Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[O:16]1[CH2:15][CH2:14][CH2:13][O:12][CH:11]1[C:7]1[O:6][C:10]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: c1coc(C2OCCCO2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point0.8 180° C.). 93 g were obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1.[Br:20]C1C=C2C(C(C)=NN2)=CC=1.FC1C=CC=CC=1C#N>O>[Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([Br:20])=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Reactant: Cc1n[nH]c2cc(Br)ccc12
Agent: N#Cc1ccccc1F
Solvent: O
Product: N#Cc1ccccc1-n1nc(CBr)c2ccc(Br)cc21
Yield: 64 %

Procedure:
In a similar manner to that described for the preparation of 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile except in Step 1 the mixture was diluted with H2O and in Step 2 the mixture was heated at reflux overnight, 6-bromo-3-methyl-1H-indazole (1 g, 4.74 mmol) and 2-fluorobenzonitrile (0.617 mL, 5.69 mmol) were converted to the title compound (800 mg, 64%) as an off white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N([CH2:16][CH3:17])CC)C.[OH2:18]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: O
Reactant: NNc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: Cl
Product: CC(=O)NNc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
12.5 g of 4-chlorophenylhydrazine hydrochloride are dissolved in 100 ml of water and then triethylamine is added until the salt has been neutralized. Extraction is carried out with AcOEt and then the extract is evaporated to dryness. The base is dissolved in 100 ml of ether, the solution is cooled to 0° C. and then 15 ml of acetic anhydride are added dropwise. The mixture is stirred at 0° C. for 15 minutes. The white precipitate formed is filtered off and is then washed with ether to produce 12.8 g of the expected compound in the form of a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[CH:43]1([N:48]([CH:59]([CH3:61])[CH3:60])[CH2:49][CH2:50][NH:51][C:52](N2C=CN=C2)=[O:53])[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([N:48]([CH:59]([CH3:61])[CH3:60])[CH2:49][CH2:50][NH:51][C:52]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]3)=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])=[O:53])[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C1CCCC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN(C(C)C)C4CCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-{2-[cyclopentyl(isopropyl)amino]ethyl}-1H-imidazole-1-carboxamide (Preparation 26) by a similar method to Example 1.
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
7.44 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 12.53 g of yellow liquid. MS: m/e 360(M+′), 315(M+—OCH2CH3), 287(M+—CO2CH2CH3), 276, 241(M+−CH3C6H4CO), 225(M+—CH3C6H4CO2), 195, 185, 151, 140, 119 (base), 91, 77.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][S-:29].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][S:29][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[S-]
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(CCOS(C)(=O)=O)C1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCCC1CN(c2ccccc2C)CCN1C(=O)OC(C)(C)C

Procedure:
A stirred solution of 1-t-butyloxycarbonyl-2-(2-methylsulfonyloxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (0.39 g; 0.98 mmol) and sodium thiomethoxide (0.21 g; 3.0 mmol) in dry THF (15 mL) was heated to reflux for 18 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The title compound was isolated as a gum (1H-NMR: consistent with structure; TLC: silica gel, 1:4 EtOAc:hexanes: single component, Rf =0.50; FABMS: M+H @ m/e=351; HPLC: >99%, retention time 12.0 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][I:22]>CCO>[IH:22].[F:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:12]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc([C@H]2NC(=S)N[C@H]2c2ccc(F)cc2)cc1
Reactant: CI
Solvent: CCO
Product: CSC1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1
Product: I
Temperature: 25 °C
Yield: 936.7 %

Procedure:
A solution of cis-4,5-bis-(4-fluorophenyl)imidazolidine-2-thione (28) (1.78 g, 0.61 mmol) and methyl iodide (0.620 g, 10.0 mmol) in abs. EtOH (30 mL) is heated at 95° C. for 26 h. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue suspended in abs. EtOH:Et2O. The insoluble material is filtered to give 2.47 g of the product 45. 1H NMR (DMSO-d6) δ 10.75 (s, 2 H), 7.15-6.95 (m, 8 H), 5.83 (s, 2 H), 2.81 (s, 3 H); MS: m/z 305 (M++1).
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:26]1C=CC=C[CH:27]=1>>[C:27]([CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1)#[N:26]
Reactant: COC(=O)c1cccc2c1CCC2O
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1cccc2c1CCC2C#N
Reaction time: 6 h

