Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(Cl)(Cl)Cl>C(#N)C>[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:20][CH:22]2[O:24][CH2:23]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCC1CO1
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Clc1nc(Nc2ccccc2)nc2c1ncn2CC1CO1
Reaction time: 48 h
Yield: 34.6 %

Procedure:
Sodium hydride (161 mg, 4 mmol; 60% suspension in mineral oil) was added to a suspension of 2-anilino-6-chloropurine (1 g, 4 mmol; Focher et al. (1988) J. Med. Chem. 31:1496-1500) in anhydrous acetonitrile (240 ml) at room temperature. After stirring for 1 hr epibromohydrin (0.35 ml, 4 mmol) was added, and the suspension was stirred for 48 hr. An equal volume of chloroform was added, and, after filtration through Celite, the filtrate was evaporated to dryness. The residue was chromatographed on silica gel, and the major product was eluted with chloroform to give 417 mg (34% yield) of 2-anilino-6-chloro-9-(2,3-epoxypropyl)purine. 1H NMR δ9.97 (s, 2-NH), 8.24 (s, 8-H), 7.40 (m, C6H5), 4.38 (m, 1'-CH2), 3.45 (m, 2'-CH), 2.72 (m, 3'-CH2). Further elution gave 46 mg (3.8% yield) of the minor 7-isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN1C(=O)CCC1.[Cu]I>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:17]3[CH:16]=[C:15]([CH3:14])[CH:19]=[N:18]3)[CH:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Reactant: Cc1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cnn(-c2ccc3c(=O)n(C)ccc3c2)c1
Yield: 52.7 %

Procedure:
6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), 4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K2CO3 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195° C. for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=5:1) gave the title compound of step 1 (160.0 mg, 52%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[N-:13]=[N+]=[N-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N.O>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH2:13])([O-:12])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2-Bromoethyl)-2-nitrobenzene (6.96 g, 30.5 mmol) in CH3CN was added a solution of NaN3 (6 g, 91.6 mmol) in water (20 ml) and the reaction mixture was refluxed for 20 hours. The solution was cooled and extracted with DCM (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in toluene (160 ml) and to this was added PPh3 (8 g, 30.5 mmol) and the reaction mixture was stirred at RT for 16 hours. The solvent was evaporated to dryness and the residue was treated with acetic acid (30 ml) and 48% HBr in acetic acid (30 ml) at 100° C. for 1 h. The reaction mixture was cooled, concentrated and extracted with DCM. The aqueous was brought to pH˜10 with NaOH (aq.) and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness (4.2 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([OH:42])[CH3:41])([CH3:34])[CH2:30][CH2:29]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)c(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 66.3 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in ethanol (4 mL) was added 10% Pd—C (60.6 mg, 0.057 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vacuum. The residue was then treated with 1M TBAF (0.949 mL, 0.949 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4,5-difluoro-2-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (85 mg, 0.126 mmol, 66.4% yield) as thick paste. 1H NMR (500 MHz, CDCl3) 6.96-6.89 (m, 1H), 6.68 (dd, J=11.7, 7.1 Hz, 1H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.31-4.09 (m, 2H), 3.93-3.81 (m, 1H), 3.44 (br. s., 2H), 2.88-2.70 (m, 4H), 2.63 (s, 4H), 2.12-1.94 (m, 4H), 1.90 (br. s., 2H), 1.57-1.42 (m, 6H), 1.41-1.31 (m, 3H), 1.27-1.18 (m, 18H). LCMS (M+H)=675.6.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:31]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 83 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37, the title compound was synthesized in the same manner as in Example 20. Yield: 83%. Melting point: 179-180° C. (ethyl acetate-hexane). [α]D°=−25.80° (c=0.48, chloroform).
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:40][CH3:41])(=O)=O.O>CC(C)=O>[CH2:40]([O:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29])[CH3:41]
Reactant: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 117.4 %

