Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]N)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].C=O.[C:29]([BH3-])#[N:30].[Na+].[C:33](O)(=O)CC>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:30]([CH3:29])[CH3:33])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Reactant: [BH3-]C#N
Reactant: CCC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 23 a solution of 8-nitro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and propionic acid to give 8-nitro-1-[ (dimethylamino)methyl]-6-(o-chlorophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:35][Si:33]([CH3:36])([C:29]([CH3:32])([CH3:31])[CH3:30])[O:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
To a dimethylformamide (hereinafter, abbreviated as DMF in some cases) (100 mL) solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (50 g) were sequentially added imidazole (29.22 g), and tert-butyldimethylchlorosilane (30.87 g) under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, a small amount of ethanol was added, the reaction solution was poured into ice water, and this was extracted with ethyl acetate:hexane (2:3). The extract was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, water and a saturated saline, dried with sodium sulfate, and concentrated under reduced pressure to obtain a titled compound (76.2 g) having the following physical property values.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C@H:22]([OH:35])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+]>>[OH:35][C@H:22]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:24]=1)[CH2:21][NH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:37])=[O:3])=[O:36])=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}benzoyl)amino]acetate (which was obtained in Example 196) by sodium hydroxide hydrolysis as a white solid; mp >85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.55-2.90 (m, 5H), 2.80 (s, 3H), 3.49 (d, J=4.5 Hz, 2H), 3.70-3.80 (m, 2H), 4.43 (dd, J=7.9, 4.4 Hz, 1H), 6.70 (d, J=7.4 Hz, 1H), 6.81 (dd, J=7.4, 2.0 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.12 (d, J=2.0 Hz, 1H), 7.54 (t, J=4.5 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H); MS (ES) m/z: 507.2 (MH+); HRMS Calcd. for C23H31N4O7S(MH+): 507.1908. Found: 507.1912.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:37])=[N:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:37])=[N:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(OC2CCOC2)ccc1Br
Product: Cc1nc(OC2CCOC2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-3-bromo-2-methyl-6-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 13) in analogy to Example 1a): MS (ISP): 481.2 (M+H)+ and 483.2 ((M-Boc)+H)+ (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][CH3:22])[CH:15]=1>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>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCc1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Yield: 26.6 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.47 g, 2.8 mmol), 4-bromo-2-ethylaniline (432 mg, 2.16 mmol), and (PPh3)4Pd (75 mg, 0.065 mmol) to afford 139 mg (20%) of 4-amino-3-ethyl-3'-nitrobiphenyl. Data for 4-amino-3-ethyl-3'-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.38 (t, J=2.1, 1H), 8.08 (m, 1H), 8.00 (m, 1H), 7.66 (t, J=8.0, 1H), 7.45 (d, J=2.3, 1H), 7.39 (dd, J=8.3, 2.3 1H), 6.83 (d, J=8.3, 1H), 4.68 (br s, 2H).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[C:5]1=[O:26])(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:35](N(CC)CC)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:6]2[NH:7][C:8](=[O:10])[C:9](=[CH:35][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:4][C:5]2=[O:26])=[N:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(OCc3ccccc3)cn2)C1=O
Reactant: CCN(CC)CC
Reactant: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=CCc1ccccc1
Temperature: 60 °C
Yield: 83 %

Procedure:
Compound A (3.51 g) was added to a 40 mL of dimethylformamide solution containing benzaldehyde (1 eq.) and 4 equivalents of triethylamine (4 eq.). The solution was refluxed at 60° C. for 16 hr and cooled at an ice bath to produce a yellow precipitate. The precipitate was then collected and washed with ethyl acetate to give 3.3 g (83%) of 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-(benzylmethylidene)piperazine-2,5-dione (Compound B). mp: 223-225° C.; 1H-NMR (400 MHz, DMSO): 5.243 (s, 2H), 6.695 (s, 1H), 6.812 (s, 1H), 7.346-7.634 (m, 12H, aromatic), 8.528 (s, 1H), 10.245 (s, 1H), and 12.289 (s, 1H).
Reaction SMILES: [C:1]([CH:8]([NH2:11])C#N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+].[NH4+].[Cl-].[CH3:18][N:19](C=O)C>>[C:1]([C:8]1[N:11]([CH2:18][NH2:19])[N:14]=[N:13][N:12]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C(N)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1nnnn1CN