Procedure:
To 40 ml. of pyridine is added 19.2 g. of methyl 1-hydroxyindan-4-carboxylate and, while the mixture is stirred at a temperature of not more than 10° C, 21 g. of p-toluenesulfonyl chloride is added in small installments. After the addition has been completed, the reaction mixture is allowed to stand at a temperature not exceeding 10° C for 6 hours. Then, following the addition of ice, the reaction mixture is extracted with ether. The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the resultant 4-carbomethoxy-1-indanyl p-toluenesulfonate is dissolved in 100 ml. of dimethylsulfoxide, followed by stirring. Then, 5.5 g. of sodium cyanide is added and the mixture is stirred at room temperature for 11 hours. Following the addition of 850 ml. of water, the reaction mixture is extracted with ether. The extract is washed with a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (600 g. silica gel; eluant: chloroform). The described procedure gives methyl 1-cyanoindan-4-carboxylate as crystals melting at 76°-77° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].O>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH3:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (2.98 ml, 38.6 mmol) was added to an ice-cold solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (Synth. Commun. 1993; 23(17); 2443) (4.5 g, 25.7 mmol) in pyridine (40 ml), and the reaction stirred for 2 hours. The solution was poured into water (150 ml), and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with 10% aqueous citric acid solution, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (34:66 to 40:60) to give the title compound, 1.0 g.
Reaction SMILES: [CH2:1]([P:3]([CH2:9][O:10][S:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])(=[O:13])=[O:12])(=O)[O:4]C(C)C)[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[CH2:1]([P:3]([Cl:24])([CH2:9][O:10][S:11]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])(=[O:13])=[O:12])=[O:4])[CH3:2]
Reactant: CCP(=O)(COS(=O)(=O)c1c(C)cccc1Cl)OC(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 50 °C
Reaction time: 65 h

Procedure:
A mixture of 20.0 g of O-isopropyl P-ethyl[[2-chloro-6-methylphenyl)sulfonyloxy]methyl]phosphinate (Compound 119), 80 ml of 1,2-dichloroethane and 4.6 ml of thionyl chloride was heated to 50° C. for four hours. 31P NMR analysis of an aliquot of the reaction showed that one third of the starting material was still present so the reaction was heated to 50° C. for 1.5 hours, cooled and let stand at room temperature for 65 hours, heated again to 50° C. for 4 hours and let stand overnight. 31P NMR indicated that starting material was still present so 2 ml of thionyl chloride was added and the reaction was heated to 50° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure to yield 19.4 g of the desired phosphinoyl chloride which was shown to be 95% pure by 31P NMR. Using the above procedure, the following phosphinoyl chloride of Formula IX was prepared form the indicated compound: P-methyl[[(2-chloro-6isopropylphenyl)sulfonyloxy]methyl]phosphinoyl chloride was prepared from Compound 197 (Example 33).
Reaction SMILES: FC(F)(F)C(NCC1C=CC=CC=1C(O)=O)=[O:4].[CH:18]1([N:24]=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[C:25]([NH:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:4]
Reactant: O=C(O)c1ccccc1CNC(=O)C(F)(F)F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Weighed into a 10 ml round-bottomed flask were 593 mg (2.4 mmol) of trifluoroacetamidomethyl benzoic acid. This acid was dissolved in 4 ml of anhydrous tetrahydrofuran and 324.4 mg (1.2 mmol) of 1,3-dicyclohexylcarbodiimide were added. It was left stirring, at ambient temperature, for 2 hours. The white precipitate of dicyclohexylurea obtained was filtered over a frit.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[CH:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[N:17][N+:18]([O-:20])=[O:19])[CH2:2][CH3:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:14]2[CH2:15][CH2:16][N:12]([CH:11]=[N:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:1][CH2:2][CH3:3])[C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:24][N:23]=1
Reactant: CCCc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1ccccc1N=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Yield: 30.8 %

Procedure:
A mixture of 0.8 g of 1-(2-n-propylphenyliminomethyl)-nitroiminoimidazolidine, 0.42 g of 2-chloro-5-chloromethylpyridine, 0.36 g of potassium carbonate and 8 ml of acetonitrile were refluxed under heating conditions for 4 hours. The reaction mixture was evaporated and purified by column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to give 0.32 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-propylphenyliminomethyl)imidazolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:39][C:37]2[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ncccc23)CC1
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cccnc2n1-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 6 (50.0 mg, 113 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6, and purification by preparative HPLC. Yield: 28 mg.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[CH2:15]1[C:20](=[O:21])[N:19]([Br:22])[C:17](=[O:18])[CH2:16]1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:22][CH2:11][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5]2.[C:17]1(=[O:18])[NH:19][C:20](=[O:21])[CH2:15][CH2:16]1
Reactant: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1CBr
Product: O=C1CCC(=O)N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 283.7 %

