Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:17])[CH3:1]
Reactant: NO
Reactant: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a stirred solution of [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (3.84 g, 17 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (2.89 g, 42 mmol). The reaction mixture was stirred at 70° C. for 6 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline as a yellow solid [4.48 g, yield 99.6%; HPLC/MS:m/z=247 (M+H); log P(HCOOH)=1.17].
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+].O>O1CCCC1>[I:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=1[CH3:19]
Reactant: COC(=O)c1cc(COc2cccc(I)c2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(C(=O)O)cc1COc1cccc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (106) (2.7 g, 7.25 mmoles) and lithium hydroxide (1.5 g, 36.25 mmoles) in tetrahydrofuran (25 ml) containing water (2 ml) was stirred at room temperature for 3 h. The tetrahydrofuran was evaporated, the residue was diluted with water and the mixture acidified to pH=1 with 1M aqueous hydrochloric acid. The precipitate was collected washed with water and dried at 70° C. in vacuo to give compound 107 (1.76 g) as a white solid. LC/MS System B; Rt=3.51 mins, m/z (ES−)=357 (M−H for C13H11IO4).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccccc1F
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2F)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl) propan-2-one (2.22 g) and 2-hydroxy-2-(2-fluorophenyl) ethanamine (1.55 g), and crystallised from hexane m.p. 60°-80° as a 55:45 mixture of diastereoisomers.
Reaction SMILES: C([O:5][C:6](=[O:27])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:26])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C(OC(=O)[C@@H]1C(SC(=O)C)CCN1C(=O)C(C)C)(C)(C)C>>[C:16]([S:15][CH2:14][CH:13]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:27])=[O:5])=[O:26])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CC(=O)SC1CCN(C(=O)C(C)C)[C@@H]1C(=O)OC(C)(C)C
Product: CC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The product of Example 38 is substituted for the 1-(3-acetylthio-2-methylpropanoyl-L-proline tert-butyl ester in the Procedure A of Example 29 to obtain 1-(3-acetylthio-2-benzylpropanoyl)-L-proline.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[CH3:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH3:23]>>[CH3:11][O:12][C:13](=[O:24])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=2)=[CH:18][C:17]=1[CH3:23]
Reactant: CCc1cc(Br)cc(Br)c1
Reactant: COC(=O)CCc1ccc(O)cc1C
Product: CCc1cc(Br)cc(Oc2ccc(CCC(=O)OC)c(C)c2)c1
Yield: 56 %

Procedure:
Compound of 1,3-dibromo-5-ethyl-benzene is reacted with 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester as in Example 18 to afford 0.898 g (56%) of the title compound. Rf=0.32 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C19H21O3Br 376, found 377 and 379 (M+1 and M+3, 100%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:6][C:5]=12.[H-].[Na+].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:6][C:5]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide (0.05 g, 0.150 mmol) in tetrahydrofuran (1.246 ml) was treated with sodium hydride (0.018 g, 0.449 mmol) in 3 portions. The reaction was stirred at ambient temperature for 45 minutes and became a partially homogeneous solution. Benzenesulfonyl chloride (0.021 ml, 0.164 mmol) was added and the mixture was stirred for 16 hours. The reaction was treated with 0.1 mL water and was concentrated under a stream of nitrogen. Reverse-phase chromatography provided the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 8.73 (dd, J=7.0, 0.9 Hz, 1H), 8.15 (dd, J=2.2, 0.8 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.89-7.75 (m, 5H), 7.73-7.59 (m, 3H), 7.46 (dd, J=7.0, 1.6 Hz, 1H), 7.37-7.31 (m, 2H), 4.75 (s, 2H), 3.96-3.88 (m, 2H), 2.67-2.52 (m, 1H), 2.48-2.37 (m, 2H), 1.95-1.72 (m, 4H); MS (ESI(+)) m/e 475 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:36][CH2:35][CH3:41])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: CCCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56246 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 194 mg, 0.59 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (214 mg, 0.65 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (157 μL, 1.36 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Butyl-1H-pyrazol-3-ylamine (82 mg, 0.59 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-butyl-1H-pyrazol-3-yl)-propionamide (150 g, 56%) as a white powder: ESI-LRMS m/e calcd for C22H30ClN3O3S [M+] 451.17, found 452.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.3 Hz, 3H, CH3), 1.07-1.21 (m, 2H, CH2), 1.25-1.37 (m, 2H, CH2), 1.45-1.96 (m, 10H, 5×CH2), 2.12-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.96 (t, J=7.1 Hz, 2H, NCH2), 6.62 (d, J=2.3 Hz, 1H, Ar), 7.24 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.1, Jm=1.8 Hz. H, Ar), 7.58 (d, Jm=1.8 Hz, 1H, Ar), 7.85 (s, 1H, NH), 8.08 (d, Jo=8.1 Hz, 1 H, Ar).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH2:11][C:10]([NH:9][CH:7]([CH3:8])[CH3:6])=[O:21])=[S:4]
