3 (5 mL) in THF (20 mL) was refluxed for 2 h, diluted with water (20 mL), extracted with EtOAc(2×20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2:EtOAc (6:1)] to give 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 34%) as a pale yellow syrup.
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][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>C(Cl)Cl.CCN(C(C)C)C(C)C>[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][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22]([NH:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[O:23])=[CH:17][CH:16]=1
Reactant: O=C(O)/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1)NOC1CCCCO1
Reaction time: 3 h

Procedure:
A solution of (2E)-3-[5-(1,3,4,9-tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]acrylic acid in DCM (2 mL) and DIEA (0.11 mL) was sequentially treated with HOBT (32 mg), EDCI (64 mg) and NH2OTHP (40 mg). After three hours, the solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with EtOAc. (2E)-3-[5-(1,3,4,9-Tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide was obtained as a yellow oil (37 mg), m/e=438 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]([NH:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([CH3:32])([CH3:31])[CH2:15]1)=[O:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH3:40]>>[CH2:39]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]([NH:13][CH:14]1[CH2:15][C:16]([CH3:31])([CH3:32])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:21])[CH2:19]1)=[O:12])=[O:10])[CH3:40]
Reactant: CCBr
Reactant: CCCCCCCCON1C(C)(C)CC(NC(=O)C(=O)Nc2ccccc2O)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)C(=O)Nc2ccccc2OCC)CC1(C)C

Procedure:
The above-named compound is prepared by reacting the compound prepared in Example 13A with potassium carbonate and ethyl bromide.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].CC[N:17](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N.O1CCOCC1>CN(C=O)C>[CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)cnc1CC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cnc1CC(C)C
Reaction time: 2 h

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinic acid (200 mg, 0.871 mmol) and DIPEA (450 mg, 3.48 mmol) in DMF (9 mL), PyBOP (498 mg, 0.958 mmol) is added at 0° C. The mixture is stirred for 15 min before 0.5 M NH3 in dioxane (6.1 mL, 3.05 mmol) is added. Stirring is continued for 2 h at rt. The mixture is concentrated to give crude 6-isobutyl-5-methyl-nicotinamide; LC-MS: tR=0.55 min, [M+1]+=193.10. This material is dissolved in DCM (8 mL), and pyridine (430 mg, 4.43 mmol) followed by trifluoroacetic anhydride (1.25 g, 5.94 mmol) is added dropwise at 0° C. The mixture is stirred at rt for 2 h before it is diluted with DCM. The mixture is washed with a 10% aq. citric acid solution followed by a sat. aq. Na2CO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 6-isobutyl-5-methyl-nicotinonitrile (126 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+1]+=175.17; 1H NMR (CDCl3): δ 0.98 (d, J=6.8 Hz, 6H), 2.20 (hept. J=7 Hz, 1H), 2.38 (s, 3H), 2.74 (d, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[O:17][CH3:18].[CH2:19]([O:21][C:22](=[O:30])[C:23]([C:25](OCC)=[O:26])=[O:24])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1([OH:24])[C:7]2[C:2](=[C:3]([O:17][CH3:18])[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH:6]=2)[NH:1][C:25]1=[O:26])=[O:30])[CH3:20]
Reactant: COc1cc(CCNC(=O)C(F)(F)F)ccc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C1(O)C(=O)Nc2c(OC)cc(CCNC(=O)C(F)(F)F)cc21

Procedure:
2.5 g of N-[2-(4-amino-3-methoxyphenyl)ethyl]trifluoroacetamide and 1.9 ml of mesoxalic acid diethyl ester are dissolved in 25 ml of acetic acid and refluxed for 4 hours. The mixture is concentrated, the residue dissolved in ethyl acetate and extracted twice by shaking with saturated sodium bicarbonate solution. The mixture is concentrated and chromatographed on silica gel with cyclohexane/ethyl acetate 1:1, thus obtaining 2.5 g of 2,3-dihydro-3-hydroxy-7-methoxy-2-oxo-5-(trifluoroacetamidoethyl)-3-indolecarboxylic acid ethyl ester, mp 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1Br.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C.Cl>CCCCCCC.CCOCC.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:19]=[O:20]
Reactant: Fc1cc(Cl)cc(Br)c1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOCC
Product: O=Cc1c(F)cc(Cl)cc1Br
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To a solution of 1,2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to −45° C. Then, iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between −40° C. to −45° C. The mixture was stirred for 30 minutes at −40° C. before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between −45° C. to −20° C. After stirring for another 15 minutes at −20° C., it was poured into a mixture of 2N HCl (20 ml) and ether (50 ml) at 0° C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with Na2SO4 and evaporated in vacuo to obtain the title compound (7.8 g, 95%) as yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]([O:32][C:33](ON=C(C1C=CC=CC=1)C#N)=[O:34])([CH3:31])[CH3:30]>O.CC(C)=O>[C:33]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)([O:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:34]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Reaction time: 3 h

