Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1>CN(C)C=O>[ClH:17].[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=4[N+:13]([O-:15])=[O:14])[CH2:30][CH2:31]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=C(NCCBr)c1ccc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccc(F)cc1[N+](=O)[O-]

Procedure:
A mixture of 16 parts of N-(2-bromoethyl)-4-fluoro-2-nitrobenzamide, 12.6 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one and 216 parts of N,N-dimethylformamide is stirred and refluxed for 3 hours. The N,N-dimethylformamide is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from methanol, yielding 1.5 parts of N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide hydrochloride; mp. 276.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:31])[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC)C(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford the product (0.023 g) as a yellow solid: 1H NMR (DMSO-d6) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.68-7.62 (m, 2H), 7.48 (t, 1H, J=7.9 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.1 Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H, J=7.3 Hz): MS ((−)-APCI) m/z 314/316 [M−H]−.
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C(#N)C>C(Cl)Cl>[I:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([S:12]([Cl:15])(=[O:13])=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Reactant: ClI
Solvent: CC#N
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc(I)c2c(c1)CCO2
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) was added dropwise to a solution of 2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol; Intermediate 54) in DCM (100 mL) at reflux temperature under nitrogen atmosphere. The reaction was heated at reflux overnight. The reaction mixture was cooled at room temperature and acetonitrile (50 mL) was added. The resultant mixture was washed with a saturated solution of NaHCO3 and the organic phase was separated followed by elimination of the volatiles under vacuum to give 8 g of brown oil which was used to the next step without further purification. 1H NMR 270 MHz (CDCl3) δ ppm 3.45 (t, J=8.91 Hz, 2H) 4.82 (t, J=8.91 Hz, 2H) 7.79 (d, J=1.48 Hz, 1H) 8.16 (d, J=1.98 Hz, 1H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)C)=[CH:16][CH:15]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:13]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCO
Product: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 246.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 1-(4-aminophenyl)ethanone (1.19 g, 1.19 mmol) in ethanol (3 mL). 2-oxo-1-p-tolylpyrrolidine-3-carboxylic acid 0.644 g (quantitative) was obtained as a bright yellow solid.
Reaction SMILES: CS(O[CH2:6][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:8][N:9]=[N+]=[N-])(=O)=O.[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29].P(=N)(OCC)(OCC)OCC>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=C(C)C=1>[Br:18][C:14]1[CH:13]=[C:12]([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[CH2:8][N:9]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH2:6]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOP(OCC)OCC
Reactant: CS(=O)(=O)OCC(CN=[N+]=[N-])(c1cccc(Br)c1)c1cccc(Br)c1
Agent: CCOP(=N)(OCC)OCC
Solvent: Cc1cccc(C)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)N1CC(c2cccc(Br)c2)(c2cccc(Br)c2)C1
Temperature: 150 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To a solution of 3-azido-2,2-bis(3-bromophenyl)propyl methanesulfonate (1.3 g, 2.66 mmol) in anhydrous toluene (10 mL) and anhydrous THF (5 mL) under N2 was added triethyl phosphite (0.49 mL, 2.79 mmol) at 25° C. The mixture was stirred for 18 h. The reaction was concentrated by rotary evaporation in a dried apparatus. The residue was dried in vacuo, and used in the next reaction without further purification. The crude triethyl phosphorimidate was dissolved in anhydrous m-xylene (5 mL) under N2 and heated in an oil bath at 150° C. for 12 h. After cooled to room temperature, the solvent was removed by rotary evaporation (vacuum pump assisted) to give a thick light orange oil which was purified by prep-TLC (eluent with EtOAc: dichloromethane=1:5) to afford 960 mg of diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate (1.9 mmol, 71% after two steps). LC/MS: [M+1]=504. 1HNMR (CDCl3), 400 MHz: δ 1.25-1.36 (m, 6H), 4.05-4.39 (m, 4H), 4.40 (d, 2H, J=5.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.[Li]CCCC.[CH:29]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: BrC1CCCCC1
