Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H:40]([O:43]CCC)[CH2:39][CH2:38]2)CCCCC1.[CH:47]1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)[CH2:51]CC[CH2:48]1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.COC([C@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([O:43][CH2:40][CH2:39][CH3:38])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:51][CH2:47][CH2:48][C@@H:19]3[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: CCCBr
Solvent: O=C1CCCCC1
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and (R)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[C:2](=[CH2:4])[CH3:3].[CH3:14][SiH:15]([CH3:25])[O:16][Si:17](C)([CH3:23])[O:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[C:26]1(C)C=CC=CC=1>>[CH3:4][CH:2]([CH2:3][Si:17]([CH3:23])([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[O:16][Si:15]([CH3:25])([CH3:14])[CH3:26])[CH2:1][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=1
Reactant: C=C(C)COc1ccc(C=O)cc1
Reactant: C[SiH](C)O[Si](C)(C)O[Si](C)(C)C
Reactant: Cc1ccccc1
Product: CC(COc1ccc(C=O)cc1)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Yield: 85 %

Procedure:
To a solution of 4-methallyloxybenzaldehyde (17.62 g, 0.1 mol) and catalyst (complex containing 3-3.5 wt % of Pt in cyclovinylmethylsiloxane, marketed by Huls under the trademark Petrarch PCO85 : 300 μl) in 50 ml of dry toluene heated to 80° C., were added dropwise over 30 minutes 24.47 g (0.11 mol) of heptamethyltrisiloxane. The mixture was maintained at this temperature for 26 hours. The reaction mixture was maintained concentrated and, after distillation at a pressure of 0.1 mmHg (fractions distilling at 135-141° C.), 34.1 g of 4-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]-propyloxy]benzaldehyde (yield: 85%) were obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:50][C:51]([F:57])([F:56])[C:52]1([NH2:55])[CH2:54][CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:55][C:52]4([C:51]([F:57])([F:56])[F:50])[CH2:54][CH2:53]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(F)(F)F)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) was charged 1-(trifluoromethyl)cyclopropanamine hydrochloride (37 mg, 0.23 mmol), followed by drop-wise addition of DIEA (0.080 mL, 0.46 mmol). After stirring first at ambient temperature for 15 minutes and then at 85° C. overnight, the reaction was cooled and directly purified by reverse-phase chromatography (5 to 60% acetonitrile/water) to yield the final product as off-white solid (15 mg, 23%). LCMS (apci) m/z=435.0 (M+H).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with decanoyl chloride there is obtained 3-(decanoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(decanoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)- benzyl alcohol hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([CH2:16][C:17]1[S:25][C:24]2[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:22][C:21]([Cl:32])=[N:20][C:19]=2[CH:18]=1)[CH3:15])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:32].[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[S:25][C:17]([CH2:16][N:14]([CH3:15])[CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 182.4 %

Procedure:
To a solution of 2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg) in dichloromethane (10 mL) was added hydrogen chloride (3 mL of a 2.0 M solution in diethyl ether). The mixture was stirred at room temperature for 16 h and then reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt as a yellow solid (380 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](O)=O)=[CH:8][CH:7]=2.[Cl:17][C:18]1[CH:19]=[C:20]([F:26])[C:21]([NH:24][NH2:25])=[N:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C#N>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([F:26])[C:21]2[N:22]([C:14]([CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[N:25][N:24]=2)[CH:23]=1
Reactant: COc1cnc2ccc(CC(=O)O)cc2c1
Reactant: NNc1ncc(Cl)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cnc2ccc(Cc3nnc4c(F)cc(Cl)cn34)cc2c1
Temperature: 150 °C

Procedure:
To a mixture of 2-(3-methoxyquinolin-6-yl)acetic acid (0.22 g, 1.0 mmol), 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (0.11 g, 0.68 mmol) and triphenylphosphine (0.97 g, 2.0 mmol) (on solid support) in DCM (5 mL) was added DIEA (0.24 ml, 1.4 mmol) followed by 2,2,2-trichloroacetonitrile (0.14 ml, 1.4 mmol) via a syringe. The mixture was then heated to 150° C. for 15 minutes in an appropriately sealed vial. The mixture was filtered and the filtrate was diluted with 50 mL of EtOAc. The solution was washed with 30 mL of satd. NaHCO3 followed by 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give light yellow solid as desired product. MS (ESI pos. ion) m/z: 343 (MH+). Calc'd exact mass for C11H12ClFN4O: 342.
Reaction SMILES: [CH3:1][NH2:2].CO[C:5]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[O:6]>CO>[CH3:10][NH3+:12].[CH3:1][NH:2][C:5]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:10]([NH:12][CH2:13][C:14]([O-:16])=[O:15])=[O:11])=[O:6]
Reactant: CN
Reactant: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1
Solvent: CO
Product: CNC(=O)c1cc(C(=O)NCC(=O)[O-])cc([N+](=O)[O-])c1
Product: C[NH3+]
Reaction time: 72 h

