Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][C:4]=1[C:5]([O:7]C)=O)=O.[NH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][N:19]=1.[C:25]([N+:29]#[C-])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:24][C:22]1[CH:21]=[CH:20][N:19]2[C:18](=[N:17][C:1]3[C:3]4[C:4](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][C:12]=4[O:13][CH3:14])[C:5](=[O:7])[NH:29][C:25]=32)[CH:23]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: COC(=O)c1cc(OC)cc(OC)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(OC)c2c(c1)c(=O)[nH]c1c2nc2cc(Cl)ccn21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under argon, methyl 2-formyl-3,5-dimethoxybenzoate (200 mg, 0.89 mmol) and 2-amino-4-chloropyridine (115 mg, 0.89 mmol) were dissolved in methanol (5 ml), after 5 minutes of stirring at room temperature tert-butylisonitrile (89 mg, 1.07 mmol) was added and after a further 10 minutes of stirring at room temperature 4-toluenesulphonic acid monohydrate (8 mg, 0.05 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 6 h and subsequently concentrated under reduced pressure and taken up in 4 ml of trifluoroacetic acid. The mixture obtained in this manner was stirred at 50° C. for 3 h and then concentrated again, ethanol and water were added to the resulting residue and the pH was then adjusted to 8 using saturated sodium bicarbonate solution. Drying and removal of the resulting precipitate by filtration gave 10-chloro-1,3-dimethoxypyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one in the form of a light-yellow solid (70 mg, 22% of theory). 1H-NMR (400 MHz, d6-DMSO δ, ppm) 13.20 (br. s, 1H, NH), 8.83 (d, 1H), 8.02 (s, 1H), 7.49 (m, 1H), 7.39 (d, 1H), 7.15 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:49]([NH:51][CH3:52])[CH3:50].[C:53]([O:56][BH-](OC(=O)C)OC(=O)C)(=[O:55])C.[Na+].O>C(Cl)Cl>[CH:53]([OH:56])=[O:55].[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:51]([CH2:49][CH3:50])[CH3:52])=[CH:12][CH:11]=2)[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: CCNC
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 176b (0.188 mmol) and N-ethylmethylamine (32.3 μL, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added and the mixture extracted with DCM. The combined organics were passed through a phase separator and concentrated to dryness. The resulting residue was purified by RP-HPLC (C18, 18 mL/min, 20-85% MeCN in H2O+0.1% HCO2H) and the relevant fractions combined and concentrated to dryness. The title product was isolated as an off white solid (26.1 mg). LCMS (Method 5): Rt 3.65 min, m/z 690.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.02 (3H, t, J=7.1 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.74-1.97 (4H, m), 1.98-2.11 (2H, m), 2.12 (3H, s), 2.40 (2H, q, J=7.1 Hz), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent), 3.49 (2H, s, obscured by solvent), 4.81 (1H, m), 5.51 (1H, t, J=4.6 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.6, 2.1 Hz), 7.24-7.47 (8H, m), 7.64 (1H, d, J=10.2 Hz), 7.69 (1H, d, J=1.6 Hz), 8.09 (1H, s), 8.17 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.0 g 4-((S)-3-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 1.242 ml benzyl bromoacetate and 4.884 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:8]1([CH3:28])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: O=O.[CH3:3][C:4](C)([O-])C.[K+].[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C(I)C>C1COCC1.O>[CH2:3]([CH:10]([C:11](=[O:12])[CH3:13])[C:9]([O:15][CH3:16])=[O:14])[CH3:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(C)=O)C(=O)OC
Reaction time: 1 h
Yield: 60 %

Procedure:
