Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[C:15]=3[F:23])[N:12]=[N:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:8][C:5]1[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[C:15]=3[F:23])[N:12]=[N:11][N:10]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: COc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O)c(F)c1F
Temperature: 0 °C
Reaction time: 48 h

Procedure:
As shown in step 4-i of Scheme 4,5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1005, 20.0 g, 7.663 mmol) in 150 mL of DCM was cooled 0° C. Boron tribromide (20.0 mL of a 1M solution in DCM, 20 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 48 hours. The reaction was carefully quenched with crushed ice and extracted with EtOAc (3×200 mL). The combined organics were washed with water, washed with brine, and dried over sodium sulfate. After filtration, the volatiles were removed under reduced pressure to yield a brown solid, which was triturated with pentane to yield 4-(5-(2-amino-5-bromopyridin-3-yl)-1H-tetrazol-1-yl)-2,3-difluorophenol (Compound 1016) as a pale brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43][N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCOCC4)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
To a solution of Intermediate 121a (0.07 mmol) in THF (2 mL) was added DIPEA (50 μL, 0.29 mmol) and morpholine (25 μL, 0.29 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by MDAP (Method 7) purification, to give the title compound (19 mg, 39%). LCMS (Method 5): Rt 3.65 min, m/z 670 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.56 (3H, d, J=6.2 Hz), 0.59 (3H, d, J=6.2 Hz), 1.16 (9H, s), 1.37-1.55 (3H, m), 1.63-1.69 (2H, m), 1.73-1.79 (1H, m), 1.85-2.00 (2H, m), 2.04-2.10 (2H, m), 2.34 (4H, t, J=4.5 Hz), 2.57 (2H, t, J=7.2 Hz), 3.09-3.19 (2H, m), 3.50 (4H, t, J=4.5 Hz), 3.95 (2H, t, J=7.2 Hz), 4.82 (1H, td, J=8.6, 5.7 Hz), 5.50 (1H, t, J=4.2 Hz), 5.99 (1H, s), 6.92 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.8, 2.3 Hz), 7.20-7.26 (1H, m), 7.30-7.36 (3H, m), 7.62 (1H, dd, J=9.7, 0.6 Hz), 7.86 (1H, d, J=2.1 Hz), 8.19 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][C:26]#[CH:27]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][C:26]#[CH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C#CCNC
Product: C#CCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Methyl-prop-2-ynyl-amine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl-methyl-prop-2-ynyl-amine as light yellow oil, MS: 429(MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[CH:4][CH:3]=1>Cl.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(N[C@H]3CCNC3)n2)[nH]1
Yield: 241.9 %

Procedure:
A solution of (S)-tert-butyl 3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (130 mg, 0.30 mmol) in 4M HCl/EtOAc (4 mL) was stirred at RT for 50 minutes. The reaction mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound (120 mg). ESI-MS m/z [M+H]+ 331.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16](=[O:19])[CH2:17][CH3:18])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CCC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to Example 90, from 1-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-butan-2-one (example 203, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 24 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (with 0.05% formic acid) (80:20 to 98:2). Light red foam (13%). MS (ESI): m/z=539.126 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.Br[C:22]1[CH:23]=[C:24]2[N:33]([CH3:34])[CH:32]=[CH:31][C:25]2=[N:26][C:27]=1[C@@H:28]([NH2:30])[CH3:29]>O1CCOCC1>[NH2:30][C@H:28]([C:27]1[N:26]=[C:25]2[CH:31]=[CH:32][N:33]([CH3:34])[C:24]2=[CH:23][C:22]=1[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)[CH3:29]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a suspension of potassium tert-butoxide (44.2 mg, 0.394 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (79 mg, 0.394 mmol) in dioxane (2 mL), was added dropwise at 90° C., a solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (50 mg, 0.197 mmol) in dioxane (1 mL). After 2 hours LCMS showed the reaction was complete. The volatiles were removed by nitrogen flow. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([O:23]CC)=O)=[C:6]2[CH2:20][CH2:19][C:9]3[N:10]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:12][C:8]=3[C:7]=12.[NH3:26].O>CO.O1CCCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:20][CH2:19][C:9]3[N:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:12][C:8]=3[C:7]=12
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1nc(-c3ccccc3)[nH]c1-2
Reactant: N
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1sc(C(N)=O)c2c1-c1[nH]c(-c3ccccc3)nc1CC2
Yield: 14 %