Procedure:
15 ml. of liquid methylamine is added at 0° C. to 42.3 g. (0.15 mole) of N-(3-methoxycarbonyl-5-nitrobenzoyl)-glycine (VIa) in 150 ml. of methanol; the reaction mixture is stored for 3 days at room temperature. Then, the mixture is concentrated to dryness under vacuum, and the residue is refluxed with absolute alcohol. After cooling, the reaction mixture is filtered, washed with alcohol and dried under vacuum. Yield: 43.2 g. M.P. 216°-217°C.
Reaction SMILES: [Na].[CH3:2][NH:3][C:4]([NH2:6])=[S:5].[C:7]([O:14]C)(=O)[CH2:8][C:9](OC)=[O:10].[CH3:16]I>CO>[OH:14][C:7]1[N:6]=[C:4]([S:5][CH3:16])[N:3]([CH3:2])[C:9](=[O:10])[CH:8]=1
Reactant: CI
Reactant: COC(=O)CC(=O)OC
Reactant: CNC(N)=S
Agent: [Na]
Solvent: CO
Product: CSc1nc(O)cc(=O)n1C
Yield: 87.9 %

Procedure:
In 250 ml of methanol was dissolved 13.1 g of metal sodium. To the resulting methanol solution were added 25 g (0.28 mol) of N-methylthiourea and 38.5 g (0.29 mol) of dimethyl malonate, and the mixture was reacted under reflux for 3 hours. Thereafter, to the solution was added dropwise 41.3 g (0.29 mol) of methyl iodide at 10° C. or lower, and the mixture was reacted at room temperature overnight. After completion of the reaction, methanol was removed under reduced pressure, and then the residue was dissolved in water. The resulting aqueous solution was made acidic with hydrochloric acid, and crystals precipitated were filtered, washed with water and dried to obtain 42.4 g (yield: 89%) of 6-hydroxy-3-methyl-2-methylthio-4(3H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[C:11]([F:12])([F:13])[F:14])[CH:4]=1)[CH3:30]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1ccc(Cl)c(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c1

Procedure:
In analogy to Example 1, step 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=500.2 [M−H+].
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([O:15]CC)=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.O[Li].O>C(O)C>[O:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc3c(cc2[nH]1)OCO3
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc3c(cc2[nH]1)OCO3
Yield: 85.2 %

Procedure:
To a solution of ethyl 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylate (I-4b: 0.4 g, 1.716 mmol) in ethanol (8 mL) was added LiOH.H2O (0.144 g, 3.433 mmol) and refluxed for 16 h. The solvent was evaporated under reduced pressure and the residue was dissolved in water (10 mL). The aqueous layer was acidified with 10% aq. HCl solution to pH 6.0, precipitated solid was filtered, residue was washed with water and dried under vacuum to afford 0.3 g (86%) of 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylic acid (I-4c) as an off-white solid.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]=[C:16]=[O:17])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(COc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 4-phenoxymethylaniline (10 g) in toluene (100 ml) was added dropwise to a solution of phosgene (20 g) in toluene (100 ml) at 10° to 20° C. The mixture was gradually heated and refluxed for 30 minutes. Thereafter, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give 7 g of 4-phenoxymethylphenyl isocyanate. M.P., 56°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH2:18][O:19][CH3:20])[NH:12][C:11](=[O:21])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)CCl.CN1CCOCC1.[N+:33]([C:36]1[CH:37]=[C:38]([C:42]2[CH2:43][CH2:44][N:45]([CH2:48][CH2:49][CH2:50][NH2:51])[CH2:46][CH:47]=2)[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([NH:51][CH2:50][CH2:49][CH2:48][N:45]3[CH2:44][CH:43]=[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=4)[CH2:47][CH2:46]3)=[O:17])=[C:13]([CH2:18][O:19][CH3:20])[NH:12][C:11](=[O:21])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COCC1=C(C(=O)NCCCN2CC=C(c3cccc([N+](=O)[O-])c3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reaction time: 18 h

