Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O.O1CCOCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH3:25])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O)C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 81.8 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-2-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-(furan-3-yl)benzoate (Intermediate 125, 0.054 g) was added to a solution of lithium hydroxide monohydrate (0.034 g) in water (0.3 ml) and dioxane (1 ml) and the mixture was stirred and heated at 130° C. for 30 minutes. The reaction mixture was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was acidified with formic acid and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 6-(benzenesulphonylmethyl)-2-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-(furan-3-yl)benzoic acid (0.043 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=O)[CH2:29]Br)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:29]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH3:20])[CH2:23][CH2:24]3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (Example 1, Step E; 30.0 g, 92.5 mmol) and 1-(1-acetylpiperidin-4-yl)-2-bromoethanone (Example 2, Step C, 32.1 g, 130 mmol) were suspended in ethanol (400 mL) and DIEA (48.3 mL, 278 mmol) was added. The resulting mixture was heated to 60° C. for 4 hours and then at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water, dried over Na2SO4, filtered and concentrated. The resulting material was purified on silica eluting with 3% MeOH/EtOAc to give 1-(4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (41.6 g, 95.0% yield) as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14]SCCC(OCC)=O)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14][OH:28])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCSc1snnc1CO
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethy l)thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmol) in dichloromethane (40 mL) was added m-chloroperoxybenzoic acid in several portions at 0° C. until the starting material was disappeared. The mixture was then sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, and was concentrated to dryness. The oxidized product was treated with trifluoroacetic anhydride (2 mL) for 30 min at room temperature. After removal of trifluoroacetic anhydride under the reduced pressure, the mixture was stirred in ethyl acetate/1% sodium hydroxide (30 ml/30 mL) for 30 min. The ethyl acetate layer was concentrated to a volume of 5 mL and methanol (10 mL) was added. Excess sodium borohydride (200 mg) was added in portions at 0° C. while stirring. After 30 min, the reaction was quenched with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol/dichloromethane) to provide 225 mg of 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-1,2,3-th iadiazole. 1H NMR (CDCl3) δ1.27 (t, 3H, J=8), 2.71 (t, 2H, J=7), 3.27 (t, 2H, J=7), 4.16 (q, 2H, J=8), 5.03 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[C:27]#[CH:28]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:26](=[O:29])[C:27]#[CH:28])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: C#CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propynoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-propynoyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[O:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36]>N.CO>[CH3:29][C:30]1[O:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:37])=[O:36]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)c(C)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,5-Dimethylfuran-3-sulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.2 mg). MS m/z 347 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][C:18](Br)=[O:19]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:18](=[O:19])[CH2:17][Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(Cc2ccccc2)c1N
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CBr

Procedure:
2-benzyl-6-methylaniline [A. W. H. Wardrop et al.: J. Chem. Soc., Perkin Trans. 1, 12, 1279 (1976)] and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[NH2:31].CCN(C(C)C)C(C)C>>[CH3:27][O:26][CH2:25][CH2:24][N:11]([CH2:10][CH2:9][O:8][CH3:7])[C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:18][N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[N:29]=2)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc(-c2nc(-c3ccccc3OC)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 31 (149 mg; 0.5 mmol; 1 eq.), Intermediate 1 (83 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 50/50) followed by crystallisation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:48])([CH3:47])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:33]2[C:34](=[O:51])[CH2:35][C:36]([CH3:49])([CH3:50])[CH2:37][C:38]=2[O:39][C:40]2[CH2:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](=[O:46])[C:45]1=2
Reactant: COc1ccc(-c2cc(C)cc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C)cc(C(=O)NS(C)(=O)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
1,1′-Carbonyldiimidazole (99.5 mg, 0.61 mmol) was added to a solution of the 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-4-methylpyridine-2-carboxylic acid produced in Example 32-3 (250 mg, 0.47 mmol) in DMF (5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1 hour and 30 minutes. Thereafter, methanesulfonamide (58.4 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 ml, 0.61 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, an aqueous solution of citric acid (454 mg, 2.36 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (230 mg, yield: 80%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:67]=[CH:66][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([S:44][C:45]3[N:46]=[CH:47][N:48]4[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=34)[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:51]3[S:50][C:49]4=[C:45]([S:44][CH:41]5[CH2:40][CH2:39][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:66]=[CH:67][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:43][CH2:42]5)[N:46]=[CH:47][N:48]4[CH:52]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SC5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)CC5)c4s3)[C@H](C)[C@H]12
Yield: 52.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 410 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 881 mg of 7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 450 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][C:18](=[O:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[NH:21]([C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=1)=[O:24])[NH2:22]>>[C:18]([O:17][C:5]1[C:4]([C:1](=[N:22][NH:21][C:23]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=2)=[O:24])[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(Cl)c(Cl)c1
Reactant: NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: CC(=O)Oc1c(C(C)=NNC(=O)c2ccc(C(=O)O)c([N+](=O)[O-])c2)csc1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from acetic acid 4-acetyl-2-(3,4-dichlorophenyl)thiophen-3-yl ester (39.5 mg, 0.12 mmol) and 4-hydrazinocarbonyl-2-nitrobenzoic acid (40.5 mg, 0.18 mmol) following the procedure described in the synthetic example 185.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:33])[CH:32]=1>COCCOC.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>[Cl:26][C:27]1[CH:28]=[C:29]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 2.2 ml of an aqueous 2M sodium carbonate solution and 30.8 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium are added to 300 mg (0.890 mmol) of the compound from Example 35A and 233 mg (1.34 mmol) of (3-chloro-5-fluorophenyl)boronic acid in 12 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. The crude product is filtered through a short kieselguhr column and the filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 116 mg (36% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][Br:22])=[CH:19][CH:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5]
Reactant: COc1ccc(-c2ccc(C)cc2)cc1P(=O)(OC)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CBr)cc2)cc1P(=O)(OC)OC
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A mixture of 4-methoxy-4′-methylbiphenyl-3-yl-phosphonic acid dimethyl ester (300 mg, 1.1 mmol), N-bromosuccinimide (190 mg, 1.1 mmol) and a few crystal of benzoyl peroxide in CCl4 (15 mL) was refluxed and irradiated with a sun lamp for 1 h. More N-bromosuccinimde (30 mg, 0.17 mmol) was added and the mixture was refluxed for 30 min. After cooling to r.t., the mixture was diluted with CH2Cl2 and washed with H2O (3×), dried (MgSO4) and concentrated. The solid residue was swished with Et2O to give 280 mg (67%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]=3[CH3:24])[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.C1COCC1.[NH3:34]>CO.[OH-].[Na+]>[NH2:34][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]=3[CH3:24])[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC1CO1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC(O)CN

Procedure:
A suspension of rac-3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (382 mg, 0.959 mmol) in 7 N NH3 in MeOH (10 mL) and THF (5 mL) is stirred at 60° C. for 15 h. The mixture is diluted with 1M aq. NaOH (30 mL) and extracted with DCM (4×75 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give rac-1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (419 mg) as a pale yellow solid; LC-MS: tR=0.90 min, [M+1]=416.42.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:37][O:38][NH2:39].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[N:39][O:38][CH3:37])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 46.5 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.19 mmol) in anhydrous ethanol (2.0 mL) was added O-methylhydroxylamine hydrochloride (80 mg, 0.96 mmol) and pyridine (80 μL, 0.99 mmol). The resulting yellow solution was heated to 90° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was mixed with water (2.0 mL) and extracted into ethyl acetate (3×2.0 mL). The combined organic phases were washed with brine (2×4.0 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. The residue was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 95:5 to 60:40) to give the desired product as a white solid (44 mg, 46% yield). 1H-NMR (500 MHz, CD3OD) δ 8.29 (1H, s), 7.35 (2H, d), 7.26-7.32 (5H, m), 7.16-7.21 (2H, m), 4.01 (3H, s), 3.02 (2H, t), 2.83 (2H, t), 2.36-2.52 (4H, m), 2.04-2.16 (1H, m), 2.01 (2H, p), 1.81-1.92 (1H, m), 1.15-1.50 (9H, br m). LCMS (Method A) RT=8.28 min, M+H+=498.10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:37]I.[H-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH3:37])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1

Procedure:
The product from step II (922 mg, 1.77 mmol) was treated with methyl iodide (2.21 mL, 35.48 mmol) and 60% oil suspension of sodium hydride (142 mg, 3.54 mmol) using procedure described in step I of example 4 to afford 1.143 g (100%) of crude 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:13](OC1C=CC=C2C=1C=CN2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C=O.[OH-].[Na+]>CCO>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]2[CH2:2][OH:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: OCn1ccc2c(O)cccc21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCn1ccc2c(OCc3ccccc3)cccc21

Procedure:
1-Hydroxymethyl-4-hydroxy-indole: A solution of 4-benzyloxyindole (1.0 g, 4.48 mmol), formaldehyde (2.0 mL, 26.8 mmol) and 2 N NaOH (2.24 mL, 4.48 mmol) in 10 mL EtOH was stirred at the room temperature for 4 h. The solvent was removed in vacuo. The crude material was purified by flash column chromatography (3:1, hexane:ethyl acetate) to yield 1.13 g of 4-benzyloxy-1-hydroxymethylindole, which was hydrogenated by 5% Pd/C in 40 mL methanol under H2 (50 psi) to yield 580 mg (79.5%) of the title compound. 1H NMR (CDCl3): 7.15-7.07 (m, 3H), 6.60-6.55 (m, 2H), 5.62 (d, J=7.5 Hz, 2H), 4.93 (s, 1H), 2.37 (t, J=7.2 Hz, 1H).
Reaction SMILES: [F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:14]([O:18][C:19]([N:21]([CH2:23][CH:24]=O)[CH3:22])=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:24][CH2:23][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH3:22])[CH2:3]1
Reactant: CCOC(=O)CC1CCNCC1F
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(CCN(C)C(=O)OC(C)(C)C)CC1F
Reaction time: 24 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 3-fluoro-4-piperidinylacetate (230 mg, 1.22 mmol) and 2-(N-tert-butoxy carbonyl-N-methylamino)acetaldehyde (211 mg, 1.22 mmol) in THF (5 mL) was added NaBH(OAc)3 (386 mg, 1.82 mmol) and acetic acid (70.0 mL, 1.22 mmol) at room temperature After being stirred for 24 hr, the reaction mixture was quenched by the addition of sat. NaHCO3 solution and extracted with EtOAc. The extracts were washed with brine, dried over Na2CO3, and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (6:1, v/v) as eluent gave ethyl 3-fluoro-1-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-piperidinylacetate (236 mg, 56%) as a reddish oil. 1H-NMR (CDCl3) δ 1.25 (t, J=7.1 Hz, 3H), 1.45 (s, 9H), 1.53 1.79 (m, 2H), 1.90–2.09 (m, 2H), 2.15 (dd, J=16.4, 7.1 Hz, 1H), 2.45–2.58 (m, 2H), 2.87 (s, 3H), 2.90–2.99 (m, 2H), 3.20 (m, 1H), 3.24–3.45 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.61, 4.73 (each broad s, 1H); ESI-MS m/z 347.