Reactant: CC(C)NC(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
Thiosemicarbazide (2.08 g, 22.8 mmol) was added to a solution of N-(1-methylethyl)-4-oxo-4-phenyl-butyramide (5.0 g, 22.8 mmol), prepared in the previous step, in 80 ml of methanol plus 6.2 ml of 1 N HCl plus 6.2 ml of water and the reaction stirred at room temperature for 2 days. An additional 1.04 g (11.4 mmol) of thiosemicarbazide was added and the reaction stirred at room temperature for 24 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried. Recrystallization of the solid from isopropyl alcohol gave the title compound (4.73 g, 53%) as a white solid, mp 66-71° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4](=[N:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)\[CH3:9])[NH2:5].CCO.Cl>[Fe].O>[ClH:1].[ClH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10](/[C:8](=[N:7]/[N:6]=[C:4]([NH2:5])[NH2:3])/[CH3:9])[CH:11]=2)=[O:27])=[CH:23][CH:22]=1
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Yield: 212.2 %

Procedure:
To a refluxing suspension of amide F4 (2.02 g, 5.36 mmol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (1.20 g, 21.44 mmol) and c.HCl (2 mL), and the resulting suspension was refluxed for 14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was re-dissolved in hot H2O, and the resulting suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The resulting residue was reprecipitated from acidified MeOH to afford triamine F5 (2.18 g, quantitative) as an amorphous cream solid; 1H NMR (400 MHz, DMSO): δ 11.30 (s, 1H, hydrazonyl-N+—H), 10.05 (s, 1H, ArC(O)NHAr), 8.21 (s, 1H, ArH), 8.20-7.55 (m, 8H, ArH & ═C(NH2)2), 7.36 (t, J=7.90 Hz, 1H, ArH), 6.91 (d, J=7.96 Hz, 1H, ArH), 5.30 (v br s, 3H, ArNH3+), 2.35 (s, 3H, Ar(CH3)═N—); LCMS (APCI+): 311 (100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[OH-:8].[Na+]>O.O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:5]1[S:1](=[O:8])[C:2](=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:3]=[CH:4]1
Reactant: O=Cc1cccs1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1C(=Cc2cccs2)C=CC1=Cc1cccs1
Reaction time: 48 h

Procedure:
About 30 mmol (3.06 g) of 2,5-dihydrothiopnene-1-oxide (MW=102) (4) and 70 mmol=(7.84 g) (6.5ml) of thiophene-2-aldehyde (MW--112, d=1.2 g/cm3) were added to a solution containing 0.9 g of NaOH in 50 ml of H2O and 12.5 ml of tetrahydrofuran. The mixture was stirred for 2 days. Purification was performed by separation by column chromatography; the reaction mixture was applied to a column of silica gel/diethyl ether. The aldehyde was eluted with ether; the product was eluted with ethyl acetate. When the solvent was stripped off in vacuo, the product precipitated. The precipitate was filtered off with suction and dried.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36]([CH3:39])([CH3:38])[CH3:37])CC.BrCC1CC1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:37][CH:36]1[CH2:39][CH2:38]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Agent: BrCC1CC1
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1[nH]c(=O)n2CC1CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 71 mg (0.531 mmol) of (bromomethyl)cyclopropane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 27 mg of the title compound were obtained (11% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: C#CC(O)(CC)CC
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (3) (0.930 g, 3 mmol) and 3-ethylpent-1-yn-3-ol (4) (0.670 g, 6 mmol) in triethylamine (4 mL) and DMF (12 mL) was added PdCl2(PPh3)2 (0.053 g, 0.075 mmol), tri-o-tolylphosphine (0.046 g, 0.15 mmol), and CuI (0.014 g, 0.075 mmol). The resulting mixture was degassed and stirred under argon at 90° C. for 6 h. The mixture was cooled to room temperature then concentrated under reduced pressure and diluted with EtOAc (100 mL) and water (70 mL). After vigorous shaking, the layers were separated. The organic layer was treated with charcoal, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (7 to 60% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (5) as a yellow oil. Yield (0.663 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.17-7.28 (m, 4H), 5.11 (s, 1H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 4H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: [SH2:1].O=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1>C(O)(C)C>[S:1]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: S
