Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C1CCSCC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1CSCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To an ice-cooled solution of 1.26 g (0.0086 mol) of product from Step C and 1.44 g (0.0142 mol) of triethylamine in 25 ml of methylene chloride was added dropwise 0.75 g (0.0095 mol) of acetyl chloride. The solution was stirred for four hours at 0° C., after which time it was washed with water, a saturated solution of sodium bicarbonate, and water. The organic phase was dried (MgSO4), filtered, and evaporated to give 1.52 g (94%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[OH-].[K+]>CC(O)C>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)cc2OC)[C@H](OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Yield: 46 %

Procedure:
A mixture of 16.6 parts of cis-ethyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1-piperidinecarboxylate, 26.36 parts of potassium hydroxide and 160 parts of 2-propanol was stirred and refluxed for 3 hours. The reaction mixture was evaporated in vacuo on a boiling water-bath. Water was added to the residue and the whole was evaporated again. The residue was boiled in water on a warm water-bath. The precipitated product was filtered off and taken up in trichloromethane. The organic phase was separated, dried, filtered and evaporated. The residue was taken up in methylbenzene. The solid residue was filtered off and dried, yielding 6.7 parts (46%) of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)-benzamide; mp. 184.3° C. (compound 211).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>CC1C=CC=CC=1>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1cccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred mixture of 28.2 parts of 3-pyridinamine, 59 parts of N,N-diethylethanamine and 450 parts of methylbenzene were added dropwise 39 parts of 4-fluorobenzoyl chloride (exothermic reaction, the temperature rose to 40° C.). Upon complete addition, stirring was continued for 2 hours at reflux temperature. After cooling, the precipitated product was filtered off and dissolved in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 52.3 parts (80.6%) of 4-fluoro-N-(3-pyridinyl)benzamide; mp. 150.2° C. (int. 66).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([C:16](=[O:19])[CH2:17]Br)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]([CH:17]=[P:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)O
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To chloroform (200 ml) are added ethyl α-[2-methoxy-4-(2-bromoacetyl)phenoxy]acetate (20 g) and triphenylphosphine (20.6 g) in an ice-bath, and the mixture is stirred for one hour. After confirming that the starting compounds are well consumed, the mixture is washed with an aqueous potassium carbonate solution. The mixture is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. To the residue is added methanol (200 ml), and thereto is added dropwise sodium hydroxide in an ice-bath. After confirming that the starting compounds are well consumed, to the mixture is added conc hydrochloric acid. The precipitated crystals are washed with water and diethyl ether, and dried to give (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (25 g).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O.CCOCC>[C:15]1(=[O:25])[N:19]([CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=Cc1cccc(OCC(O)CCl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1

Procedure:
The distilled product from Example 1 (21.1 g, 0.098 mol) and potassium phthalimide (37 g, 0.20 mol) are dissolved in 100 ml of N,N-dimethylformamide and the mixture is heated 22 hours on a steam bath under N2. The mixture is cooled, diluted with 200 ml of ether and filtered. The filtrate is concentrated to remove ether and diluted to 500 ml with water to give the crystalline title product, 30.8 g, mp 122°-126°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C([O:34]O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:34][C@@H:8]3[C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(C)(C)OO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Temperature: 80 °C

Procedure:
A solution of 23.3 g of 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol in 350 ml of toluene was combined dropwise, after adding vanadium(IV) oxide acetylacetonate, within 35 minutes with 23.3 ml of 80% tert.-butyl hydroperoxide, dissolved in 115 ml of toluene. The reaction solution was maintained at 80° C. for another 30 minutes, then cooled, diluted with diethyl ether, washed with sodium bisulfite solution, sodium bicarbonate solution, and water, and dried and evaporated, thus obtaining 24.5 g of 3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol, mp 162°-163° C. (diisopropyl ether).
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2(O)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:31][C:32]([CH3:37])([CH3:38])[C:33]([CH3:35])([CH3:36])[O:34]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Pyridine (0.353 mL, 4.380 mmol) and trimethylsilyl triflate (0.396 mL, 2.189 mmol) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-pyran-4-ol (Example 130-(3); 0.55 g, 1.095 mmol) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (548 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18]O)[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].O>CN(C=O)C>[Br:41][CH2:18][CH2:17][C:15]1[N:16]=[C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:20])(=[O:10])=[O:9])[S:13][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCBr)cs1
Temperature: 0 °C
Yield: 41 %

