Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl>CN(C=O)C.O>[CH2:1]([O:5][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: CC(C)C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3.17 mL (0.042 mol) of 2-butyn-1-ol in 60 ml of DMF at room temperature was added 1.70 g (0.040 mol) 60% sodium hydride. The resulting mixture was stirred for 0.5 h and then a solution of 2.45 g (8.478 mmol) the product of Example 11 dissolved in 20 mL of DMF was added to the reaction. The reaction mixture was then heated to reflux for 24 h, cooled to room temperature and then acidified to pH 2 with 10% HCl solution. After stirring for 1 h the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organics were then dried over MgSO4, filtered and concentrated in vacuo. The, residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:2) to provide 1.67 g (58%) of the desired carboxylic acid product as a white solid identical to the product of Example 8.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][N:32]=[C:33]=[S:34]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:33]([NH:32][CH2:31][C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[S:34])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: S=C=NCc1ccco1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)NCc5ccco5)c4c(c23)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 15 ml of acetonitrile. 120 μl (2 molar equivalents) of 2-furylmethyl isothiocyanate was added and the reaction was maintained at room temperature overnight then for 5 hours at 55° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 212 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=75%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:33]O>C(OCC)(=O)C.CCCCCC>[CH3:33][O:24][C:23]([C:21]1[NH:22][C:18]([C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:17])=[N:19][CH:20]=1)=[O:25]
Reactant: CO
Reactant: O=C(O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Yield: 89 %

Procedure:
A solution of 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid (60 mg) and concentrated sulfuric acid (1 mL) in methanol (100 mL) was heated to reflux overnight. After removal of solvent, the mixture was dissolved in ethyl acetate and washed with 5% sodium hydroxide solution. The organic layers were dried over magnesium sulfate and evaporated to dryness. The product 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid methyl ester (55 mg, yield 89%) was purified by flash column chromatography (ethyl acetate:hexane=1:1). 1H NMR (acetone-d6) δ 3.84 (s, 3H), 5.65 (s, 2H), 7.2–7.4 (m, 6 H), 7.48 (m, 1H), 7.95 (s, 1H), 8.45 (m, 1H), 9.48(s, 1H) ppm; ESMS calcd (C21H16ClN3O3): 393.09; found: 394.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([N:28]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:56])(=[O:55])[NH2:54])=[CH:43][CH:42]=1)[C:29]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27].N12CCCN=C1CCCCC2>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:54][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:30])=[CH:46][CH:45]=1)(=[O:56])=[O:55])=[O:6]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCc2ccccc21
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCc2ccccc21
Temperature: 55 °C
Reaction time: 29 h
Yield: 67.8 %

Procedure:
A solution of 21 mg (0.13 mmole) of 2-chlorobenzoic acid and 22 mg (0.13 mmole) of 1,1'-carbonyldiimidazole (CDI) in 0.8 mL of THF was stirred under N2 at 65° C. for 2.5 hours. Subsequently, a solution of 32 mg (0.067 mmole) of 1-[N-pentyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]indoline (from Step B) and 20 μL (0.13 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 0.8 mL of THF was added. After stirring for 29 hours at 55° C., the mixture was partitioned between EtOAc and 5% citric acid (aqueous). The organic layer was washed with water and brine, then dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution with 0.5-1.0% MeOH in CH2Cl2) to give 28 mg (68%) of the title compound as an off-white solid, mp 83°-85° C.; homogeneous by TLC (95:5 MeOH--CH2Cl2); FAB-MS m/e 616 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)=[O:5])[CH3:2].Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][NH:24]/[C:23]/1=[N:32]\[C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34]>>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][NH:8][C:9]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([N:29]2[CH2:30][CH2:31][C:26]3([NH:22]/[C:23](=[N:32]/[C:33]([C:35]4[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=4)=[O:34])/[NH:24][CH2:25]3)[CH2:27][CH2:28]2)=[O:16])[CH:12]=1)=[O:20])[CH3:2]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)O)c1
Agent: Cl
Product: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1

Procedure:
The title compound was prepared from 3-[3-(2-ethoxycarbonyl-ethyl)-ureido]-benzoic acid (Int. F) and 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride using an analogous method to Example 1; LC-MS Rt 0.81 mins; 587.4 and 589.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12]
Reactant: O=C(O)c1cccc(Oc2ccccn2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccccn2)c1

