Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:37]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:37])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 219), using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 488 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 11.10 (br s, 1H), 7.72-7.63 (m, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.42 & 7.33 (2 singlets, amide rotamers, Ar—H, 1H), 7.25 (s, 1H), 4.86 (br d, J=11.2 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.17-4.03 (m, 1H), 3.61-3.38 (m, 2H), 3.29-3.14 (m, 1H), 2.46-1.70 (m, 13H), 1.45 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[N:8][CH:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: Oc1cc2nnnn2c2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2nnnn2c2cnccc12
Temperature: 90 °C

Procedure:
A suspension of tetrazolo[1,5-a][1,7]naphthyridin-5-ol (3.5 g) in phosphorous oxychloride (15 mL) was heated at 90° C. for 2 hours. The reaction mixture was concentrated under vacuum. The residue was poured into ice water, dichloromethane was added followed by the addition of 10% sodium hydroxide to neutral pH. The product was partitioned into dichloromethane. The dichloromethane layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide 3.8 g of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176-177° C. Analysis: Calculated for C8H4ClN5: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.80; %H, 2.16; %N, 34.45.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:15])[CH2:11][N:12]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]([OH:15])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC(O)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCc1ccccc1
Yield: 70.2 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 5.7 g of 3-benzyloxy-2-hydroxypropylazide (prepared as described in Preparation 47), 2.09 g of lithium aluminum hydride and 250 ml of anhydrous tetrahydrofuran were used, to give 3.5 g of the title compound as white crystals, melting at 72° C. to 74° C.
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(N)=O)c2c3cc(NS(C)(=O)=O)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of methane sulphonyl chloride (30 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphon-amido-9H-4-carbazolecarboxamide(20 mg), mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].CI.CCCCCC.C(OCC)(=O)C>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(OCC)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:23])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncn2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc2c(-c3ccncn3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(4-fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine (Example 1, 0.2 g, 0.69 mmol) in dry tetrahydrofuran (5 mL) was cooled to −78° C. under nitrogen and lithium diisopropylamide (0.45 mL of a 2M solution in heptane/tetrahydrofuran/ethylbenzene, 0.9 mmol) was added dropwise. The reaction mixture was stirred for about 10 minutes and methyl iodide (0.2 mL, 4 mmol) was added. The solution was allowed to warm to room temperature and stirred for a further 1.5 hours. The reaction mixture was diluted with diethyl ether (20 mL), water (20 mL) added, and the organic phase separated. The aqueous phase was further extracted with ether (20 mL) and the combined ether phases were dried over anhydrous magnesium sulfate, filtered and the solvents evaporated to give a yellow solid. Chromatography on silica gel eluting with 9:1 hexane/ethyl acetate gave the title compound, 0.080 g (38%). 1H NMR (DMSO-d6): δ 2.72 (s, 3H), 7.05 (d, J=6.3 Hz, 2H), 7.32 (t, J=8.8 Hz, 2H), 7.46 (dd, J=7.0, 8.6 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 8.32 (d, J=9.0 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 9.15 (s, 1H); APESI+MS m/z 305 (M+1)−.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][CH:44]([CH2:43][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:22])=[CH:16]5)=[N:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCC5CCN(C(=O)OC(C)(C)C)CC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (423 mg, 1.45 mmol), (prepared as described for the starting material in Example 82), triphenylphosphine (685 mg, 2.61 mmol), 4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (500 mg, 2.32 mmol), (prepared as described for the starting material in Example 10), and diisopropyl azodicarboxylate (528 mg, 2.61 mmol) in methylene chloride (18 ml) was stirred overnight at ambient temperature. The mixture was then poured onto a column of silica and eluted with ethyl acetate. After evaporation of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (478 mg, 68%).