Reactant: COc1ccccc1N1CCN(CCCc2ccccn2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(c2ccccn2)C2CCCCC2)CC1
Reaction time: 8 h

Procedure:
To a dry toluene (14 ml) solution of 1-(2-methoxyphenyl)-4-(3-pyridinylpropyl)piperazine (1.5 g, 4.82 mmol) under argon at 0° C. was added nBuLi (7.4 ml, 1.3M). After anion formation the solution was treated with cyclohexylbromide (1.18 ml, 9.64 mmol) in toluene (2.8 ml). The reaction mixture was allowed to attain room temperature and stirred overnight. The reaction mixture was treated with HCl (1N) and the organic layer discarded. The acid layer was washed with ether, taken to pH 13 with solid NaOH (cool) and extracted with chloroform.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (Ia, R2 =CH3, R3 =H) (E/Z=1/17, 90 mg, 0.21 mmole) and potassium carbonate (44 mg, 0.32 mmole) in DMF (3 ml) was added at 0° C. pivaloyloxymethyl iodide (77 mg, 0.32 mmole). The mixture was stirred at 0° C. for 40 minutes, diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in CHCl3 and chromatographed on a silica gel column (silica gel: 3 g) by eluting with 1% methanol in CHCl3 to yield 85 mg (75%) of the title compound. Mp. 100°-104° C. Estimated purity 90% (by HPLC).
Reaction SMILES: [OH-].[Li+].O.[CH:4](=[C:6]1[CH2:15][N:14]2[C@H:8]([CH:9]=[N:10][C:11]3[CH:20]=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:60])[CH2:33][C:34]([S:37][CH2:38][C:39]([NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][C:56]([O:58]C)=[O:57])=[O:40])([CH3:36])[CH3:35])[CH:26]=[C:25]([CH2:61][O:62][C:63]5[C:79]([O:80][CH3:81])=[CH:78][C:66]6[C:67](=[O:77])[N:68]7[CH2:74][C:73](=[CH:75][CH3:76])[CH2:72][C@H:69]7[CH:70]=[N:71][C:65]=6[CH:64]=5)[N:24]=4)[C:18]([O:82][CH3:83])=[CH:17][C:12]=3[C:13]2=[O:16])[CH2:7]1)[CH3:5].P([O-])([O-])([O-])=O>C1COCC1.C(Cl)Cl>[CH:75](=[C:73]1[CH2:74][N:68]2[C@H:69]([CH:70]=[N:71][C:65]3[CH:64]=[C:63]([O:62][CH2:61][C:25]4[CH:26]=[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:60])[CH2:33][C:34]([S:37][CH2:38][C:39]([NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[O:40])([CH3:35])[CH3:36])[CH:28]=[C:23]([CH2:22][O:21][C:19]5[C:18]([O:82][CH3:83])=[CH:17][C:12]6[C:13](=[O:16])[N:14]7[CH2:15][C:6](=[CH:4][CH3:5])[CH2:7][C@H:8]7[CH:9]=[N:10][C:11]=6[CH:20]=5)[N:24]=4)[C:79]([O:80][CH3:81])=[CH:78][C:66]=3[C:67]2=[O:77])[CH2:72]1)[CH3:76]
Reactant: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCN(C)CC(C)(C)SCC(=O)NCCOCCOCCOCCOCCC(=O)OC)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCN(C)CC(C)(C)SCC(=O)NCCOCCOCCOCCOCCC(=O)O)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
17.5 μl of an aqueous lithium hydroxide solution and 100 μl of water are added to 18 mg of methyl 3-{2-[2-(2-{2-[2-(2-([2-(2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}ethoxy)ethoxy]ethoxy}propanoate in solution in 270 μl of THF. After 2 h, the mixture is diluted in DCM and a phosphate buffer is added to pH=3. The resulting aqueous phase is extracted 3× with DCM, the combined organic phases are dried over MgSO4 and concentrated under RP and the residue is purified by flash chromatography on silica (Interchrom Puriflash Silica 15/35U 2G) using a gradient from 3 to 15% of methanol in DCM. 11.5 mg of 3-{2-[2-(2-{2-[2-(2-{[2-(2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}-ethoxy)ethoxy]ethoxy}propanoic acid are thus obtained. LC/MS (D): rt=0.88 min; [M+H2O+Na]+: m/z 1154; [M+H2O+H]+: m/z 1133; [M+H]+: m/z 1115.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:15]1[CH2:16][CH2:17][CH:12]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:13][CH2:14]1