Procedure:
An ice-cold mixture of EXAMPLE 181A (2.03 g, 6.10 mmol), triphenylphosphine (4.80 g, 18.31 mmol) and carbontetrabromide (6.07 g, 18.31 mmol) in DMF (30 mL) was stirred for 1.5 h, and was then poured into water. The mixture was extracted with DCM, dried (sodium sulfate) and the solvent was evaporated. The crude material was twice purified by flash chromatography on silica gel gradient eluting with 0-4% acetone in DCM giving N-[4-(2-bromoethyl)-1,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide as a solid (990 mg, 41%). MS (Ionspray, [M+H]+) m/z 394; Anal. Calcd. (found) for C12H12BrClN2O2S2: C, 36.4 (36.6)%; H, 3.1 (3.3)%; N ,7.1 (7.2)%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:33]=[O:34])C>C1COCC1>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:33]([OH:34])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 70.3 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (500 mg, 1.65 mmol) was dissolved in THF (20 mL), and the solution was treated with TMEDA (0.80 mL, 5.3 mmol), sec-butyl lithium-hexane solution (0.99 mol/L, 5.3 mL, 5.3 mmol) and DMF (0.281 mL, 3.63 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (385 mg, yield 71%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CN1CCC(N2CCOCC2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCC(N2CCOCC2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 47.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-morpholinopiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 105, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-morpholinopiperidin-1-yl)acetamido)propanamide (22.4 mg, 47.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.94 (d, 1H), 7.60 (d, 2H), 7.30 (m, 5H), 7.22 (t, 2H), 7.03-6.98 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.78 (m, 1H), 3.70 (m, 1H), 3.56 (t, 4H), 2.96-2.83 (m, 4H), 2.41 (m, 4H), 2.05 (m, 3H), 1.73 (m, 2H), 1.39 (m, 2H). MS (EI) for C33H39FN4O5. found 591.7 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][CH:7]=1.C[Si]([C:25]#[N:26])(C)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][CH:11]=1)[C:25]#[N:26]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2F)cc1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1F

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(2,4-difluorobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 88%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6](=[O:9])[CH2:7][Cl:8])=O.[CH2:10]([O:17][C@@H:18]1[C@@H](CO)[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C@@H:18]1[C@@H:2]([CH2:3][O:5][C:6](=[O:9])[CH2:7][Cl:8])[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: O=C(CCl)OC(=O)CCl
Solvent: c1ccncc1
Product: O=C(CCl)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 45 %