Procedure:
A mixed solution of N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 135 (300 mg, 0.76 mmol), potassium carbonate (105 mg, 0.76 mmol) and diethyl sulfate (117 mg, 0.76 mmol) in acetone (15 mL) was refluxed with heating for 14 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of the title compound. Melting point: 174-175° C. (hexane).
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])[CH3:11])N(C)C)(C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])/[CH:21]=[CH:6]/[N:10]([CH3:11])[CH3:12])=[C:16]([OH:23])[CH:15]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc(Br)cc1O
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1O
Yield: 82.8 %

Procedure:
A solution of 1-tert-Butoxy-N,N,N′,N′-tetramethylmethanediamine (19.2 mL, 93.0 mmol) and solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (10 g, 46.5 mmol) in toluene (100 mL) was heated at 35° C. for 16 hours and at 80° C. for 1 hour. The solvent was removed under reduced pressure. The resulting solid was subjected to flash chromatography with eluant of dichloromethane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (10.4 g, 38.5 mmol, 82%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[CH:11])[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1.I[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1>>[CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[C:11][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1
Reactant: Cc1cc(I)ccn1
Reactant: C#Cc1nc(C)n(C2CC2)c1C
Product: Cc1cc(C#Cc2nc(C)n(C3CC3)c2C)ccn1

Procedure:
The title compound, MS: m/e=252.1 (M+H+), was prepared in accordance with the general method of example A, step 1 from 1-cyclopropyl-4-ethynyl-2,5-dimethyl-1H-imidazole and 4-iodo-2-methyl-pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23](O)=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:9]=[C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])[CH2:18]3)[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1cccc2[nH]c([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)nc12
Yield: 20.6 %

Procedure:
Into a microwave vial was added 3-methylbenzene-1,2-diamine (150 mg, 1.23 mmol) and (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (281 mg, 1.23 mmol). The mixture was dissolved with pyridine (6.2 mL). Triphenylphosphite (469 mg, 1.51 mmol) was added and the vial was capped. The reaction was microwaved at 220° C. for 10 minutes. Solvent was removed under vacuum and the residue was purified by preparatory LC/MS (20-30% CH3CN in H2O) to give (R)-tert-butyl 3-(4-methyl-1H-benzo[d]imidazol-2-yl)piperidine-1-carb oxylate (39A) (80 mg, 21% yield). ESI-MS:m/z 316.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:16]([S-])=[S:17])C.[K+].C(O)C>O>[S:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C#N)c1ccc2oc(=S)[nH]c2c1

Procedure:
A mixture of 2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.), potassium ethylxanthate (5.3 g.), ethanol (30 ml.) and water (5.0 ml.) was heated under reflux for four hours. The mixture was filtered, diluted with water (15 ml.), acidified with acetic acid and then diluted with more water. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173°-6° C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and distilled chloroform (200 ml.). After 20 hours, most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.), 1N sodium hydroxide (50 ml.) and water (3 × 100 ml.) The dried (Na2SO4) organic solution was evaporated to yield 2-[2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was shown to be a single compound by thin layer chromatography. The oil distilled at 128°-134° C./0.3 mm.Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6](Br)[C:7](=O)[CH3:8])[CH3:2].C(N(CC)CC)C.[C:19]([SiH2:23][O:24][C:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:30]2[CH:31]=[C:26]([C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:24][SiH2:23][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:27]=[CH:28][C:29]2=[N:32][C:7]=1[CH3:8])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(N)nc1
Reactant: CCOC(=O)CC(Br)C(C)=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c(C)nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Yield: 55 %