Reactant: OC1CCOCC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a solution of the 1H-indazol-5-ol (150 mg, 1.12 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml) were added 4-hydroxytetrahydropyran (0.107 ml, 1.12 mmol), triphenylphosphine (293 mg, 1.12 mmol) and a 40%-diethyl azodicarboxylate-toluene solution (0.517 ml, 1.14 mmol) at 0° C. After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole (11.4 mg, 47%).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].FC(F)(F)C1C=C(NN)C=CC=1.[O:18]=[CH:19][C@@H:20]([C@H:22]([C@@H:24]([C@@H:26]([CH2:28][OH:29])[OH:27])[OH:25])[OH:23])[OH:21].FC(F)(F)C1C=C(NN=[CH:40][C@@H:41]([C@H:43]([C@@H:45]([C@@H:47]([CH2:49][OH:50])O)[OH:46])[OH:44])[OH:42])C=CC=1>O>[C@@H:28]1([O:29][C@H:47]([C@H:45]([C@@H:43]([C@@H:41]([CH2:40][OH:3])[OH:42])[OH:44])[OH:46])[CH:49]=[O:50])[O:21][C@H:20]([CH2:19][OH:18])[C@@H:22]([OH:23])[C@H:24]([OH:25])[C@H:26]1[OH:27]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=NNc1cccc(C(F)(F)F)c1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)[O-]
Agent: NNc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 90 °C

Procedure:
To this oligosaccharide (10 μmol), sodium acetate (30 μmol) in a small vial (Pierce reacti-vial, 0.2 mL capacity, with Tuf-bond Teflon-silicone cap seals) was added 150 μL water. 3-(trifluoromethyl)phenylhydrazine (40 μmol, Aldrich) was added, the sample sealed under nitrogen, and heated to 90° C. for 48 hours. The oligosaccharide was converted (>98%) to D-glucose and D-glucose 3-(trifluoromethyl)phenyl hydrazone, in a 1:2 ratio.
Reaction SMILES: [Li].C([O:4][C:5](=O)[CH:6]=[C:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)C.O.[OH-].[Na+]>O1CCCC1>[CH:11]([N:9]1[CH2:10][CH:7]([CH2:6][CH2:5][OH:4])[CH2:8]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 75.7 %

Procedure:
Lithium aluminumhydride (889 mg, 23.4 mmol) was suspended in tetrahydrofuran (50 mL), and under a nitrogen stream, a tetrahydrofuran (30 mL) solution of (1-benzhydrylazetidin-3-ylidene)acetic acid ethyl ester (2.40 g, 7.81 mmol) was added dropwise over 20 minutes at 0° C. with stirring. The reaction liquor was stirred for two hours at the same temperature, and then while cooling the reaction liquor in ice, water (889 μl), 1 N sodium hydroxide (889 μl) and water (8.57 mL) were added in this order. The resulting mixture was dried over anhydrous sodium sulfate. The insoluble was separated by filtration, and the mother liquor was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate:n-hexane=1:1 to ethyl acetate), to obtain the title compound (1.58 g, 76%) as an oily matter.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:6])[CH3:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=[O:10]>ClCCl>[F:7][C:8]([F:13])([F:12])[C:9]([NH:2][CH2:3][C:4](=[O:6])[CH3:5])=[O:10]
Reactant: CC(=O)CN
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(=O)CNC(=O)C(F)(F)F

Procedure:
Aminoacetone hydrochloride (13.29 g, 121 mmol) was slurried in 200 mL of dichloromethane and stirred vigorously as 22 mL (146 mmol) of trifluroacetic acid was added. The mixture was heated to reflux with stirring for about I hr at which time the evolution of gas had ceased. The resulting mixture was concentrated by evaporation at 60° C. and the residue was dissolved in 200 mL of ether. Solid sodium bicarbonate was cautiously added with stirring until foaming ceased. The resulting slurry was filtered through a 2×5 cm silica gel plug and the plug was eluted with an additional 100 mL of ether. The combined filtrates were concentrated by evaporation at temperatures up to 60° C. The residue was kugelrohr distilled at a pot temperature of 100°-110° C. and a pressure of 18 torr (2.4 kPa) to obtain 9.7 g (47 percent of theory) of the title compound as a waxy white solid. An analytical sample prepared by recrystallization from pentane was a white solid melting at 71°-73° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:6]2[CH:5]=[C:4]([Br:3])[CH:8]=[N:7]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil, 1.36 g, 34 mmol) is added portionwise to a stirred solution of 4-bromopyrazole (4.58 g, 30.9 mmol) in DMF (20 ml). The resulting mixture is stirred for 1 h at 0° C. and 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 61, 8.62 g, 30.9 mmol) is added. The resulting pale suspension is heated at 100° C. for 1 h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient hexanes: TBDME from 1:0=>0:1) to afford the title compound as a colorless solid, Rt=1.213 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 330 (M+1, 79Br)+.