Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:25][CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.O>[N:35]([C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:25][CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])=[N+:36]=[N-:37]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OS(C)(=O)=O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)N=[N+]=[N-])n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 50 °C
Reaction time: 42 h
Yield: 75 %

Procedure:
To a microwave vial containing (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol) in DMF (1 mL) was added sodium azide (13 mg, 0.20 mmol). Resulting reaction mixture heated to 50° C. for 1 hr in a sand bath then to 80° C. for 42 hr. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with brine, dried (Na2SO4), filtered and concentrated to a yellow residue of (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.030 mmol, 74.2% yield). LCMS m/z 471.2 (M+H)+, Rt 0.92 min.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.CCOCC>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCCCCOC1CCCCO1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(CCCCCCOC1CCCCO1)C(=O)OCC
Temperature: 60 °C

Procedure:
Sodium (1.13 g, 49 mmol) in small quantities was dissolved in dry ethanol (100 ml) with constant stirring under a blanket of dry nitrogen. Diethyl malonate (8.0 g, 50 mmol) was added in one portion and the solution heated at 60° C. for 1 hour. 2-(6-Chloro-hexyloxy)-tetrahydropyran (9.3 g, 42.2 mmol) was added in one portion and the temperature raised to 75-80° C. and maintained at this level for 24 hours. After cooling, the inorganic solid was removed by filtration and solvent evaporated from the filtrate. The residue was dissolved in CH2Cl2 (50 ml), extracted with water (30 ml×2), dried (MgSO4) filtered and volatiles removed to leave a pale yellow oil. This oil was subject to chromatography on silica gel using pet ether 40:60/ether (200:40) as the eluent. The required product eluted with an rf=0.15 and was isolated as a colourless oil. Yield 8.7 g, (60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>O1CCCC1>[CH:19]1([CH2:18][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (81.7 mg, 0.26 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) and nicotinoyl chloride hydrochloride (47 mg, 0.26 mmol). The resulting reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded N-{4-[2-cyclopentyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C25H26N4O2 (M+) 414.2055, found 414.2056.
Reaction SMILES: [CH:1]1([C@@H:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:33][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([C@@H](C(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C

Procedure:
3.0 g (10.93 mmol) of tert-butyl(2S)-cyclopentyl-(4-methylphenyl)acetate were heated to reflux in 20 ml of chloroform, and 90 mg (0.55 mmol) of 2,2′-azobis(2-methylpropanenitrile) and 2.72 g (15.31 mmol) of N-bromosuccinimide were then added in 5 portions every 30 min. The mixture was stirred under reflux for 6 h and then cooled to RT and concentrated on a rotary evaporator. The residue was purified by chromatography on 120 ml of silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 2.8 g (72% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[CH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]=2[N:21]=[CH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21

Procedure:
2′-O-Nonyladenosine was treated with benzoyl chloride in a manner similar to the procedure of B. L. Gaffney and R. A. Jones, Tetrahedron Lett., Vol. 23, p. 2257 (1982). After chromatography on silica gel (ethyl acetate-methanol), the title compound was obtained. Analysis for: C26H35N5O5. Calculated: C, 62.75; H, 7.09; N, 17.07. Found: C, 62.73; H, 14.07; N, 13.87.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].CCN(C(C)C)C(C)C.O>O1CCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Yield: 78.8 %