Procedure:
3-Bromo-4-oxo-pentanoic acid ethyl ester (1.77 g, 7.86 mmol, 2.0 equiv) and triethylamine (1.10 ml, 7.86 mmol, 2.0 equiv) are added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyridin-2-ylamine in iso-propanol (10 ml). The reaction mixture is heated to reflux for 5 hours. After cooling, volatiles are removed in vacuo. The residue is taken up with water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/AcOEt 1:1 to 1:4) affords the title compound (1.10 g, 55%). MS (ES+): 487 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31]C(C2CCNCC2)=N[N:34]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O/[N:42]=[C:43](\[CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1)/N>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31][N:42]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)[N:34]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(/C(N)=N\O)CC1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
CDI (511.3 mg, 3.1 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (726 mg, 2.6 mmol) in DMF (15 mL). The mixture was stirred at rt for 1 h, then, (E)-tert-butyl 4-(N′-hydroxycarbamimidoyl)piperidine-1-carboxylate (631.8 mg, 2.6 mmol) was added at rt. The mixture was stirred at rt for 2 hrs, and then stirred at 50° C. for another 6 hrs. The mixture was diluted with EtOAc (150 mL) and washed with 1 M HCl (2×), water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:5 to 1:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (968 mg, 76%) as a white solid. ESI-MS (EI+, m/z): 506.2 [M+Na]+. 1H-NMR (400 MHz, CDCl3): δ 7.47-7.36 (m, 5H), 4.99-4.94 (m, 2H), 4.73 (d, J=6.0 Hz, 1H), 3.93 (d, J=9.6 Hz, 1H), 3.72 (s, 1H), 3.08-2.90 (m, 4H), 2.72 (d, J=9.6 Hz, 1H), 2.15 (dd, J=12.0, 5.2 Hz, 1H), 2.09-1.93 (m, 5H), 1.85-1.79 (m, 1H), 1.59-1.50 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[N+:49](C1C=CC(N)=CC=1)([O-:51])=[O:50]>C(O)(=O)C>[N+:49]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1)([O-:51])=[O:50]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc([N+](=O)[O-])cc1
Yield: 10 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 4-nitroaniline (225 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 31 mg (0.089 mmol, 10% yield) of the title compound.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][NH:11][C@@H:12]([CH3:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:12]([CH3:20])[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]3[C:33]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 67.6 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-4) 1.41 g (4.78 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.4 g (5.23 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 2.38 g (68%).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]2[O:12][C:11]([CH3:18])([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:19]=1)(=[O:3])[CH3:2].O.[C:25]1(C)C=CC(S(O)(=O)=O)=C[CH:26]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:25]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C:11]1([CH3:18])[CH2:10][CH2:9][C:8]2[CH:19]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]=2[O:12]1)[CH3:26]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)O)CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)OCC)CC2
Yield: 385.4 %

Procedure:
A solution of 692 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid and 100 mg of p-toluenesulfonic acid monohydrate in 10 ml of absolute ethanol was stirred and refluxed for 17 hours. The resulting solution was cooled and treated with a small amount of saturated sodium bicarbonate then concentrated in vacuo to remove the ethanol. The residue was treated with ether and the ether solution was processed in the usual manner given 752 mg of a yellow oil. This material was chromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethyl acetate provided 706 mg (92.9%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH:26]=[CH2:27])(O)=[O:2].C(Cl)(=O)C(C)(C)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C(N(CC)CC)C>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH:26]=[CH2:27])=[C:5]2[CH2:4][C:1](=[O:2])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:25]
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Reactant: NCc1ccccn1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)NCc1ccccn1
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a solution of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (190.1 mg) were added pivaloyl chloride (62.8 mg) and triethylamine (52.7 mg) at 0° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2-aminomethylpyridine (154 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at ambient temperature. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-[(pyridin-2-ylmethyl)carbamoylmethyl]-3-vinylquinoline (34.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 1, 400 mg (1.53 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) in 8 ml of pyridine/methylene chloride 1:1 are reacted at 0° C. with 288 μl (1.68 mmol) of octanoic acid chloride to form 4-(3-chlorophenylamino)-3-octanoylamino-1H-pyrazolo[3,4-d]pyrimidine (18 hours RT): HPLC: tRet(grad20-100)=14.5; FAB-MS: (M+H)+=387.
Reaction SMILES: [CH3:1][C:2]([SH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:5][CH2:4][CH2:3][C:2]([CH3:6])([SH:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(C)(S)CCO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)(C)S
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H).