Procedure:
To a solution of 2,3-dimethyl-6-nitro-2H-indazole (3.00 g, 15.69 mmol) in CCl4 (500 mL) was added AIBN (0.51 g, 3.14 mmol) and NBS (3.06 g, 17.26 mmol). The mixture was heated to 80° C. for 5 hours then stirred at rt overnight. Approximately half of the solvent was removed in vacuo, and the mixture was filtered. The filtrate was conc. in vacuo, and the crude product was purified by silica gel column chromatography eluting with ethyl acetate and hexane to afford 3-(bromomethyl)-2-methyl-6-nitro-2H-indazole with some succinimide present (4.41 g, 104% TY). 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=2.1 HZ, 1H), 7.98 (dd, J=9.3, 2.1 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 4.87 (s, 2H), 4.28 (s, 3H). MS (ES+, m/z) 270, 272 (M+H).
Reaction SMILES: CO[C:3](=[O:39])[NH:4][CH:5](C1C=CC=CC=1)[C:6](=[O:32])[N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:40][O:41][C:42](=[O:69])[NH:43][CH:44]([C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[NH:56][C:57]([C:60]2[S:64][CH:63]3[CH:65]=[C:66](Br)[S:67][CH:62]3[CH:61]=2)=[CH:58][N:59]=1)=[O:49])[CH:45]([CH3:47])[CH3:46].[C:70]([O-:73])([O-])=O.[K+].[K+]>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>[CH3:40][O:41][C:42](=[O:69])[NH:43][CH:44]([C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[NH:56][C:57]([C:60]2[S:64][CH:63]3[CH:65]=[C:66]([C:20]4[CH:21]=[CH:22][C:17]([C:14]5[NH:13][C:12]([CH:8]6[CH2:9][CH2:10][CH2:11][N:7]6[C:6](=[O:32])[CH:5]([NH:4][CH2:3][O:39][O:73][CH3:70])[C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[N:16][CH:15]=5)=[CH:18][CH:19]=4)[S:67][CH:62]3[CH:61]=2)=[CH:58][N:59]=1)=[O:49])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Product: COOCNC(C(=O)N1CCCC1c1ncc(-c2ccc(C3=CC4SC(c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)=CC4S3)cc2)[nH]1)c1ccccc1
Temperature: 85 °C
Yield: 63.8 %

Procedure:
[2-Oxo-1-phenyl-2-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester (204 mg, 0.385 mmol), (1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (137 mg, 0.268 mmol), Pd(PPh3)4 (31 mg, 0.0268 mmol) and K2CO3 (2M in H2O, 0.4 mL, 0.8 mmol) were combined in 1,2-dimethoxyethane (2.7 mL). After 10 min of degassing with bubbling N2, the reaction mixture was heated to 85° C. for 19 h. After this period, it was cooled and diluted MeOH. The suspension was filtered over a thiol SPE cartridge to remove the palladium, then concentrated. The crude residue was purified by HPLC to afford the title compound (103 mg, 46%). MS (ESI) m/z 835 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:28][CH3:29])[CH:13]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Si:21]([O:20][C@H:13]1[C@H:12]([CH2:28][CH3:29])[NH:11][C:15](=[O:16])[CH2:14]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[Si:21]([O:20][C@@H:13]1[C@H:12]([CH2:28][CH3:29])[NH:11][C:15](=[O:16])[CH2:14]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@H](CC)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC[C@@H]1NC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59 %
Yield: 13 %

Procedure:
To a solution of ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-(tert-butyldimethylsilyloxy)hexanoate (64.0 g) in methanol (500 mL) was added 10% palladium carbon (containing 50% water, 6.5 g), and the mixture was stirred at room temperature for 3.5 hr under a hydrogen atmosphere and filtered. Sodium methoxide (13.6 g) was added to the filtrate, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1→1/4) to give the title compound (yield: 21.6 g, 59%) and (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (yield: 4.64 g, 13%) as a colorless solid and a colorless oil, respectively.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH2:24]([C:26]1[O:30][C:29]([NH2:31])=[N:28][N:27]=1)[CH3:25].CC(C)=O>CN(C=O)C>[CH2:24]([C:26]1[O:30][C:29]([NH:31][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:28][N:27]=1)[CH3:25]
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: CCc1nnc(N)o1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
500.5 mg (1.64 mmol) (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)methanone and 186.8 mg (1.64 mmol) 5-ethyl-[1,3,4]oxadiazol-2-ylamine were suspended in 1.5 ml DMF and stirred for 6 h at 130°. The reaction mixture was allowed to cool to room temperature and 5 ml of acetone were added. After stirring for 5 min, the product was filtered, washed with acetone and dried in vaccuo to yield 219.5 mg of 9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)amide as a white solid, m.p. 256-257° C. and MS: m/e=321.2 (M+)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25])=[N+:2]=[N-:3]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN=[N+]=[N-]
Temperature: 25 °C

Procedure:
Sodium azide (14.7 g) was added to a solution of 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (22.8 g prepared according to the method of Part F) in N,N-dimethylformamide (75 mL). The reaction mixture was heated at reflux for several hours and then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (100 ml) and then extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum to provide crude 1-(2-azidoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an oil.