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[C:11]([Br:18])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>O.O1CCOCC1>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:1])=[C:11]([Br:18])[CH:10]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1Br
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A solution of NaOH (7.8 g, 190 mmol) in water (60 mL) was cooled in an ice bath, and bromine (2.51 mL, 49 mmol) was slowly added. A solution of 1-(4-tert-butyl-2-bromophenyl)ethanone (3.1 g, 12 mmol) in dioxane (60 mL) was slowly added, and the cooling bath was removed. After being stirred at room temperature for 3 h the reaction was acidified with concentrated hydrochloric acid. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-tert-butyl-2-bromobenzoic acid (3.1 g, 100% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.3 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.41 (dd, J=8.3, 1.9 Hz, 1H), 1.34 (s, 9H) ppm.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]1[O:12][C@@H:11]([C:13]#N)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O-:28].[Na+].C[OH:31]>>[CH3:27][O:28][C:13]([C@H:11]1[CH2:10][CH2:9][CH:8]([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:12]1)=[O:31]
Reactant: CO
Reactant: C[O-]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CC[C@H](C#N)O1
Agent: [Na+]
Product: COC(=O)[C@H]1CCC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)O1

Procedure:
(R)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-tetrahydro-furan-2-carbonitrile was treated with sodium methoxide in MeOH to afford (R)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-tetrahydro-furan-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:36]=[CH:35][C:16]3[N:17]([CH2:31][CH2:32][O:33][CH3:34])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.[O:37]1CC(O)O[CH2:39][CH:38]1O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:37][CH2:38][CH2:39][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:36]=[CH:35][C:16]3[N:17]([CH2:31][CH2:32][O:33][CH3:34])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: OC1COC(O)CO1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(CCO)CC3)ccc21
Yield: 34.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-ylmethyl]-amide (45 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (136 mg), [1,4]dioxane-2,5-diol (54 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 542.7.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[NH:11][C:10]1=[O:22])([CH3:8])[CH3:7])(=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br.[OH-].[Na+]>CN(C)C=O.CO.O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:11]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:17]=2)[N:9]([C:6]([CH3:8])([CH3:7])[CH2:5][OH:4])[C:10]1=[O:22]
Reactant: COc1ccc(CBr)cc1Cl
Reactant: CC(=O)OCC(C)(C)n1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n(C(C)(C)CO)c3ncc(C(F)(F)F)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a solution of 3-(2-acetoxy-1,1-dimethylethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) in anhydrous N,N-dimethylformamide (1.5 mL) was added portionwise sodium hydride (20.8 mg, 60% dispersion in mineral oil) at 5° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 3-chloro-4-methoxybenzylbromide (117 mg), the mixture was stirred at room temperature for 4 hours. After adding tetrahydrofuran (2 mL), methanol (1 mL) and 1N-sodium hydroxide solution (1 mL), the mixture was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water, 1N-hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was washed with diethyl ether to give 1-(3-chloro-4-methoxybenzyl)-3-(1,1-dimethyl-2-hydroxyethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (161.6 mg) as an orange solid.