Procedure:
5-(BOC-Phe-Nle-AHCP-aminomethyl)-tetrazole is obtained, analogously to Example 4, from BOC-Phe-OH and 5-(H-Nle-AHCP-aminomethyl)-tetrazole [obtainable by reacting BOC-aminoacetonitrile with NaN3 in DMF in the presence of NH4Cl at 80°-90° to give 5-BOC-aminomethyltetrazole (M.p. 153°-155°), splitting off the BOC group to give 5-aminomethyltetrazole, subjecting the latter to a condensation reaction with BOC-Nle-AHCP-OH to give 5-BOC-Nle-AHCP-aminomethyltetrazole and again splitting off the BOC group].
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][S:10]([O:13][CH3:14])(=[O:12])=[O:11]>>[F:9][S:10]([O-:13])(=[O:12])=[O:11].[CH3:14][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: COS(=O)(=O)F
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])F
Yield: 96 %

Procedure:
Trichloroisothiazole (37.7 g, 0.20 mol) and 38 ml of methyl fluorosulfonate were mixed under a nitrogen atmosphere. The mixture was heated at 70°-80° for 30 min. The resulting solid was washed with ether and benzene to yield 55.6 g (96%) of 2-methyl-3,4,5-trichloroisothiazolium fluorosulfonate, mp 162 (d). Analysis-calculated for C4H3Cl3FNO3S2 : C, 15.87; H, 0.99; N, 4.63; Found: C, 15.81; H, 1.02; N, 4.49.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH:34]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([C:42](=[O:43])[CH2:41][CH2:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Reactant: O=C(Cl)CCC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(C(=O)CCC1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (10 mL) was treated with dry triethylamine (0.11 mL), then with a solution of 3-cyclohexylpropionyl chloride (45 mg) in dry dichloromethane (5 mL). After stirring at room temperature overnight the reaction mixture was washed with water, then the organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) to give 7-chloro-2-(3-cyclohexylpropionyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-8-carboxylic acid amide (80 mg) as a white solid, m.p. 181–182° C. MS: 416 [MH]+, 414 [MH]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C([CH:14]([CH2:18][C:19](Cl)=[O:20])[C:15](Cl)=[O:16])C.O.[NH2:23][NH2:24]>CO>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:15](=[O:16])[CH2:14][CH2:18][C:19]([NH:23][NH2:24])=[O:20])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: NN
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Solvent: O
Solvent: CO
Product: CC1(C)CC(NC(=O)CCC(=O)NN)CC(C)(C)N1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminosuccinamide was prepared by the reaction of 4-amino-2,2,6,6-tetramethylpiperidine with ethyl succinyl chloride followed by hydrazinolysis of the resulting ester with 85% hydrazine hydrate in methanol.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C)=O)=[CH:4][CH:3]=1.[I:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C:25]([CH2:30][C:31](O)=[O:32])=[N:26][S:27](=[O:29])(=[O:28])[C:22]=2[CH:21]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]([OH:15])=[C:30]([C:25]3[NH:24][C:23]4[CH:34]=[CH:35][C:20]([I:19])=[CH:21][C:22]=4[S:27](=[O:28])(=[O:29])[N:26]=3)[C:31]2=[O:32])=[CH:17][CH:18]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-(4-fluoro-benzylamino)-cyclopentanecarboxylate (2.50 g, 10 mmol) in anhydrous N,N-dimethylformamide (25 mL) under a nitrogen atmosphere, (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 3.66 g, 10 mmol), N-methylmorpholine (2.20 mL, 20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) were added sequentially. After stirring at 25° C. for 16 h, the reaction mixture was diluted with ethyl acetate, washed with a 1.0 M aqueous hydrochloric acid solution and saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude amide intermediate.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 54–68, 4-morpholinecarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 377.2295.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[O:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)[CH2:15][CH2:16][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)C1CCC(=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(O)(c2nccs2)CC1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a flask containing THF (82 mL) was added isopropylmagnesium chloride/lithium chloride (1.2 M in THF, 37.7 mL, 45 mmol). A solution of thiazole (3.5 g, 41 mmol) in THF (20 mL) was added slowly. The reaction was stirred for one hour. A solution of tert-butyl 4-oxocyclohexanecarboxylate (12.23 g, 62 mmol) in THF (20 mL) was added and the reaction was stirred for 3 hours. The reaction was then quenched slowly with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (9.25 g, 33 mmol, 79% yield). MS ESI: [M+H]+ m/z 284.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19][C@H:18]1[CH2:30][OH:31])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:24])[CH3:25])[CH2:19][C@H:18]1[CH:30]=[O:31])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O