Procedure:
A solution of 4-Fluoro-3-nitro-aniline (2.00 g, 12.8 mmol), 3-Trifluoromethyl-benzoyl chloride (1.895 mL, 12.8 mmol), Hunig's base (4.463 mL, 25.6 mmol) in tetrahydrofuran (50 ml) was stirred at room temperature for 1 hour. Afterwards water (450 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound (3.311 g, 97%).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]2[CH:31]=[CH:32][C:33]([CH2:37][CH3:38])=[C:34]([Pb+3])[CH:35]=2)=[CH:28][CH:27]=1.C(Cl)(Cl)Cl.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]2[CH:35]=[CH:34][C:33]([CH2:37][CH3:38])=[C:32]([CH:4]3[C:3](=[O:12])[CH:2]4[CH:6]([CH:7]5[O:10][CH:1]4[CH:9]=[CH:8]5)[C:5]3=[O:11])[CH:31]=2)=[CH:28][CH:27]=1
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 40 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (1.7 g, 0.01 mol), 4-dimethylaminopyridine (5.0 g, 0.04 mol) and 4′-chloro-4-ethylbiphen-3-yllead triacetate (9.2 g, 0.015 mol) under an atmosphere of nitrogen is added dry chloroform (50 ml)). The reaction mixture is heated at 40° C. for 5 hours, then cooled to room temperature. The mixture is diluted with ethyl acetate (50 ml), acidified with 2N aqueous hydrochloric acid (50 ml), and the mixture is filtered to remove solids. The filtrate is poured into a separating funnel and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-ethylbiphen-3-yl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:24]([CH3:25])=[N:23][N:22]([CH3:26])[C:18]2=[N:19][C:20]=1Cl)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[O-]CCCC.CC(C)([O-])C.[K+].[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:24]([CH3:25])=[N:23][N:22]([CH3:26])[C:18]2=[N:19][C:20]=1[NH:51][CH2:50][CH:47]1[CH2:49][CH2:48]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: NCC1CC1
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2nc(NCC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.5 g, 0.9 mmol), potassium-tert-butoxide butoxide (0.43 g, 3 mmol), cyclopropylmethyl amine (0.275 g, 3 mmol), and Pd(OAc)2 (0.01 g, 0.004 mmol), BINAP (0.03 g,0.04 mmol) was prepared in a 10 mL pressure vial. The pressure vial was placed in the focused microwave oven (CEM Discovery) and irradiated for 20 min at 110° C. by using 250 Watt microwave power. After this mixture was cooled to RT, ethyl acetate (100 mL) was added to the vial. The organic layer was washed with water (3×100 mL) and dried and concentrated. The resultant oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 10% ethyl acetate in hexane afforded a colorless solid (0.485 g, yield: 90%).
Reaction SMILES: Cl.Cl.Cl.[Br:4][C:5]1[C:6]([C:22]2[S:26][C:25]3[C:27](OC)=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[N:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:9][CH:10]=1.[Cl:33]C1C2SC=CC=2C=CC=1>>[Br:4][C:5]1[C:6]([C:22]2[S:26][C:25]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[N:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: Clc1cccc2ccsc12
Reactant: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)sc12
Agent: Cl
Product: CN1CCN(CCCNc2ncc(Br)c(-c3cc4cccc(Cl)c4s3)n2)CC1