Under nitrogen atmosphere free of water and oxygen, to a three-necked flask equipped with a dropping funnel were successively added 0.15 mol of potassium tert-butoxide and 150 ml of THF, then stirrer was started. 0.12 Mol of methyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath. Upon completion of the dropping, the reaction was continued at room temperature for further 1 hr. Then 0.18 mol of ethyl iodide was slowly dropped at room temperature, and then the reaction was heated to reflux for 6 hrs. At the end of the reaction, solvent was evaporated by using a rotatory evaporator, and saturated saline was added to just dissolve the solid. Organic phase was separated, and aqueous phase was extracted with a suitable amount of diethyl ether for three times. The combined organic phase was washed well with saturated saline, then dried over anhydrous sodium sulfate. Solvent was removed by using a rotatory evaporator, and the residue was distilled under reduced pressure to give 0.072 mol of product. Yield 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=O)[CH2:13][CH2:12]1.[NH2:21][NH2:22].O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:21][NH2:22])=[O:19])[CH2:13][CH2:12]1
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 90.9 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:7]=1[Cl:23]>CO.O1CCCC1>[Cl:23][C:7]1[CH:8]=[C:9]([CH:12]([OH:22])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:10]=[CH:11][C:6]=1[C:5]([OH:24])=[O:4]
Reactant: COC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(O)C=Cc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
An aqueous solution of sodium hydroxide (1N, 3 mL, 3 mmol) was added to a solution of 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid methyl ester (Example 92; 310 mg, 0.97 mmol) in methanol/tetrahydrofuran (1:1; 6 mL). The solution was stirred at room temperature overnight and then evaporated to dryness. Water (4 mL) was added and the solution was acidified with 1N hydrochloric acid solution (3.3 mL). The mixture was stirred at room temperature for 1 h, then the solid was filtered off, washed with water and dried to afford 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid (243 mg, 82% yield) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:3]1=O.[NH2:26][OH:27].[OH2:28]>CS(C)=O>[OH:27][N:26]=[C:11]([C:6]1[C:5]2[C:4]3([C:24]4=[CH:23][C:18]5[O:19][CH2:20][CH2:21][O:22][C:17]=5[CH:16]=[C:15]4[O:14][CH2:13]3)[C:3](=[O:28])[N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: O
Reactant: NO
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C#N)cccc21
Solvent: CS(C)=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(N)=NO)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile (0.35 g, 1.05 mmol) in dimethylsulfoxide (10 mL) was added hydroxylamine (50% w/w solution in water, 3.0 mL). The reaction mixture was stirred for 16 h at ambient temperature, poured into water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes to afford N′-hydroxy-1′-methyl-2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-4′-carboximidamide (0.37 g) as a colorless solid. To a 10 mL microwave reaction vessel were added N′-hydroxy-1′-methyl-2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-4′-carboximidamide (0.20 g, 0.54 mmol), acetic anhydride (0.50 mL) and pyridine (2.00 mL). The solution was heated at 160° C. for 0.5 h in a microwave reactor, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (3/1) followed by recrystallization from diethyl ether to afford 1-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.08 g, 37%) as a colorless solid: mp 199-201° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.70 (dd, J=8.0, 0.8 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.03 (dd, J=7.8, 0.8 Hz, 1H), 6.39 (s, 1H), 6.03 (s, 1H), 5.14 (d, J=8.6 Hz, 1H), 4.82 (d, J=8.6 Hz, 1H), 4.16-4.00 (m, 4H), 3.28 (s, 3H), 2.50 (s, 3H); MS (ES+) m/z 391.9 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)#[C:2][CH3:3].[CH:9]1(C#C)C[CH2:10]1>>[CH:3]1([C:2]#[C:1][C:4]2[CH:5]=[N:6][NH:7][CH:8]=2)[CH2:10][CH2:9]1
Reactant: C#CC1CC1
Reactant: CC#Cc1cn[nH]c1
Product: C(#CC1CC1)c1cn[nH]c1

Procedure:
The title compound was synthesized according to the procedure described for 4-(prop-1-yn-1-yl)-1H-pyrazole (intermediate 61) above, but using cyclopropylacetylene. LC/MS (ESI−) m/z=133.1 (M+H).