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(=S)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen sulfide gas was bubbled into a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10.05 mmol, 1.00 equiv) in isopropanol (20 mL) contained in a 100-mL 3-necked round-bottom flask. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and the crude product was used in the next step directly without purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38](O)[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1>ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[C:38]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:37]=[C:36]([C:41]#[N:42])[CH:35]=2)[O:31][N:30]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Trifluoromethanesulfonic anhydride (22.9 μL, 0.14 mmol) and triethylamine (23.7 μL, 0.17) were added under argon to a vial containing 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol) in dichloromethane (1 mL). The vial was then sealed and the reaction was left stirring overnight at ambient temperature. The reaction mixture was placed directly onto a flash column and purified by eluting with hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 to afford 11 mg (25%) of 3-(2-pyridyl)-5-(3-cyano-5-(trifluoromethylsulfonyloxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.88 (d, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.24 (d, 1H), 7.93 (t, 1H), 7.83 (s, 1H), 7.52 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:38][CH:37]=[CH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:38][CH:37]=[CH:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1=CCNC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CC=CC4)c3)ccc2C)cc1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with 3-pyrroline. There was thus obtained the title compound in 58% yield; NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 2.2 (s, 3H), 2.5 (m, 4H), 3.6 (s, 2H), 4.15 (s, 4H), 6.05 (m, 1H), 6.45-6.55 (m, 1H), 6.9 (s, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 7.45 (d, 2H), 7.57 (m, 1H), 7.8 (m, 1H), 7.95 (d, 2H), 9.8 (s, 1H), 10.12 (broad s, 1H); Mass Spectrum: M+H+501.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[CH:29][CH:30]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cn1ccc(-c2ccc(CCl)cc2)n1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.97 g), 3-[4-(chloromethyl)phenyl]-1-methyl-1H-pyrazole (0.65 g) and sodium carbonate (0.67 g) in a mixed solvent of 1,2-dimethoxyethane (12.0 mL)-water (4.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.18 g) under argon atmosphere, and the mixture was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.65 g).
Reaction SMILES: C(Cl)Cl.[N+:4]([O-:7])([OH:6])=[O:5].OS(O)(=O)=O.O[CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].[K+]>O>[N+:4]([O:7][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([O-:6])=[O:5]
Reactant: O=C([O-])CCCO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCO[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
CH2Cl2 (10 ml) was added to the HNO3/H2SO4 mixture, and the resulting solution was stirred for 15 minutes. Potassium 4-(hydroxy)butanoate (500 mg, 3.52 mmol) was then added in small portions to the methylenechloride solution kept at 0-5° C. The mixture was kept under stirring for 6 hours while the temperature was allowed to reach 25° C. gradually. Water (50 ml) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (3×25 ml). The combined organic phases were washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. 4-(Nitrooxy)butanoic acid was obtained as a yellow oil (300 mg, 57%) and used in the next step.
Reaction SMILES: ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[C:15]1=[O:22].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:13][N:14]1[CH2:18][CH2:17][N:16]([C:19]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)=[O:20])[C:15]1=[O:22]
Reactant: CN1CCN(C(=O)Cl)C1=O
Reactant: Nc1ccc2c(c1)NC(=O)C2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2ccc3c(c2)NC(=O)C3)C1=O
Reaction time: 5 h

Procedure:
bis(trichloromethyl)carbonate in tetrahydrofuran was added dropwise within 1 hour to the compound D78 in tetrahydrofuran in such a way that the internal temperature was kept at 55-60° C. The mixture was stirred for 5 h at this temperature. The formation of 3-methyl-2-oxoimidazolidine-1-carbonyl chloride was confirmed by TLC. The 6-aminoindolin-2-one (D4) was added to the mixture in situ and the mixture was refluxed for 4 h. The completion of reaction was monitored using TLC. The residue obtained after workup using saturated sodium carbonate was further purified using flash chromatography on silica gel to afford the title compound D79.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCC1>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Temperature: 70 °C
Yield: 33.2 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (400 mg, 1.70 mmol) in EtOH was added hydantoin (186 mg, 1.86 mmol) and pyrrolidine (14 μL, 0.17 mmol). The reaction was stirred at 70° C. over weekend. Precipitate was filtered and air dried to yield 180 mg (33% yield) 5-((5-chloro-7-(cyclopropylamino)pyrazolo-[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=319)