Procedure:
To a suspension of 3-(2-pyridyloxy)benzoic acid (1.80 g) in thionyl chloride (5.4 ml), dimethylformamide (0.2 ml is added, and the resultant mixture is stirred at room temperature for 2.5 hours. The reaction mixture is evaporated under reduced pressure to remove the excessive thionyl chloride, and the residue is combined with anhydrous pyridine (0.73 g) and anhydrous benzene (40 ml). The precipitated pyridine hydrochloride is filtered off. The filtrate is evaporated to remove the benzene, and the residue is dissolved in anhydrous ether (20 ml). The ether solution is filtered to remove the insoluble substance. The filtrate is evaporated to remove the ether, whereby 3-(2-pyridyloxy)benzoyl chloride is obtained. IR (CCl4): 1774 cm-1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[C:14]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[CH:27]=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][N:30]=[CH:29]5)[CH:24]=3)[NH:19][CH:18]=2)=[O:16])=[C:13]([F:35])[CH:12]=[CH:11][C:10]=1[NH:36][S:37]([C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[F:47])(=[O:39])=[O:38]>O.C(OCC)(=O)C>[C:1]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:23]3[CH:24]=[C:25]4[C:17]([C:15]([C:14]5[C:9]([F:8])=[C:10]([NH:36][S:37]([C:40]6[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=6[F:47])(=[O:39])=[O:38])[CH:11]=[CH:12][C:13]=5[F:35])=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(-c3ccc4[nH]ncc4c3)cc12
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)n1ncc2cc(-c3cnc4[nH]cc(C(=O)c5c(F)ccc(NS(=O)(=O)c6cc(F)ccc6F)c5F)c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
Into a reaction flask, a mixture of acetic anhydride (12 mg, 0.11 mmol) and N-{2,4-difluoro-3-[5-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-0002, 22 mg, 0.031 mmol) is stirred at room temperature overnight, then diluted with water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, then brine and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-0005, 3 mg, 20%). MS (ESI) [M+H+]+=607.8.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[CH2:8][O:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([OH:26])[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[CH:11][CH:10]=2)=[N:5]1)[CH3:3].Cl[C:28]1[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:19]=[C:14]([C:12]2[NH:13][C:9]([C:6]3[O:7][CH2:8][C@@H:4]([C@H:2]([OH:1])[CH3:3])[N:5]=3)=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:26][C:28]2[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[CH:17]=1)[CH3:25]
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
3-(5-{(4S)-4-[(1R)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (766 mg, 2.13 mmol) synthesized in Example (114c) was dissolved in acetonitrile (15 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (590 mg, 3.06 mmol) synthesized in Example (97c) and potassium carbonate (870 mg, 6.29 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/ethyl acetate=5%-8%) to afford the desired compound (890 mg, yield 81%) as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]1([CH3:12])[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1>>[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: Cc1ccccc1C
Reactant: C=CC=C
Product: C=CCCCc1ccccc1C

Procedure:
The synthesis of 2,6-NDC typically includes several steps. In a typical synthesis, orthoxylene and butadiene are reacted over an alkali metal or other catalyst to yield a 5-orthotolyl pentene (5-OTP) alkenylation product. The 5-OTP is then cyclized over an acid catalyst to yield 1,5 dimethyltetralin (1,5-DMT). The 1,5 DMT is dehydrogenated over a noble metal or other dehydrogenation catalyst to yield 1,5 dimethylnaphthalene (1,5-DMN), which is subsequently isomerized to produce 2,6-DMN.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:36])([F:35])[C:19]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[N:20]=1.Cl.C1COCC1>C(OCC)(=O)C>[F:36][C:18]([F:17])([F:35])[C:19]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]([C:28]2[CH:29]=[CH:30][C:31]([NH:32][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])=[CH:33][CH:34]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg), 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (206 mg), WSCD hydrochloride (172 mg) and THF (3 ml) was stirred overnight at room temperature. After adding ethyl acetate, the reaction solution was washed as th water, saturated sodium bicarbonate aqueous solution, 1 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromtaography (eluent; n-hexane:ethyl acetate=7:1-5:1) to give tert-butyl 4-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenylaminocarbonyl]piperidine-1-carboxylate (279 mg) as a colorless amorphous solid. 4 N Hydrochloric acid ethyl acetate solution (2.60 ml) was added to a mixture of this solid (263 mg) and ethyl acetate (2.6 ml), followed by stirring at room temperature for 2 hours and 45 minutes. The reaction solution was concentrated under a reduced pressure, diethyl ether was added to the thus obtained residue, and the mixture was concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, [4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-4-carboxyanilide hydrochloride (201 mg) was obtained as colorless powder crystals.
Reaction SMILES: Br[C:2]([Cl:5])(Cl)[Cl:3].O=[C:7]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:3][C:2]([Cl:5])=[C:7]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Reactant: ClC(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C=CC(=C(Cl)Cl)CO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
0.046 ml (2 equivalents) of bromotrichloromethane is added to 50 mg (0.23 mmol) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 49, and 214 mg (0.92 mmol) of triphenylphosphine in suspension in 0.5 ml of acetonitrile, which is stirred beforehand at 0° C. for 2 hours. The reaction medium is protected from light and is again stirred at ambient temperature for 15 minutes. After the conventional treatments, purification on a column of silica gel (ethyl acetate/heptane 5/95) provides 48 mg (74%) of methyl 3-(dichloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a white solid; M.p.=119–121° C.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH2:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35].CN(C1C=CC=CN=1)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][CH:39]([NH:47][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:35]
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: CCOC(=O)CCC(N)CC(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (5.0 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.7 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Diethyl-3-aminoadipate (4.0 g, 18.5 retool) was added followed by dimethylaminopyridine. After 1 hour, the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 3.0 g of a white solid: 1HNMR (d6 -DMSO) δ1.14 (t, 6H, J=7 Hz), 1.55 (m, 1H), 1.7 (m, 1H), 2.3 (m, 2H), 2.57 (m, 2H), 2.67 (m, 2H), 4.02 (q, 4H, J=7 Hz), 4.03 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1, J=8.1 Hz), 9.06 (bs, 2H), 9.15 (bs, 2H), 10.22 (s, 1H); MS (FAB) m/z 435.2 (MH+).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Br[C:12]1[N:16]([C@H:17]2[O:29][C@@H:28]([CH2:30][O:31]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@@H:18]2[O:19]C(=O)C)[C:15]2[CH:35]=[C:36]([Cl:40])[C:37]([Cl:39])=[CH:38][C:14]=2[N:13]=1.C(O)C>CN(C=O)C>[Cl:39][C:37]1[C:36]([Cl:40])=[CH:35][C:15]2[N:16]([C@H:17]3[O:29][C@@H:28]([CH2:30][OH:31])[C@H:23]([OH:24])[C@@H:18]3[OH:19])[C:12]([NH:6][CH3:4])=[N:13][C:14]=2[CH:38]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methylamine hydrochloride (3.0 g, 45 mmol), triethylamine (3 mL), and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (25 mL) and stirred at 80° C. for 24 h. The reaction mixture was separated between saturated sodium bicarbonate (50 mL) and ethyl acetate (150 mL). The organic layer was dried with sodium sulfate, concentrated and absorbed onto silica gel (15 g). This material was dry loaded onto a silica gel column (5 cm×10 cm, 230-400 mesh) with 1:10 methanol:dichloromethane. The main product came off the column as a white solid (0.22 g, 0.62 mmol, 54%) m.p. 238-240° C.; [a]20D=(−) 15.2 (c=0.5 DMF).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]2[C:4](=[C:5]([O:19]CC=CC)[CH:6]=[CH:7][C:8]2([CH3:18])C)[C:3]1=[O:24].[CH2:25]1[C:34]2C(=CC=CC=2)C[CH2:27][CH2:26]1>>[CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([OH:19])[C:6]([CH:26]([CH3:27])[CH:25]=[CH2:34])=[CH:7][C:8]=2[CH3:18])[C:3]1=[O:24]
Reactant: CC=CCOC1=C2C(=O)C(C)C(c3ccccc3)C2C(C)(C)C=C1
Reactant: c1ccc2c(c1)CCCC2
Product: C=CC(C)c1cc(C)c2c(c1O)C(=O)C(C)C2c1ccccc1