Reaction SMILES: ClC1N=CC(NCC2C=CC(OC)=CC=2)=CC=1C(F)(F)F.COC1C=CC(C[NH:29][C:30]2[CH:31]=[C:32]([C:42]([F:45])([F:44])[F:43])[C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:34][CH:35]=2)=CC=1>>[F:44][C:42]([F:43])([F:45])[C:32]1[C:33]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[N:34][CH:35]=[C:30]([NH2:29])[CH:31]=1
Reactant: COc1ccc(CNc2cnc(-c3cccnc3)c(C(F)(F)F)c2)cc1
Agent: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Product: Nc1cnc(-c2cccnc2)c(C(F)(F)F)c1

Procedure:
The title compound was synthesized as described for Intermediate 1, Step 5 using N-(4-methoxybenzyl)-3-(trifluoromethyl)-[2,3′-bipyridin]-5-amine as the starting material. 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, 1H), 8.64 (dd, 1H), 8.30 (dd, 1H), 7.78 (m, 1H), 7.35 (m, 1H), 7.32 (d, 1H), 4.05 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N:32]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. morpholine-4-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 59 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)morpholine-4-sulfonamide (percentage yield: 86%), was obtained.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[S-:12][C:13]#[N:14].[K+].BrBr.[OH-].[NH4+]>C(O)(=O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]2[N:8]=[C:13]([NH2:14])[S:12][C:6]=2[CH:5]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OC(F)F)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To 4-(difluoromethoxy)aniline (9.55 g, 60 mmol) in acetic acid (90 mL) was added potassium thiocyanate (KSCN) (12.41 mL, 240 mmol). The mixture was stirred for 20 minutes (KSCN dissolved into solution). To this mixture bromine (3.08 mL, 60.0 mmol) in acetic acid (40 mL) was added dropwise over 20 minutes. The reaction was stirred at room temperature overnight. It was poured into a mixture of 800 ml ice water and 200 ml saturated ammonium hydroxide. The product was extracted with ethyl acetate (5×). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 6-(difluoromethoxy)benzo[d]thiazol-2-amine (12.6 g, 52.4 mmol, 87% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][CH:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:28])[C:24](O)=[O:25]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[CH:23]([CH3:22])[C:27]([NH:29][CH2:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: CC(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (epimers) as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: O=C(O)CCCc1ccccc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCCc4ccccc4)c3Cl)c2n1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg), 4-phenylbutyric acid (40 mg) and dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50 mg) and 1-hydroxybenzotriazole (41 mg). After being stirred for an hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(4-phenylbutyrylglycyl)-amino]benzyloxy]-2-methylquinoline (105 mg) as a colorless glass.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]I.Cl>C1COCC1.CCOCC.[Zn]>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: ClCCCI
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: ClCCCN1CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Step 1. To a solution of thiomorpholine (1.0 g, 9.7 mmol) and 1-chloro-3-iodopropane (1.98 g, 9.7 mmol) in dry THF (30 ml) was added activated zinc powder (0.64 g, 9.7 g atom). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (9.7 ml, 9.7 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)thiomorpholine hydrochloride (0.40 g, 19%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.20-2.25 (m, 2H), 2.78-2.81 (m, 2H), 3.09-3.27 (m, 6H), 3.68-3.71 (m, 2H), 3.74 (t, J=6.4 Hz, 2H), 11.20 (brs, 1H). Step 2. To a solution of OZ288 (0.38 g, 1.07 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.09 g, 2.13 mmol) and tetrabutylammonium hydrogensulfate (0.07 g, 0.21 mmol). After the mixture was stirred at rt for 30 min, 4-(3-chloropropyl)thiomorpholine hydrochloride (0.23 g, 1.07 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated to afford OZ462 free base (0.433 g, 81%) as a colorless solid. To a solution of the above free base (0.41 g, 0.82 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.08 g, 0.82 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried under vacuum at 40° C. to afford trioxolane OZ462 (0.42 g, 86%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.32-2.41 (m, 2H), 2.46-2.54 (m, 1H), 2.70 (d, J=14.7 Hz, 2H), 2.80 (s, 3H), 2.96-3.07 (m, 2H), 3.24-3.34 (m, 2H), 3.45-3.54 (m, 2H), 3.87 (d, J=11.8 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 11.19 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.66, 24.86, 26.44, 26.84, 31.57, 34.66, 34.76, 36.37, 36.75, 39.42, 41.97, 54.35, 56.23, 64.61, 108.32, 111.36, 114.22, 127.74, 139.14, 156.40. Anal. Calcd for C30H45NO7S2: C, 60.48; H, 7.61; N, 2.35. Found: C, 60.60; H, 7.54; N, 2.17.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COCCCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC[C@H]1CNCCN1