Procedure:
Chloroacetic anhydride was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at room temperature overnight. Then the same subsequent procedures as in Reference Example 54 were conducted, giving 0.11 g of the title compound as an oil in a yield of 45%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)Cl.[Br:28]Br>Br.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH:11]([C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1)[Br:28]
Reactant: BrBr
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccc(Br)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.52 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester (Example 29) in 50 ml. of carbon tetrachloride is added dropwise a solution of 0.51 ml. of bromine in 20 ml. of carbon tetrachloride. After 30 minutes 2 drops of 30% hydrobromic acid in acetic acid is added and the mixture is stirred at room temperature for 2 hours. The solvent is decanted from the resulting gum. The gum is dissolved in dichloromethane, washed twice with water, once with sodium chloride solution, dried over magnesium sulfate and clarified with charcoal. The filtrate is evaporated to dryness in vacuo giving the desired product as 3.87 g. of a gum.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Reactant: CCCCCCCCCCCCCCCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 48 h
Yield: 55.1 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.0 g, 6.5 mmol) and 1-bromohexadecane (2.0 g, 6.5 mmol) in dichloromethane (40 ml) containing triethylamine (1 ml) is kept under nitrogen for 2 days at room temperature. The reaction is worked up in the usual manner to give a syrup which is put on a silica gel column and eluted with 2-5% ethyl acetate in chloroform. The desired fractions are pooled and concentrated to dryness. Crystallization from aqueous ethanol gives hexadecyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (1.9 g, 55%), m.p. 49°-50°, [α]D +9° (c, 1.5, chloroform).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][N:22]=[C:23]1[C:27]2([CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH2:26][NH:25][CH2:24]1>C(#N)C>[C:34]([O:33][C:31]([N:29]1[CH2:30][C:27]2([C:23](=[N:22][O:21][CH3:20])[CH2:24][N:25]([C:11]3[N:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:26]2)[CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 47.5 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 840 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was stirred for 3 hours at 45-50° C. Then the precipitated solid was filtered and dried to give 650 mg of the titled compound (yield: 93.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:33])=[N:9][CH:10]=1)=[O:4].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([CH:25]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:33])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(C(=O)c4ccccc4)c(C)c3C)C[C@H]2C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(c3nnc(C(O)c4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (R)-4-(6-benzoyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (8 mg, 0.017 mmol) in MeOH (2 mL) is added sodium borohydride (170 μg, 0.004 mmol) in 15 minutes and the reaction mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with DCM and washed with NaHCO3 and water. The organic solvent is separated and the solvent is removed under reduced pressure. Purification by HPLC of the crude product with acetonitril in water (from 10% to 100% with 3% 1-propanol) at 220 nm wavelength detection provides the desired product as off white powder. (6 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[O:24]2)[CH3:21])[CH2:17]1.C(O)(=O)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:29][C@@H:30]2[C@@H:23]([CH2:22][N:20]([CH3:21])[CH:18]3[CH2:17][CH:16]([CH2:15][CH2:14][C:13]4[NH:1][C:2]5[CH:7]=[CH:6][C:5]([CH:8]6[CH2:9][O:10][CH2:11]6)=[CH:4][C:3]=5[N:12]=4)[CH2:19]3)[O:24][C@@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[C@@H:26]2[O:27]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2cc(C3COC3)ccc2N)C1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 65 °C
Yield: 64.8 %

Procedure:
N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.446 g, 0.752 mmol) was taken up in acetic acid (7.7 mL, 140 mmol) and heated at 65° C. for 3.5 h; HPLC/LC MS indicated complete conversion. At 3.75 h the acetic acid was removed by distillation with minimal warming to afford an orange oil, which was taken up in CH2Cl2 (45 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The aqueous layer was treated with NaCl until saturated and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford a light orange oil. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.28 g, 65%) as a light orange foam:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:13]([O:15]C)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:15])[CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=C1OC(Cc2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1

Procedure:
Benzyl isocyanate (1.2 g, Aldrich) was added at room temperature to a stirred solution of the product from step (b) (2.03 g) in toluene (25 ml). When addition was complete, the mixture was refluxed for 40 hours. The toluene was evaporated in vacuo and the residue flash chromatographed through a silica column using chloroform to give the desired product as a colourless oil which crystallised on standing (2.9 g). The product was recrystallised from IPA as fine white needles (1.8 g), mp 92°-93° C. The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([O:10]CC)=[O:9])[N:6]=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:15]([O:14][N:13]=[C:7]([C:5]1[N:6]=[C:2]([NH:1][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:3][CH:4]=1)[C:8]([OH:10])=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCON=C(C(=O)OCC)c1csc(N)n1
Product: CCCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 58.6 %

Procedure:
Stages 4 and 5: 35.2 g (0.13 mole) of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate are tritylated with 44.6 g (0.155 mole) of trityl chloride (97% pure) analogously to Example 4, stage 4, and the product is split, without further purification, as described in Example 4, stage 5, to give 37 g of 2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid.