Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27])C1C=CC=CC=1.C[OH:30]>CC(O)=O.[Pd]>[C:12]([OH:27])(=[O:30])[CH3:11].[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27]
Reactant: CO
Reactant: O=C(N[C@H]1CCN(CCn2ccc3cnccc32)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@H]1CCN(CCn2ccc3cnccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H2O, 5 drops of 1 N NaOH and further quenched with saturated NH4Cl solution. The mixture is concentrated in vacuo to about 1/2 volume, partitioned between EtOAc and 10% Na2CO3 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in in vacuo. The crude product obtained is partially purified by column chromatography in a gradient of 2% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester. FAB MS, [M+H]+=379. To a solution of this crude [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is stirred at room temperature under a balloon of H2 for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3x). The crude product is concentrated in vacuo and then azeotroped with toluene to give 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate as a residue (wet with excess HOAc). FAB MS, [M+H]+=245. The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1. Part J. The crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: C[Al](C)C.[C:5](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[CH3:21][C@:22]12[CH2:39][CH2:38][C@H:37]3[C@@H:27]([CH2:28][CH2:29][C:30]4[C@:35]3([CH3:36])[CH:34]=[CH:33][C:32](=[O:40])[CH:31]=4)[C@@H:26]1[CH2:25][CH2:24][C:23]2=[O:41].O>CCCCCC.C(OCC)(=O)C.[Ni+2].C/C(/[O-])=C/C(C)=O>[CH3:5][C:34]1[C@@:35]2([CH3:36])[C:30]([CH2:29][CH2:28][C@@H:27]3[C@@H:37]2[CH2:38][CH2:39][C@@:22]2([CH3:21])[C@H:26]3[CH2:25][CH2:24][C:23]2=[O:41])=[CH:31][C:32](=[O:40])[CH:33]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Temperature: 58 °C
Yield: 20.1 %

Procedure:
12 ml (12 mmol) of trimethylaluminum of a 10% solution in hexane is introduced at room temperature under nitrogen atmosphere. With stirring, 2.64 g of 2,6-di-tert-butyl-4-methylphenol is added in portions. The solution is stirred for 30 more minutes and 2.84 g (10 mmol) of androsta-1,4-diene-3,17-dione in 20 ml of ethyl acetate is added at 25° C. The solution is heated to 58° C. At 58° C., 143 mg of nickel(II)-acetylacetonate is added. The solution is stirred for 2.5 more hours at a temperature of 60° C. After cooling, 1.1 ml of water is added for hydrolysis and stirred for 15 minutes. The inorganic solid is filtered off and rewashed twice with 50 ml of ethyl acetate. After concentration by evaporation of the ethyl acetate phases, a crude product is obtained, which is chromatographed on silica gel with hexane/ethyl acetate as eluent with increasing ethyl acetate portion. 1.5 g of initial material is recovered. 0.60 g of 1-methyl-androsta-1,4-diene-3,17-dione of melting point 168°-170° C. is obtained. The yield is 20% of theory or 42% taking into consideration the initial material recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][CH2:14][C:15]1([OH:39])[C:20](=[O:21])[O:19][CH2:18][C:17]2[C:22]([N:24]3[C:28](=[CH:29][C:16]1=2)[C:27]1[N:30]=[C:31]2[C:36](=[CH:37][C:26]=1[CH2:25]3)[CH:35]=[CH:34][C:33]([NH2:38])=[CH:32]2)=[O:23]>[Pd]>[CH3:13][CH2:14][C:15]1([OH:39])[C:20](=[O:21])[O:19][CH2:18][C:17]2[C:22]([N:24]3[C:28](=[CH:29][C:16]1=2)[C:27]1[N:30]=[C:31]2[C:36](=[CH:37][C:26]=1[CH2:25]3)[CH:35]=[CH:34][C:33]([NH2:38])=[CH:32]2)=[O:23].[NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C=O
Agent: [Pd]
Agent: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(N)cc3nc2-1
Product: Nc1ccc(C=O)c(N)c1

Procedure:
In a manner similar to that described for 10-nitro-20(RS)-camptothecin, a mixture of 2-amino-4-nitrobenzaldehyde is treated with the tricyclic ketone 11 yielding 11-nitro-20(RS)-camptothecin which in turn is reduced to 11-amino-20(RS)-camptothecin by palladium/carbon. Alternatively, the 11-amino-20(RS)-camptothecin is obtained by reaction of 2,4-diaminobenzaldehyde with ketone 11.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9]I.[CH3:11][O:12][C:13](=[O:42])[N:14]=[C:15]([S:40][CH3:41])[C:16]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([OH:38])[C:31]=1[F:39])=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:20][CH:19]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:42])[N:14]=[C:15]([S:40][CH3:41])[C:16]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH2:9][CH2:8][F:7])[C:31]=1[F:39])=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
After adding 3.32 g of potassium carbonate and 3.13 g of 1-fluoro-2-iodoethane to a solution of 5.5 g of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 100 ml of DMF, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (5.88 g) as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31]C)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CS(C)=O>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[OH:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4OC)c3)csc12
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1O
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(2-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (28.0 mg, 0.061 mmol) (from Example 14 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the residue was treated with MeOH (2 mL). The resulting white precipitate was filtered, washed with cold MeOH and dried to give 3-[3-(2-hydroxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 7 mg, 25%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:18][CH:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[N:1]1([CH:6]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CC(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)C(C(=O)c1ccc(Cl)cc1)n1cncn1

Procedure:
2-(1,2,4-Triazol-1-yl)-4'-chloroacetophenone (0.01 mol) was dissolved in dimethylformamide (5.0 ml) at room temperature and treated with sodium hydride (0.01 mol). When the reaction was complete (3 hours), the mixture was cooled to 0° and α-methylbenzyl chloride (0.01 mol) was added dropwise with stirring. After stirring at room temperature for 20 hours, the mixture was poured into water and the product filtered off. Recrystallisation from chloroform/petroleum ether (60°-80°) gave the title compound as a colourless crystalline solid, m.p. 163°-5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]/[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:21]/[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])/[C:19]#[N:20])=[C:14]([F:27])[CH:13]=1.[OH-].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=3[F:27])([C:19]#[N:20])[CH:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: C/N=C/c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of [1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (0.77 g, 5.00 mmol) and (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (1.72 g, 5.00 mmol) in DMSO (5 mL) was added KOH powder (0.56 g, 10.00 mmol) in one portion. The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc three times (3×50 mL). The combined organic layers were washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash column (SiO2, 1%-15% of EtOAc in hexanes) after concentration to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (0.73 g, 36.1%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1292, rac-(2S,3S,4R)-4-(4-chloro-2-fluoro-phenyl)-2-(3-chloro-phenyl)-3-(2,2-dimethyl-propyl)-pyrrolidine (0.0.42 g, 20.8%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1294, and (2S,3R,4R)-4-(4-chloro-2-fluoro-phenyl)-2-(3-chloro-phenyl)-3-(2,2-dimethyl-propyl)-pyrrolidine (0.42 g, 20.8%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1294.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(NC1C=C(Cl)NC(C)([N+]([O-])=O)C=1C(OCC)=O)CCC>CO.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCCCN
Agent: CCCCNC1=C(C(=O)OCC)C(C)([N+](=O)[O-])NC(Cl)=C1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.5 Mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of n-butylamine are added dropwise. The solvent is then removed in vacuo and 500 ml. of benzene are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting oil is dissolved in 300 ml. of methanol and yields on cooling 110 g. of 4-butylamino-6-chloro-2-methyl-2-nitropyridine-3-carboxylic acid, ethyl ester (70%), m.p. 33°-35° (methanol).
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][NH:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19]([NH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[I:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:23]([C@@H:22]([NH:21][C:19](=[O:20])[O:18][CH3:17])[CH:26]([CH3:28])[CH3:27])=[O:24])=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H]1CN[C@H](c2nc3cc(I)ccc3[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To 5-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-benzimidazole (2.29 g, 7.00 mmol) and (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (1.49 g, 7.70 mmol) in DMF is added HATU (3.46 g, 9.1 mmol) and DIPEA (2.4 mL, 14.0 mmol) at rt. The reaction mixture is stirred at rt overnight. To the reaction mixture is added water (350 mL) with fast stirring upon which a white solid precipitated out. The solid is suction filtered and dried under vacuum to give methyl N-[(1S)-1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.73 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[S:18]([O:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]=[CH:32][O:31]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:17][C@@H:32]2[O:31][C@@H:30]([CH2:29][O:28][S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH2:35][CH2:34][CH2:33]2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.10 g of α-(4-chlorophenyl)-2,4-dichlorobenzyl alcohol and 1.78 of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were dissolved in 40 ml of diethyl ester, and a catalytic amount (2 drops) of phosphorus oxytrichloride was added to the solution. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added. The mixture was then concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 15:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 3.41 g of the title compound in the form of a colourless oil.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+]>C(OC(=O)C)(=O)C>[C:16]([NH:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8])(=[O:18])[CH3:17]
Reactant: Cc1sc(Br)nc1N
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(Br)sc1C
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 4-amino-2-bromo-5-methylthiazole hydrobromide (50 mM, 13.7 g) in acetic anhydride (100 ml) was treated dropwise with pyridine (10 ml) while cooling in an ice bath. After stirring for 1 hour the reaction mixture was poured onto 20% aqueous sodium acetate (1 l) and the aqueous solution extracted with dichloromethane (3×500 ml.). The combined organic layers were dried and evaporated under reduced pressure to give an oil which crystallised on trituration with ether. The crude product was recrystallised from ethanol to give the 4-acetamido-2-bromo-5-methylthiazole (11.7 g, 50%). mp 129°.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][OH:5].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.N1C=CC=C[CH:18]=1>C(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:1][N:2]=[C:3]([CH:4]([OH:5])[CH3:18])[N:6]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N=C(CO)NO
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(O)c1noc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 9 %

Procedure:
To a solution of N,2-dihydroxyacetimidamide (2.7 g, 26.4 mmol) in pyridine (20 mL) was added dropwise 4-fluorobenzoyl chloride (3 g, 18.9 mmol) in DCM (30 mL) at 0° C. to 10° C. The reaction was stirred for 6 hours at room temperature and the solid was filtered and washed with DCM (50 mL). The solid was dissolved in ethanol and the solution refluxed for 16 hours at 85° C. The mixture was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; using 10% ethyl acetate in hexane) to obtain 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol as white solid (0.35 g, 9% yield). 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, 1H), 7.20 (dd, 1H), 5.06 (q, 1H), 1.66 (d, 3H).
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C.O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][C@@H:18]([OH:17])[CH2:19][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Yield: 100 %

Procedure:
A mixture of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (prepared in an analogous fashion to the compound of Preparation A(vi) above; 0.72 g, 3.2 mmol) and 4-[(2S)-oxiranylmethoxy]benzonitrile (from step (i) above; 0.56 g, 3.2 mmol) in IPA/water (11 mL of 10:1) was stirred at 60° C. for 18 h. The solvent was then evaporated to give 1.3 g (100%) of the sub-title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH:10]([C:11]2[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=2[C:13]([N:15]([CH:34]=[N:35][NH2:36])[CH2:16][CH:17]([P:26]([O:31]CC)(=[O:30])[O:27]CC)[P:18]([O:23]CC)(=[O:22])[O:19]CC)=[O:14])[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3].Br[Si](C)(C)C>O1CCOCC1.CO.O>[CH3:1][S:2]([CH:5]1[CH:10]([C:11]2[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=2[C:13]([N:15]([CH:34]=[N:35][NH2:36])[CH2:16][CH:17]([P:18]([OH:22])(=[O:19])[OH:23])[P:26]([OH:31])(=[O:27])[OH:30])=[O:14])[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOP(=O)(OCC)C(CN(C=NN)C(=O)c1ccccc1C1CCNCC1S(C)(=O)=O)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)C1CNCCC1c1ccccc1C(=O)N(C=NN)CC(P(=O)(O)O)P(=O)(O)O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.5 g (2.4 mmol) of tetraethyl 2-[(3-methylsulfonyl-4-piperidylbenzoyl)-(aminoiminomethyl)amino]ethane-1,1-bisphosphonate from Example 1 are dissolved in 60 ml of absolute dioxane at 60° C. The reaction mixture is subsequently allowed to reach room temperature, and 1.64 g (10.8 mmol) of bromotrimethylsilane are added. The mixture is stirred at room temperatures for 16 hours and subsequently heated at 60° C. for a further 4 hours. Solvent and volatiles are subsequently removed at 40° C./0.1 torr. 15 ml of water are then added to the residue, and the mixture is stirred at room temperature for 4 hours. The resulting residue is filtered off and washed several times with ethanol. The residue resulting from this is subsequently boiled in 20 ml of methanol and 10 ml of water.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH2:12][C:13]([OH:15])=O)([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[S:10][CH2:11][CH2:12][C:13]2=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccccc1SCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)c1cccc2c1SCCC2=O
Temperature: 25 °C
Reaction time: 64.2 h
Yield: 17 %

Procedure:
3-(2-Isopropylphenylthio)propanoic acid from Step 1 (6.85 g, 30 mmol) was dissolved in trifluoroacetic acid (20 mL), treated with trifluoroacetic anhydride (12 mL) and stirred at room temperature (64.2 hours). The reaction was concentrated in vacuo, and the residue dissolved in ethyl acetate, extracted with 5% NaOH, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil which was passed through a column of silica gel eluted with 12% ether/hexane to give 8-isopropylthiochroman-4-one as a brown oil (1.05 g, 17%): 1H NMR (CDCl3) 300 MHz 8.01 (d, J=7.0 Hz, 1H) 7.38 (d, J=7.5 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 3.19 (m, 3H) 2.96 (m, 2H) 1.25 (d, J=7.0 Hz 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:18]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=302.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([F:9])=[C:6]([SH:8])[CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([F:9])=[C:6]([S:8][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:7]=1
Reactant: COc1cc(Cl)cc(S)c1F
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 5-chloro-2-fluoro-3-methoxybenzenethiol (303 mg) and DMF (dry) (12 mL) were added K2CO3 (239 mg) and methyl 4-chloro-3-oxobutanoate (0.204 mL) at 0° C. The mixture was stirred at room temperature for 45 min. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (402 mg).