Reaction time: 2 h

Procedure:
Into a stirred, room temperature solution of (S)-2-(4-methoxybutyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.198 g, 0.53 mmol) in CH2Cl2 (2.6 mL), add TFA (2.6 mL) and stir for 2 h. Concentrate the mixture under reduced pressure, dilute with H2O and load onto an SCX column (10 g). Wash the resin with H2O (3×100 mL), MeOH (3×100 mL) and elute the product with 2 M NH3 in MeOH (3×100 mL). Concentrate the purified fractions under reduced pressure and azeotrope the residue with CH2Cl2/hexanes (1:2). Place the residue under vacuum to give the title compound: orange crystals (0.093 g), mass spectrum (m/e):173.4 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([SH:15])=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:34][C:35]1[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([S:15][CH2:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CCCc1c(CSc2nnc(S)s2)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1c(CSc2nnc(SCc3ccc(C(=O)OCC)cc3)s2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a mixture of 340 mg of 2-[(4-acetyl-3-hydroxy-2propylbenzyl)thio]-5-mercapto-1,3,4-thiadiazole, 150 mg of anhydrous potassium carbonate and 5 ml of N,N-dimethylformamide was added 220 mg of ethyl p-(bromomethyl)benzoate followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of toluene. After washing with water and drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (9:1) gave 0.38 g of oily ethyl p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thiomethyl]benzoate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[C:4]([C:17]1[C:16]([NH2:21])=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)[CH:20]=[CH:19][N:18]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Solvent: CCO
Product: CC(C)(C)c1nccc(N2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)c1N
Yield: 67 %

Procedure:
Following Method 2 of Example 49, (S)-4-(3-(tert-butyl dimethylsilyloxy)piperidin-1-yl)-3-nitropyridine in ethanol was reduced yielding tert-butyl (S)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine (67% yield 3 steps). LCMS (m/z): 308.2 (MH+); LC Rt=3.47 min.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[OH:22])C1C=CC=CC=1.C(O)(=O)C.O1CCCC1.Cl[C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40]>C(O)C.O.[OH-].[OH-].[Pd+2]>[CH2:42]([O:41][C:39]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[OH:22])=[O:40])[CH:43]=[CH2:44]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(O)c2ccncc2)N(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(4-pyridyl)methanol (32.73 g) in ethanol (300 ml) was added acetic acid (9.4 ml) and palladium hydroxide on carbon (10 g). The mixture was stirred vigorously under an atmosphere of hydrogen at room temperature for 6 hours. The palladium catalyst was removed by filtration and washed with ethanol. The combined organic layer was evaporated under reduced pressure to give a residue. To a solution of the residue in water (300 ml) and tetrahydrofuran (THF) (300 ml) was added dropwise allyl chloroformate (9.6 ml) under pH 9~10 at 0° C. After stirring the mixture at 0° C. for 1 hour, the reaction mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluting with ethyl acetate:n-hexane=7:3) to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(4-pyridyl)methanol (21.74 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:20].C(NCC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13](=[S:20])[NH2:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C#N)ccc1OCc1ccccc1
Reactant: S
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
Through a solution of 4-(benzyloxy)-3-propylbenzonitrile (1.23 g, 4.91 mmol) (Example 30) in DMF (35 mL) was passed H2S for 30 min at rt. Diethyl amine (0.76 mL, 7.36 mmol) was added and the solution was heated to 60° C. for 4 h. The mixture was cooled to rt, and the residual H2S was removed by passing argon through the solution for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of the filtrate under reduced pressure resulted in a yellow solid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13].[CH3:14]COC(C)=O>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]1[CH2:14][CH2:13]1
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2c1ccc(Br)c2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.2 g, 9.21 mol) and Pd(OAc)2 (100 mg) in EtOAc (50 mL) was added a solution of CH2N2 in ether (100 mL) slowly. The resulting mixture was stirred at room temperature overnight, then quenched with acetic acid, filtered and the filtrate washed with water and brine, dried and concentrated to provide 5-bromo-4-cyclopropyl-2-benzofuran-1(3H)-one.