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30].[ClH:33]>CN1CCCC1=O.O1CCOCC1>[ClH:33].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)(O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCC(C)(C)O)cc3)cc2s1
Temperature: 150 °C
Yield: 25 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (135 mg, 0.34 mmol) and 1-amino-2-methylpropan-2-ol (153 mg, 1.718 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 20 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate (3×20 ml) and washed with water (4×25 ml). The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on silica, on an 8 g 15-35 μm AIT column, eluting with a 9/1 ethyl acetate/cyclohexane mixture. After evaporating off the solvent, 55 mg of a colorless solid are obtained. The product is dissolved in a minimum amount of dioxane, and 4 N hydrochloric acid dissolved in dioxane is added. The precipitate obtained is filtered off by suction, washed with dioxane and then dried under vacuum at 40° C. to give 42 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride, i.e. a yield of 25%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](=[O:18])[CH2:4]1>C(Cl)Cl.N1C=CC=CC=1>[C:12]([O:11][C:9]([C@@H:8]([N:6]1[C:5](=[O:18])[CH2:4][CH:3]([CH:2]=[O:1])[CH2:7]1)[CH2:16][CH3:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(C=O)CC1=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
In a three necked flask, under argon, a solution of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 (4.0 g, 0.016 mol.) in CH2Cl2 (8 ml) is added to a suspension of CrO3 (6.2 g, 0.062 mol.) in pyridine (11.3 ml)/CH2Cl2 (80 ml) stirred at room temperature. The temperature increases to 30° C. and the suspension is stirred for 0.2 h. The suspension is filtered through celite and the filtrate is washed successively with HCl 1N, brine, dried over magnesium sulfate and concentrated in vacuo to afford the crude aldehyde which is purified by column chromatography on silicagel (hexane/acetone 70/30 (v/v)) to afford 2.03 g of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 (41%). Alternatively, the reaction can also be conducted with racemic ester to afford the racemic aldehyde with a similar yield. Analysis of a 1/1 mixture of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396: 1H NMR (250 MHz, (CDCl3): 0.91 (t, 3H), 1.44 (s, 9H), 1.55-1.77 (m, 1H), 1.90-2.15 (m, 1H), 2.63-2.82 (m, 2H), 3.47-3.61 (m, 1H), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H of one of the diastereoisomers), 4.48-4.62 (m, 1H), 9.74 (s,(broad, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:35]([C:29]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=3[F:27])(=[O:37])=[O:36])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (35 g, 89.5 mmol) (Intermediate 27) in pyridine (400 mL), 2,5-difluorobenzene-1-sulfonyl chloride (20.9 g, 98.5 mmol) was added dropwise. The reaction was stirred at rt for 2 h. Then the reaction was washed with water (400 mL), and extracted with DCM (2×400 mL). The organic layer was washed with water, brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (22.7 g, 44.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75-10.83 (br, 1H), 8.32 (d, J=5.3 Hz, 1H), 7.28-7.60 (m, 6H), 6.48 (d, J=5.3 Hz, 1H), 3.65-3.80 (m, 4H), 3.50-3.65 (m, 4H); m/z (ES+): 568 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=O)[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[NH2:26][C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.C([O-])(O)=O.[Na+]>[C:21]([O:20][C:18]([NH:17][C@H:4]([C:3]1[N:26]=[C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)=[CH:31][N:32]2[CH:2]=1)[C@@H:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1ccc(-c2ccc(N)nc2)cc1
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of benzyl (2R,3S)-5-bromo-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-oxopentanoate (Preparation 65, 400 mg, 0.966 mmol) in THF (15 mL) was added 4-(6-aminopyridin-3-yl)benzonitrile and the reaction stirred at room temperature for 3 days followed by 40° C. for 18 hours. The reaction was diluted with saturated aqueous NaHCO3 solution (80 mL), and extracted with EtOAc (3×50 mL). The organic layers were collected, dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 0-60% MeCN in water followed by silica gel column chromatography eluting with 40% EtOAc in heptanes to afford the title compound.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH3:14])[O:3]1.[C:24]([NH:27][NH2:28])(=[O:26])[CH3:25]>C(O)C.Cl>[C:24]([NH:27][N:28]=[C:2]([C:11]1[C:6]([CH2:5][CH:4]([OH:3])[CH3:14])=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1)[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NN
Reactant: COc1ccc2c(c1)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c(CC(C)O)c1
Yield: 66.3 %

Procedure:
To a solution of 4 (1.6 g) in 25 ml of ethanol was added acetic hydrazide (0.4 g) and 2 drops of concentrated HCl. The resulting solution was heated to reflux for 3 hours. The solvent was removed under reduced pressure. The residue was treated with NaHCO3, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4. Removal of the solvent gave the desired product (1.25 g).