Procedure:
A suspension of 2.175 g of m-benzoyl-L-phenylalanine in 25 ml of water and 1.15 g of triethylamine was treated with 3.35 g of BOC-ON in 40 ml of acetone. After 3 h, acetone was removed and the aqueous residue was extracted three times with ether (discarded). The aqueous solution was acidified to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and stripped. The residue was triturated for 7 days with petroleum ether. The waxy insoluble solid was triturated for 14 days with an additional portion of petroleum ether and finally for 7 days with a third portion. The resulting white solid weighed 1.786 g after vacuum drying, [α]D25 +22.2±0.9°, C=0.86 g/100 ml ethanol. Anal.: Calcd. for C21H23NO5 :C, 68.28; H, 6.28; N, 3.79. Found: C, 68.01; H, 6.49; N, 3.68.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[C:8]#[N:9])[CH2:3][CH2:2]1.C(O)([C:18](F)([F:20])[F:19])=O.O(C(C)(C)C)O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:19][CH:18]([F:20])[C:13]1[N:12]=[CH:11][C:10]([CH:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:8]#[N:9])=[CH:15][N:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#CC(c1cncnc1)N1CCOCC1
Agent: CC(C)(C)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC(c1cnc(C(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
To a solution of 2-morpholino-2-(pyrimidin-5-yl)acetonitrile (1.03 g, 5.04 mmol) and DFMS (4 g, 13.61 mmol) in DCM (40 mL) and H2O (16 mL) at room temperature was added CF3COOH (575 mg, 5.04 mmol) followed by slow addition of 2-hydroperoxy-2-methylpropane (3.24 g, 70% solution in H2O) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. The reaction mixture was portioned between DCM (50 mL) and saturated NaHCO3 solution (50 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by Prep-TLC (Petroleum ether:EtOAc=10:1˜2:1) to give 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg, yield: 11.7%). 1H NMR (CDCl3 400 MHz): δ9.01 (d, J=10.0 Hz, 2H), 6.67 (t, J=54.4 Hz, 1H), 4.91 (s, 1H), 3.95-3.62 (m, 4H), 2.81-2.46 (m, 4H).
Reaction SMILES: [C:1]([NH:11][C:12](=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])SC)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]>>[C:16]([N:15]=[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: NCCCCCC(=O)O
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A methanolic (350 mL) solution of N, N'-dicarbobenzyloxy-S-methyl-isothiourea (60 g, 0.18 mol), triethylamine(18.2 g, 0.18 mol), and 6-aminocaproic acid (23.3 g, 0.18 mol) was refluxed for 30 min and subsequently stirred at room temperature for 4 h. The solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and concentrated. The residual solid was recrystallized from ethyl acetate/hexane to afford 52.3 g (66%) of the title product, mp 93° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](O)C2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 60 mg, 0.134 mmol) and (6-methylpyridin-3-yl)boronic acid (36.8 mg, 0.19 mmol) were dissolved in DME (0.5 mL). A solution of 2 M aq. NaHCO3 (0.2 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and then treated with Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol). The RM was stirred under argon at 90° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.09 min, UPLC-MS (Condition 7) m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.75 (m, 1H) 1.76-1.87 (m, 1H) 2.52 (s, 3H) 2.86 (d, J=11.73 Hz, 1H) 3.11-3.24 (m, 2H) 3.27-3.43 (m, 1H) 4.17 (br. s, br. s, 1H) 4.83 (br. s, br. s, 1H) 7.28-7.39 (m, 3H) 7.69 (dd, J=7.82, 1.96 Hz, 1H) 7.79-7.89 (m, 2H) 7.98 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).