Procedure:
11 Grams of 2,3-dihydro-2,4-dimethyl-3-phenyl4-methyl-7-crotyloxy-1H-inden-1-one was added to 55 ml of tetrahydronaphthalene and the mixture was heated and refluxed for 6 hours with stirring condition. After the reaction was completed, the reaction mixture was concentrated by removal of the solvent, and the residue thus obtained was purified by means of a silica gel column chromatography. 11.2 Grams of 2,3-dihydro-2,4-dimethyl-3-phenyl-6-(1-buten-3-yl)-7-hydroxy-1H-inden-1-one was obtained as cis-trans mixture. Yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:15](OCC)=[O:16]>O1CCCC1>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:15][OH:16]
Reactant: CCOC(=O)c1cnc2cc(C(C)(C)C)nn2c1N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncc(CO)c(N)n2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidine-6-carboxylate (740 mg, 2.82 mmol, 1.00 equiv) in tetrahydrofuran (12 mL) was added dropwise LiBHEt3 (8.5 mL of a 1 M solution in THF, 3.0 eq.) at 0° C. under nitrogen. After addition, the resulting solution was stirred for 4 h at 25° C. Additional LiBHEt3 (0.85 mL of a 1 M solution in THF, 0.85 mmol, 0.3 eq.) was added and the mixture was stirred for another 1 h. After a total of 3 h, the reaction was then quenched with water and extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried and concentrated. The residue was loaded onto a silica gel column with CH2Cl2/MeOH (30:1) as an eluent to give Compound [CCXXXVI] as a white solid: LCMS (m/e) 221 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.02 (s, 1H), 7.32 (s, 2H), 6.22 (s, 1H), 4.94 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:43]=[N+:44]=[N-:45])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:43]([CH:5]([C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[N+:44]=[N-:45]
Reactant: CCOC(=O)Cc1csc(NC=O)n1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(N=[N+]=[N-])c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
A solution of ethyl[2-(N-formylamino)thiazol-4-yl]acetate (1 g, 0.0047 mol) in THF (10 mL) was stirred under argon at −78° C. and potassium bis(trimethylsilyl)amide (2.8 g, 0.014 mol) in THF (10 mL) was added. After stirring for 30 minutes, 2,4,6-triisopropylbenzenesulfonyl azide (3.6 g, 0.012 mol) was added as a solid in one portion. After 5 minutes, acetic acid (1.4 mL, 0.018 mol) was added and the mixture warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), separated and the organic layer dried (MgSO4). Evaporation of the solvent and purification of the residue by silica gel chromotography afforded the azide (0.95 g, 80%).