Procedure:
A mixture of ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxylate (0.50 g), a 10% (w/w) ammonia solution (30 ml) in methanol and tetrahydrofuran (30 ml) was heated in a sealed tube at 100° C. for 3 days. The reaction mixture was poured over water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxamide (65 mg, 14%), which was then recrystallized from ethanol. Colorless prisms. Melting point 206-207° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc([N+](=O)[O-])cc32)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(N)cc32)n1
Yield: 18.1 %

Procedure:
10% Palladium-carbon (18 mg, manufactured by Merck Chemicals, Ltd.) was added to a solution of ethyl 2-(6-nitro-3-phenyl-1H-indazol-1-yl)thiazole-4-carboxylate (234 mg), which had been synthesized from the compound of Reference Example 24 according to the method of Example 3, in methanol (20 mL manufactured by Wako Pure Chemical Industries, Ltd.) at room temperature, and the mixture was stirred overnight in a hydrogen atmosphere. After completion of the reaction, the 10% palladium-carbon was removed by filtration, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4), to give 39.1 mg of the title compound. LC-MS: HPLC retention time 1.95 minutes, m/z 365 (M+H), condition C-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CO.O>C1COCC1>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:2]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: c1cnc2ccsc2c1
Temperature: -78 °C
Yield: 62.7 %

Procedure:
Dissolve 7-bromo-thieno[3,2-b]pyridine (3.69 g, 17 mmol) in dry THF (20 mL) and cool to −78° C. Add n-BuLi (1.6 M in hexane, 21.2 mL, 34 mmol) slowly to the mixture at −78° C. and stir at −78° C. for 20 min. Add MeOH/H2O=1/1 (20 mL) and stir at room temperature for 1 h. Extract the reaction mixture with CH2Cl2. Wash the organic portion with saturated NaCl solution, dry over Na2SO4, and evaporate. Purify the resulting residue using silica gel chromatography, eluting with 100% hexane to hexane:ethyl acetate=10:1 to give the title compound (1.44 g, 62%). ES/MS m/z 136 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.C(Cl)(C(Cl)=O)=O.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[CH:12]=[CH:13]/[C:14]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:16]
Reactant: O=C(O)/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl
Reactant: NCCCCCCO
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl)NCCCCCCO
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A suspension of the acid (284 mg, 0.87 mmol) from Example 1B in 5 mL of methylene chloride was stirred with (COCl)2 (84 μL, 0.97 mmol), and one drop of DMF under nitrogen atmosphere for 90 minutes. The solvent was then removed under vacuum. The residue (COCl)2 was removed with benzene (2×) in vacuo. To a separate flask, previously filled with 6-amino-1-hexanol (12 mg, 0.10 mmol), Hunig's base (22.8 μL, 0.13 mmol) and DMAP (1.1 mg, 0.008 mmol) in 2.0 mL of CH2Cl2, the acid chloride (30 mg, 0.087 mmol) in 1.0 mL of CH2Cl2 was then dropped in slowly. After 30 minutes, the reaction mixture was poured into 3N HCl and extracted with ethyl aceetate (EtOAc). The organic layer was washed with brine, dried with Na2SO4, condensed under reduced pressure. The crude product was purified by preparative TLC to give 21.0 mg (90%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.31-1.48 (m, 4H), 1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 5.63 (br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H), 7.05 (dd, J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1, 7.5 Hz, 1H), 7.99 (d, J=15.9 Hz, 1H). MS (DCI/NH3) (M+NH4)+ at m/z 441, 443, 445.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:18])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:6]=1.CC(C)=[O:21]>O>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]=[C:5]([NH:6][C:2](=[O:21])[CH3:1])[C:4]([OH:3])=[O:18])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(=O)Oc1ccc(C=C2N=C(C)OC2=O)cc1
Solvent: O
Product: CC(=O)NC(=Cc1ccc(OC(C)=O)cc1)C(=O)O