Procedure:
To a solution of oxalyl chloride (2.53 ml) and dichloromethane (90 ml) was dropwise added dimethyl sulfoxide (4.31 ml) at -40° C.~-50° C. with stirring and the mixture was stirred at the same temperature for 5 minutes. To the solution was added dropwise a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsiloxy-2-(hydroxymethyl)pyrrolidine (8.70 g) in dichloromethane (45 ml) at -40° C.~-50° C. After 10 minutes with stirring, triethylamine (19.2 ml) was dropwise added to the solution and the mixture was stirred at 0°~10° C. for 30 minutes. The insoluble material was filtered off and the filtrate was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsiloxy-2-formylpyrrolidine.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.C(OP([O-])OCC)C.C(N(CC)CC)C>C(O)C.ClCCl>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23](/[CH:25]=[CH:26]/[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: O=C1O[C@@H](Cn2cc(/C=C/Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (0.4 g, 0.69 mmol) was dissolved/supended in ethanol (2 ml) and diethylphosphite (0.36 ml, 2.79 mmol). Triethylamine (0.195 ml, 1.39 mmol) was added and the reaction mixture heated under vigorous stirring at 90° C. for 5 hours. It was cooled to room temperature, diluted with dichloromethane, washed with phosphate buffer (pH 7) and dried over sodium sulfate. Chromatography on silica gel with dichloromethane/DMF (50:1 to 40:1) gave 151 mg (44%) of the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:38])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:38])[C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (1.02 g, 3.39 mmole) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (2.61 g, 5.08 mmole) in dichloromethane (30 ml) was stirred at room temperature for 16 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a yellow solid (1.00 g). MS: (+) m/z 427.05 (M+1), MS: (−) m/z 425.01 (M−1).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[I:20][CH3:21]>CO>[I-:20].[OH:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=1)[CH2:3][N+:4]1[CH:8]=[CH:7][N:6]([CH3:21])[CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc(C(O)Cn2ccnc2)cc1
Reactant: CI
Solvent: CO
Product: Cn1cc[n+](CC(O)c2ccc(NS(C)(=O)=O)cc2)c1
Product: [I-]

Procedure:
Heat a solution of 4.0 g (14.2 mmole) of (±)-N-[4-[1-hydroxy-2-(1H-imidazol-1-yl)ethyl]phenyl]methanesulfonamide, 2 ml (32.1 mmole) of iodomethane and 50 ml methanol in a glass pressure tube to 80° C. for 24 hours. Remove the solvent in vacuo. Crystallize the residue from acetone. Recrystallize from acetone to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[ClH:13].[CH3:14][N:15]([CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH3:16]>C(O)C.O.C(O)(C)C>[ClH:13].[ClH:13].[CH3:14][N:15]([CH2:17][C:18]([NH:20][N:21]=[C:1]([C:4]1[N:5]=[C:6]([C:10](=[N:21][NH:20][C:18](=[O:19])[CH2:17][N:15]([CH3:16])[CH3:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2])=[O:19])[CH3:16]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CN(C)CC(=O)NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CC(=NNC(=O)CN(C)C)c1cccc(C(C)=NNC(=O)CN(C)C)n1
Yield: 95 %

Procedure:
A solution of 2,6-diacetylpyridine (Aldrich Chemical, Milwaukee, Wis., 0.815 g, 5 mmole) in hot ethanol (10 ml) was mixed with a solution of dimethylaminoacethydrazide hydrochloride (Avocado/Alfa Aesar, Ward Hill, Mass.) in warm water (10 ml). The mixture was heated to reflux briefly and allowed to cool. After 3 hrs the mixture was diluted with 20 ml isopropanol, causing a copious precipitate to form. The precipitate was filtered out and washed with isopropanol. Drying gave 2.065 g (95%) white crystalline solid, melting pt. 280-282° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([C:7]([NH2:9])=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.CC(C)=[O:15]>>[OH:15][N:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][CH:6]([C:7]([NH2:9])=[O:8])[C:2]1([CH3:12])[CH3:1]
Reactant: CC(C)=O
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1
Product: CC1(C)CC(C(N)=O)C(C)(C)N1O
Reaction time: 2 h

Procedure:
A solution of 0.066 M DMD in acetone (9 ml, 0.59 mmol) was added to a cold stirred solution of 2,2,5,5-tetramethyl-pyrroline-3-carboxamide (Frinton, Vineland NJ, 100 mg, 0.59 mmol) in acetone (5 ml). The mixture was stirred for two hours. Evaporation of the solvent on a rotary evaporator gave a colorless crystalline solid which was dried in vacuo for 6 hours. Sublimation of the solid at 10-3 torr gave a white solid, mp 65-171.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:13]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml triethylamine and 0.18 ml of 4-anisoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 30 minutes. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. Chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5 then CH2Cl2/CH3CN 8/2 then methylene chloride/methanol/ammonium hydroxide 85/15/1.5). 275 mg of expected product is collected.