Procedure:
Using the methods of [5-bromo-4-(7-methoxybenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is synthesized from 7-chloro-benzo[b]thiophene and isolated as a solid. ES+(m/z) 480 (35Cl, 79Br), 482 (37Cl, 79Br or 35Cl, 81Br) and 484 (37Cl, 81Br) [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[S:20][C:21]([N+:24]([O-])=O)=[N:22][N:23]=2)[CH:3]=1>CCO.O.Cl>[NH2:24][C:21]1[S:20][C:19]([O:18][C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=3[CH:5]=2)=[N:23][N:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(Cl)c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(Cl)c21
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)acetate (430 mg, 1.08 mmol) in EtOH (15 mL) and H2O (5 mL) was added 2 drops of conc. HCl and the mixture was heated to reflex for 2 h. Upon cooling, the reaction mixture was filtered and the EtOH was removed under the reduced pressure and the residue was extracted with EtOAc (3×10 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil (330 mg). MS (ESI) m/z=370 [M+H]+.
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:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 279.1) and pyrimidin-5-ylboronic acid to afford a white resinous powder. HPLC (Condition 4) tR=4.41 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.93 (m, 2H) 2.91 (d, J=11.34 Hz, 1H) 3.20-3.44 (m, 3H) 4.22 (br. s, 1H) 4.90 (d, J=3.52 Hz, 1H) 7.81 (d, J=8.60 Hz, 1H) 8.07-8.16 (m, 1H) 8.29-8.38 (m, 1H) 8.80-8.85 (m, 1H) 8.90 (s, 2H) 8.95-9.03 (m, 1H) 9.17-9.24 (m, 1H) 10.44 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.B([O-])([O-])O[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:2]2[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)/C=C/c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(-c2ccc(C(C)(C)C)cc2)s1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Under argon atmosphere, a solution of methyl (E)-3-(5-bromothiophen-2-yl)acrylate (0.23 g), 4-tert-butylphenyl borate (0.3 g) and potassium carbonate (0.26 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphine palladium (32 mg), and the mixture was refluxed for 18 hours and then cooled to room temperature. To the organic layer was added ethyl acetate, and the mixture was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:9) to give pale yellow crystals of methyl (E)-3-[5-(4-tert-butylphenyl)thiophen-2-yl]acrylate (240 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].C(O)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@@H:9]3[NH:8][CH:3]=[O:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=CN[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
N-[(1S,2S)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 9, 240 mg, 05 mmol), formic acid (50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for 1 hr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc:Hexane) to afford the title compound (180 mg, 97%) as a white foam.
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CN(C)C=O>[F:1][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [F-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 110 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Cesium fluoride (499.02 g, 3.19 mol) was added into a flask equipped with a stirrer under a nitrogen gas stream, and was agitated for one hour at 110° C. Methyl 2-chloro-3-nitrobenzoate (229.00 g, 1.06 mol) and N,N-dimethylformamide (2000 ml) were added thereto, and the reaction mixture was agitated for one hour at 140° C. The reaction mixture was naturally cooled to room temperature, and then was filtered, and the filtrate was concentrated under reduced pressure. The concentration residue was poured into water and agitated for a while, and then a solid that precipitated was collected by filtration and dried under reduced pressure. As a result, 160.03 g (yield: 76%) of the indicated compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1/[CH:37]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrole-2-carbaldehyde (166 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@@H:10]1[O:20][CH2:21][CH:22]=[CH2:23])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@@H:10]1[O:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl (3S,4R)-4-[(tert-butoxycarbonyl)amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 17, 5 g, 12.7 mmol) was dissolved in dichloromethane (200 mL) and trifluoroacetic acid (9.79 mL, 127 mmol) was added. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was basified with saturated sodium bicarbonate solution (pH ˜8) and the layers were separated. The aqueous layer was extracted with dichloromethane; organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2.7 g (93.24%). MS (ES) (M+H): 228. for C11H20N2O3.
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].[C:45]([O:49][C:50]([NH:52][C:53]1[CH:57]=[CH:56][O:55][C:54]=1[C:58]([OH:60])=O)=[O:51])([CH3:48])([CH3:47])[CH3:46].Cl>CN(C=O)C>[NH2:4][C:58]([C:54]1[O:55][CH:56]=[CH:57][C:53]=1[NH:52][C:50](=[O:51])[O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:60]
Reactant: CC(C)(C)OC(=O)Nc1ccoc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccoc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
Diisopropylethylamine (14.75 mL) was added to a suspension of PyBOP (10.4 g), ammonium chloride (1.81 g) and 3-[(tert-butoxycarbonyl)amino]-2-furoic acid (Intermediate 81) (3.83 g) in DMF (50 mL). The resulting mixture was stirred at ambient temperature for 90 minutes, poured into 0.4 M HCl (250 mL) and extracted into DCM (3×100 mL). The combined organics were washed with water (80 mL) and brine (80 mL), dried (MgSO4), and evaporated The product was purified by flash chromatography on silica, eluting with 20-70% EtOAc in isohexane to afford the title compound as a white solid (3.38 g, 89%);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([CH3:19])[C:11]=1[O:17][CH3:18]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 70 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
To 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (1.09 g, 4.19 mmol, 1.1 eq) was added SOCl2 (10 mL, 12.6 mmol, 3.0 eq). The reaction was heated to 70° C. and stirred for 6 h, then the solvent was removed. The residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (0.405 g, 2.8 mmol, 1.0 eq) and NaHCO3 (1.17 g, 13.9 mmol, 5 eq) in THF (8 mL) at 0° C. The reaction was warmed to room temperature, stirred for 2 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine dried (Na2SO4) and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as a white solid (209 mg, 19%).