Procedure:
75.8 g (0.3 mol) of 2-methyl-4-(p-acetoxy-benzylidene)-5(4H)-oxazolone are dissolved in a mixture of 725 ml of acetone and 281 ml of water and thereafter the solution is heated to the boil, under a reflux condenser, for 15 hours. Hereupon, a yellowish precipitate separates out. The reaction mixture is cooled and then filtered. The resulting crystals are recrystallised from acetone-water. p-Acetoxy-α-acetylaminocinnamic acid of melting point 236°-237° C. is obtained.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:11]=[C:5]([NH:4][CH2:3][C:2](=[O:1])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)NCC(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of ethyl 2-(2-hydroxypropylamino)-2-oxoacetate (2.1 g, 13 mmol) in DCM (30 mL) was added Dess-Martin periodinane (6.2 g, 14.6 mmol) in portions at 0° C. and the resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with DCM and extracted with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried and concentrated to give crude product, which was purified via silica gel chromatography eluting with DCM/methanol (60:1) to give ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 81.2% yield) as yellow syrup. LCMS retention time 0.392 min, LCMS MH+ 174.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1(C2CCNCC2)C[CH2:35][CH2:34]1>>[N:8]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-azetidin-1-yl piperidine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (97 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[C:27]1([CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: O=C=NCCc1ccccc1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)NCCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and 2-phenylethyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CDCl3) δ 196.5, 159.2 (dd), 156.0, 155.6 (dd), 148.1, 139.6, 138.9, 136.5, 135.1, 133.9, 132.2, 131.9, 128.7, 128.5, 126.4, 124.6 (dd), 124.2 (dd), 123.1, 121.1, 116.2, 112.7, 111.6 (dd), 104.9 (dd), 41.5, 36.3, 19.6
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C@H:13]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:25])[CH3:2].[Cl:27]N1C(=O)CCC1=O>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:11]([Cl:27])=[CH:10][N:9]=[C:8]([NH:12][C@H:13]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]1=[O:25])[CH3:2]
Reactant: CCOC(=O)Cn1ccnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (5.8 g, 16.3 mmol) in dichloroethane (90 ml) was added N-chlorosuccinimide (2.17 g, 16.3 mmol) and the reaction mixture was stirred at 85° C. for 1 h 30 and at room temperature for 18 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% diethyl ether in hexane to 45%) to give (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a thick syrup. 1H NMR (CDCl3, 400 MHz): δ 7.38–7.20 (m, 5H); 6.85 (s, 1H); 6.10 (bd, J=8.8 Hz,1H); 4.92 (A of AB, d, J=17.7 Hz, 1H));); 4.86 (B of AB, d, J=17.7 Hz, 1H)); 4.40–4.30 (m, 1H); 4.25 (q, J=7 Hz, 2H); 3.52 (A of ABX, dd, J=12.4, 4.6 Hz, 1H); 3.40 (B of ABX, dd, J=12.4, 4.6 Hz, 1H); 3.00 (A of ABX, dd, J=13.5, 6.4 Hz, 1H); 2.92 (B of ABX, dd, J=13.5, 7.4 Hz, 1H); 1.29 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([N:10]=[C:11]=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]>ClCCCl.N1C=CC=CC=1>[C:5]([NH:10][C:11]([NH:4][C:1](=[O:3])[CH3:2])=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CC(N)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)NC(C)=O
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of acetamide (0.59 g; 10 mmol) in 1,2-dichloroethane (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (10 ml) was dropwise added. After completion of the addition, pyridine (5 drops) was added to the solution, and then stirring was continued at room temperature for 12 hours. 1,2-Dichloroethane was evaporated under reduced pressure to give 1-methacryloyl-3-acetylurea (1.36 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 92°-94° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[S:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[S:23][CH:24]=[N:25][CH:26]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Reactant: c1cscn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncs1
Temperature: 130 °C
Reaction time: 60 h

Procedure:
3-Iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1, 100 mg, 0.237 mmol), thiazole (60 mg, 0.712 mmol), KOAc (69.9 mg, 0.712 mmol) and Pd(OAc)2 (0.267 mg, 1.187 μmol) were added to a vial, which was sealed, evacuated/purged with argon. DMA (720 μL) was added and the RM was stirred at 130° C. for 2.5 days. The RM was diluted with THF (3 mL), stirred overnight with Si-Thiol (1.44 mmol/g, 16.49 mg, 0.024 mmol) and filtered. The filtrate was treated with 2 M HCl (40 mL) and extracted with TBME. The combined extracts were washed with 1 M HCl, sat. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 10% to 15% in 2.4 min) to afford the title compound as a colorless solid. UPLC-MS (Condition 2) tR=1.18 min, m/z=379.2 [M+H]+, m/z=377.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 7.37 (d, J=8.31 Hz, 2H) 7.54 (d, J=8.07 Hz, 1H) 7.86-7.91 (m, 2H) 7.93 (dd, J=7.82, 1.96 Hz, 1H) 8.02 (d, J=1.96 Hz, 1H) 8.10 (d, J=0.73 Hz, 1H) 9.23 (d, J=0.73 Hz, 1H) 10.43 (s, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D47) (195 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E21) (78 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 4.99 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.55 (1H, d), 7.90 (1H, dd), 8.47 (1H, dd), 8.70 (1H, d), 11.12 (1H, s), 12.15 (1H, br s). δF (DMSO-d6, 376 MHz): −118.0. MS (ES): C23H19FN4O4 requires 434; found 435.1 (M+H+).