Procedure:
A solution of (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid (1.2 eq), EDC (1.5 Eq.), N-methylmorpholine (2.0 Eq.) in dichloromethane was stirred at room temperature for 15 minutes, followed by addition of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine (1.0 eq.) to the reaction mixture. The resulting solution was stirred for 18 hours, concentrated and chromatographed on silica to give (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:26]>>[NH2:2][C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)=[O:26]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C#N)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C(N)=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
One gram (2.91 mmol) of 5-cyano-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was added batchwise to 15 ml of concentrated sulfuric acid, and the resulting mixture was stirred for 24 hours at ambient temperature. The solution was then poured onto 300 ml of ice water, and the product precipitated was subjected to suction filtration and recrystallized from methanol.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:2]=2)[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:27][CH2:26]1
Reactant: COC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-methoxypiperidine (0.090 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.211 g, 78% yield); 1H NMR (400.132 MHz, DMSO) δ 1.24-1.49 (2H, m), 1.63-1.93 (2H, m), 2.94-3.14 (2H, m), 3.30 (3H, s), 3.34-3.44 (2H, m), 3.88 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.30-7.43 (3H, m), 7.80-7.90 (2H, m), 7.96 (1H, d), 8.27 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.57 min (M+H=378.20).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([N:32]=[N+]=[N-])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.C(O)(=O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH2:32])[CH2:11][C@@H:12]([CH:29]([CH3:30])[CH3:31])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)C(C)C

Procedure:
40 mg of 5(S)-azido-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy -3-(2-methoxymethoxyethyl)-phenyl]-octanoic acid (N-butyl)-amide are hydrogenated in 10 ml of methanol/acetic acid (9:1) in the presence of 20 mg of 10% Pd/C at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by FC (2.4 g of silcia gel, dichloromethane/methanol =9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.17; HPLC Rt =11.44 and 12.63 minutes (diastereoisomeric mixture); FAB-MS (M+H)+ =525.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:3]1=[O:13]
Reactant: BrCCCOC1CCCCO1
Reactant: Cc1c([N+](=O)[O-])c(=O)[nH]c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Temperature: 65 °C
Yield: 47.7 %

Procedure:
To a solution of 1,6-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione (6 g, 0.032 mol) in DMF (20 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (10.85 g, 0.049 mol) and K2CO3 (13.44 g, 0.097 mol). The reaction was heated at 65° C. for 2 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was washed with aq. 1N LiCl (3×30 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl) pyrimidine-2,4(1H,3H)-dione (5 g, 47.1% yield) as a yellow oil. LCMS: [MH+-THP] 244 and TR=1.180 min. Used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si:34]([O:51][CH2:52][CH:53]([OH:58])[C:54]([O:56][CH3:57])=[O:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:59](O)(=[S:61])[CH3:60]>C1COCC1>[Si:34]([O:51][CH2:52][CH:53]([O:58][C:59](=[S:61])[CH3:60])[C:54]([O:56][CH3:57])=[O:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(O)=S
Reactant: COC(=O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of triphenylphosphine (101 g, 385 mmol, 2 eq) in THF (1.5 L) was added diisopropylazodicarboxylate (76 mL, 386 mmol, 2 eq) at 0° C. The mixture was stirred at 0° C. for 1 hr and was followed by the addition of a solution of methyl 3-t-butyldiphenylsilyloxy-2-hydroxypropionate (example 39) (68.89 g, 192 mmol) and thioacetic acid (27.6 mL, 386 mmol, 2 eq.) in THF, to the same temperature. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The solution was concentrated to dryness and the solid was washed with hexane (5×300 mL). The organic solution was filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (95:5) to give the pure compound (49.3 g) in 62% yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([N:20]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
Temperature: -5 °C

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.22 ml) was added dropwise over 5 minutes to a stirred solution of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.306 g) and N,N-diisopropylethylamine (0.21 ml) in dry DMF (1 ml) at −15° C. The resultant solution was allowed to warm to −5° C. over 40 minutes then ethyl acetate (30 ml) was added and the mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 30-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.266 g) as an oil; 1H NMR (d6-DMSO): −0.1 (s, 9H), 0.7 (t, 2H), 2.45 (s, 3H), 3.6 (t, 2H), 3.85 (s, 3H), 5.2 (s, 2H), 7.8 (d, 1H), 8.0 (s, 1H), 8.8 (d, 1H), 9.1 (s, 1H); mass spectrum (+ve FAB, DMSO/Glycerol): 445 (M+H)+.