Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:16]=1[NH2:17].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:21][C:15]=2[CH3:14])[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: Cc1cc(N2CCOCC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (630 mg), 2-methyl-4-(morpholin-4-yl)aniline (500 mg), diisopropylethylamine (900 μL), and N-methylpyrrolidone (5 mL) was stirred at 110° C. overnight. The reactant was left to be cooled, and then water was added thereto, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=8:2→5:5) to obtain 5-chloro-6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (660 mg) as an orange solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:8][C:9]=1[CH2:10][OH:11].CI.[CH3:30]COC(C)=O>CN(C=O)C.O>[NH2:3][C:4]1[N:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:8][C:9]=1[CH2:10][O:11][CH3:30]
Reactant: CCOC(C)=O
Reactant: CC(C)n1cc(-c2nc(CO)c(N)nc2-c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-bath cooling, NaH (60% pure, 18 mg) was added to a suspension of 5-[5-amino-6-(hydroxymethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (100 mg) in DMF (1.0 ml). After 10 minute stirring, MeI (127 mg) was added to the mixture. After 10 minutes stirring at the same temperature, the mixture was allowed to warm to 25° C. After 3.5 hours stirring, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography, triturated with IPE, and dried in vacuo to give 5-[5-amino-6-(methoxymethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[CH:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:18]>>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([C:1](=[O:18])[CH3:2])=[CH:4][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: C#Cc1ccc(C)nc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C)nc1
Temperature: 50 °C
Yield: 2704.3 %

Procedure:
1.0 g 5-ethynyl-2-methylpyridine (8.5 mmol) was loaded into a flask provided with magnetic anchor and was dissolved in 10 mL of a 1:4 toluene/sulfuric acid mixture (0.29 mmol). The resulting solution was heated to 50° C. overnight, then after quenching to room temperature, the solution was basified by the addition of NaHCO3, then it was extracted with AcOEt (3×20 mL) and finally, anhydrified on anhydrous MgSO4. The organic phase was then concentrated under vacuum yielding 1.06 g product, equal to a molar yield of 91% as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=12.[CH3:14][C:15]1[NH:16][CH:17]2[CH:22]([CH:23]=1)[CH:21]=[C:20]([OH:24])[CH:19]=[CH:18]2.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+].Cl>CCOC(C)=O.CO.CS(C)=O>[CH3:14][C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:24][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=13)=[CH:19][CH:18]=2
Reactant: CC1=CC2C=C(O)C=CC2N1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Temperature: 165 °C
Yield: 76.2 %

Procedure:
To a solution of 3 mL of DMSO was added 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid (0.6 g, 2.63 mmol), 2-Methyl-3a,7a-dihydro-1H-indol-5-ol (0.42 g, 2.63 mmol), MeOH (0.5 mL) and Cs2CO3 (1.7 g, 5.35 mmol) then sealed and warmed to 165° C. for 3 h and cooled to 25° C. To the reaction solution was added 50 mL of EtOAc then portioned between 50/50 NaHCO3 (50 mL). The aqueous layer was then acidified using concentrated HCl drop wise to afford 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.65 g, 76%) as a white solid. HPLC: Rt 3.62 min. (92% area). 1H NMR (DMSO-d3, 400 MHz) δ: 11.07 (1H, s), 8.45 (1H, d, J=5.3 Hz), 7.98 (1H, s), 7.23 (1H, d, J=8.9 Hz), 7.19 (1H, d, J=7.5, 3.4 Hz), 6.78 (1H, dd, J=6.3, 2.3 Hz) 6.57 (1H, d, J=5.5 Hz), 6.03 (1H, s), 2.26 (3H, s). LCMS (ACPI) M+H+ m/z: 325.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]C(CC)C.[C:31](=[O:33])=[O:32]>CCOCC.O>[CH3:15][C:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[C:31]([OH:33])=[O:32])[CH2:6][CH2:7]1)=[O:12])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)cc21
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2ccc(F)c(C(=O)O)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 6-fluoro-2,3-dihydro-1H-indole-1-carboxylate (8.7 g, 0.037 mol) in Et2O (150 mL) at −78° C. was added TMEDA (7.2 mL, 0.048 mol) and a solution of 1M sec-BuLi (44 mL, 0.044 mol) dropwise. The reaction mixture was stirred for 1 h at −78° C. and then poured onto crushed CO2 (250 mL). The mixture was allowed to warm to room temperature overnight. The suspension was diluted with water (200 mL) and diethyl ether (50 mL), and the layers were separated. The aqueous fraction was acidified with 1M HCl and extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure giving 8.0 g (77%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2OC)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a mixture of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]acetaldehyde (D103) (87.6 mg, 0.217 mmol) and ethyl 4-piperidinecarboxylate (137 mg, 0.870 mmol) in Dichloromethane (DCM) (5 mL) was added 3 drops of HOAc. The mixture was stirred at room temperature for 20 min. Then sodium triacetoxyborohydride (92 mg, 0.435 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight (16 h). The reaction was quenched with water. DCM was removed. The residue was extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to afford ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylate (D104) (38.7 mg). MS (ES): C28H34ClN3O4S requires 513.2. found 514.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[NH:10][C:11](=[O:26])[C:12]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24]O)[CH:14]=1.[N:28]1[CH:33]=CC=C[CH:29]=1.CS(OS(C)(=O)=O)(=O)=O.CNC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[NH:10][C:11](=[O:26])[C:12]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][N:28]([CH3:33])[CH3:29])[CH:14]=1
Reactant: c1ccncc1
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1ccccc1Cl
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1cc(C2=C(c3ccccc3Cl)C(=O)NC2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To a solution of Compound 1 (45 mg, 0.118 mmol) in THF (5 mL) was added pyridine (41 mg, 0.5 mmol). The mixture was stirred at room temperature for 15 min and then methanesulfonic anhydride (65 mg, 0.37 mmol) was added and the mixture was heated to 50° C. for 2 h. TLC and mass spectra showed the formation of Compound 2a. To the crude product was added excess 1.0 M solution of dimethylamine in THF (1 mL). The mixture was heated from 50 to 65° C. overnight. The solvent was concentrated in vacuo. The crude product was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated NaHCO3, brine, and evaporated in vacuo to give a crude product (50 mg). The crude product was separated by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, from 98:2:0.2 to 95:5:0.5) to give 15 mg (31%) of Compound 2 as a yellow solid. 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 8.23 (m, 1H), 7.44-7.33 (m, 4H), 6.75-6.71 (m, 1H), 6.62-6.60 (m, 1H), 4.41-4.38 (m, 2H), 2.3-2.28 (m, 2H), 2.25 (s, 6H), 2.12-2.05 (m, 2H). ES-MS m/z 409 (MH+).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2C=C(CN3CCN(C(OC(C)(C)C)=O)CC3)SC=2N=1.Cl.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[C:39]3[CH:54]=[C:53]([CH2:55][N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[S:52][C:40]=3[N:41]=[C:42]([C:44]3[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[N:48][CH:49]=3)[N:43]=2)[CH2:34][CH2:33]1.[C:62](O)(=[O:66])[C@H:63]([CH3:65])[OH:64]>>[OH:64][C@@H:63]([CH3:65])[C:62]([N:59]1[CH2:60][CH2:61][N:56]([CH2:55][C:53]2[S:52][C:40]3[N:41]=[C:42]([C:44]4[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[N:48][CH:49]=4)[N:43]=[C:38]([N:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[C:39]=3[CH:54]=2)[CH2:57][CH2:58]1)=[O:66]
Reactant: N#Cc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Reactant: C[C@H](O)C(=O)O
Agent: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(C#N)nc4)nc3s2)CC1

Procedure:
Tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 6-cyanopyridin-3-yl-3-boronic ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)pyridine-2-carbonitrile was reacted with L-Lactic acid via General Procedure B to give 7 mg of 404 after reverse phase HPLC purification. MS (Q1) 494.2 (M)+
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:9]2)[C@@H:5]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:4]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C1C(=O)N(Br)C(=[O:44])C1.Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[C:15]([O:14][C:13]([N:12]([CH3:20])[C:8]1[S:9][C@H:10]2[O:11][C@H:3]([C:2]([OH:44])=[O:1])[C@@H:4]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C@H:5]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@H:6]2[N:7]=1)=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](C(=O)O)[C@H]2OCc2ccc(OC)cc2)cc1
Yield: 58.6 %

Procedure:
A mixture of tert-butyl (3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (1 g, 1.74 mmol), KHCO3 (780 mg, 7.8 mmol), TBAB (28 mg, 0.09 mmol) and TEMPO (14 mg, 0.09 mmol) in dichloromethane (30 mL) and H2O (6 mL) was treated with NBS (620 mg, 3.5 mmol) overnight at room temperature. The reaction mixture was adjusted to acidic (pH at 3) with hydrochloric acid, and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to provide a residue, which was purified by a silica gel column, eluted with 20˜50% ethyl acetate in petroleum ether to give compound 29 as a white solid (600 mg, 58%). (ES, m/z): [M+H]+ 589.0, 1H NMR (300 MHz, CDCl3) δ 7.25-7.32 (m, 2H), 6.85-6.90 (m, 2H), 6.08-6.10 (d, J=6.3 Hz, 1H), 4.50-4.62 (m, 5H), 4.22-4.29 (m, 2H), 3.97 (m, 1H), 3.81 (s, 6H), 3.34 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: C(O[C:6](=[O:13])[CH2:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9])(C)(C)C.[Mg].C(Cl)(Cl)(Cl)Cl.[CH3:20][C:21]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:22]=1C(Cl)=O>CO.C(#N)C.C(OCC)(=O)C>[CH:10]1([C:8](=[O:9])[CH2:7][C:6]([C:22]2[C:21]([CH3:20])=[N:29][C:28]([C:30]([F:32])([F:33])[F:31])=[CH:27][CH:26]=2)=[O:13])[CH2:11][CH2:12]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)CC(=O)C1CC1
Agent: [Mg]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
14.8 g (0.080 mol) of 3-cyclopropyl-3-oxo-propionic acid tert-butyl ester are dissolved in 25 ml of MeOH and 1.93 g (0.080 mol) of magnesium are added. 7 ml of carbon tetrachloride are added dropwise while cooling in an ice bath and the reaction mixture is stirred at 22° C. for 1 hour to complete the reaction. After concentrating by evaporation, the residue is suspended in 100 ml of acetonitrile and, at 22° C., 16.31 g (0.073 mol) of 2-methyl-6-trifluoromethyl-nicotinoyl chloride (prepared in the manner described in Example P1), dissolved in 50 ml of acetonitrile, are added dropwise. After 6 hours, the reaction mixture is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The separated ethyl acetate phase is washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in 160 ml of methylene chloride and 10 ml of trifluoroacetic acid are added dropwise at 22° C. After 18 hours, the reaction mixture is poured into water and extracted with methylene chloride. The methylene chloride phase is washed with water and then with brine, dried over sodium sulfate and concentrated by evaporation. 17.3 g (88% of theory) of 1-cyclopropyl-3-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-propane-1,3-dione are obtained in the form of an oil, which can be used further without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](=[O:11])[O:23][C:20]2[CH:21]=[CH:22][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: COc1cccc(N(C)C(=O)Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cccc(N(C)C(=O)Oc2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 2.01 g of N-(6-methoxy-2-pyridyl)-N-methylcarbamoylchloride, 1.36 g of 4-isopropylphenol, and 1.38 g of anhydrous potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using benzene as an eluent to give 2.56 g of pure 4-isopropylphenyl N-(6-methoxy-2-pyridyl)-N-methylcarbamate as solid in the yield of 85%. A part of the solid was recrystallized from hexane and crystals having melting point of 64° to 65° C. were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:48][O:49][C:50](=[O:55])[C:51]([NH2:54])([CH3:53])[CH3:52]>CN(C=O)C.O>[CH3:48][O:49][C:50](=[O:55])[C:51]([NH:54][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)([CH3:53])[CH3:52]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.2 %

Procedure:
DIPEA (407 mg, 0.28 mL, 3.15 mmol) was added to a stirred solution of 4-benzyloxy-benzoic acid (200 mg, 0.87 mmol)(prepared by the method as described above) in DMF (2 mL). HOBT (142 mg, 1.05 mmol) and EDCI (201 mg, 1.05 mmol) were then added at room temperature. After 2 minutes, 2-amino-2-methyl-propionic acid methyl ester (161 mg, 1.05 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 200 mg (70% yield) of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid methyl ester. LCMS Purity: 93%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].[O:34]1[CH2:36][CH2:35]1>C(Cl)Cl>[OH:34][CH2:35][CH2:36][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: C1CO1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CCO)CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a sealed tube charged with a magnetic stir bar was added (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (Compound 326) (0.1 g, 0.229 mmol) was added DCM (3 mL) and the reaction cooled to 0° C. To the cooled reaction mixture was added oxirane which was condensed into the reaction vial (˜1 mL). The reaction was allowed to stir to rt over 4 h and was then conc. in vacuo to afford the crude material which was purified via silica gel chromatography (12 g) using ethyl acetate/MeOH (4:1) as eluent to afford the title compound as a white solid (50 mg). LCMS 481 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ) δ 11.58 (s, 1 H), 7.77-7.65 (m, 2 H), 7.59 (d, J=7.8 Hz, 1 H), 7.11-6.99 (m, 2 H), 6.14 (s, 1 H), 4.54-4.44 (m, 1 H), 4.31 (d, J=5.1 Hz, 3 H), 4.13 (dd, J=7.1, 10.3 Hz, 1 H), 3.83 (s, 3H), 3.42 (q, J=6.0 Hz, 2 H), 2.93 (br. s., 1 H), 2.71-2.56 (m, 4 H), 2.31 (br. s., 2 H), 2.19 (s, 3 H), 2.03-1.83 (m, 2 H), 1.64 (br. s., 1 H), 1.53 (d, J=6.9 Hz, 3 H), 1.32 (d, J=11.1 Hz, 1 H), 1.02 (d, J=10.3 Hz, 1 H), 0.65 (d, J=11.8 Hz, 1 H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:50])[C@@H:14]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([Br:49])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:15][NH:16][C:17]1[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)(C)(C)C>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:17]([NH:16][CH2:15][C@H:14]([NH:39][S:40]([C:43]2[CH:44]=[CH:45][C:46]([Br:49])=[CH:47][CH:48]=2)(=[O:42])=[O:41])[C:13]([OH:50])=[O:12])[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=1
Reactant: Cc1nc(NC[C@H](NS(=O)(=O)c2ccc(Br)cc2)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2ccc(Br)cc2)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 ml of TFA were added to a solution of 70 mg of (2S)-3-(2-methyl-7-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(4-bromobenzenesulfonylamino)-propionic acid tert-butyl ester (example 5b) in 5 ml of DCM and stirred for 2 h at room temperature. Solvent and TFA were removed in vacuo, the residue was lyophilized from AcOH/H2O (1:1). Yield: 76 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][C:6]1([CH2:19][OH:20])[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1>O1CCOCC1>[F:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][C:6]1([CH2:19][OH:20])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)(Cc2ccccc2F)C1
Agent: Cl
Solvent: C1COCCO1
Product: OCC1(Cc2ccccc2F)CCCNC1
Reaction time: 4 h

Procedure:
Hydrochloric acid in dioxane (1.5 mL, 4M) was added to a flask containing tert-butyl 3-(2-fluorobenzyl)-3-(hydroxymethyl)piperidine-1-carboxylate (0.43 g, 1.33 mmol). 1,4-dioxane (1.5 mL) was added to the reaction mixture. The reaction was allowed to stir for 4 hours. Upon reaction completion, the reaction was concentrated, and 346 mg of crude product was recovered and progressed to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>O>[N:1]([C:2]1[C:9]([Br:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH:4]=[O:5])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Br)cc(Cl)cc1C=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1c(Br)cc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-3-bromo-5-chlorobenzaldehyde (3.0 g, 12.8 mmol) in a water (4 mL) and hydrochloric acid (4 mL) mixture at 0° C. was added a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (ca. 2 mL) dropwise. After 30 min, the ice bath was removed and the reaction stirred at room temperature for 30 min forming a white suspension. The solids were removed by filtration. The mother liquor was cooled to 0° C. and treated with sodium azide (0.8 g, 12.8 mmol) in water (2.0 mL). The ice bath was removed and stirring was continued for 30 min. The resulting solid was collected by filtration and dried in vacuo for several hours to afford 2.6 g (76%) as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H).