Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]2[O:3]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[C:38]([N+:39]([O-:41])=[O:40])=[C:37](Cl)[N:36]=[CH:35][N:34]=1>>[Cl:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([NH:17][CH2:16][C:14]2[CH:13]=[CH:12][C:10]3[N:11]=[C:7]([N:6]4[C@@H:5]5[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]5[O:3][C:2]4([CH3:22])[CH3:1])[S:8][C:9]=3[CH:15]=2)[C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CN)cc2s1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CNc3ncnc(Cl)c3[N+](=O)[O-])cc2s1
Reaction time: 4 h
Yield: 46 %

Procedure:
To a stirred mixture of (2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methanamine (236 mg, 0.7 mmol) from Step 4 of this Example and DIEA (388 μL, 2.2 mmol) at 0° C. under argon was added 4,6-dichloro-5-nitropyrimidine (159 mg, 0.8 mmol) in one portion. The mixture was stirred for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes) to afford 6-chloro-N-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg, 43%) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 7.81 (br s, 1H), 7.57-7.63 (m, 2H), 7.22-7.31 (m, 1H), 4.85 (d, J=5.7 Hz, 2H), 3.11 (m, 1H), 2.82 (m, 1H), 2.11-2.16 (m, 1H), 1.90 (m, 1H), 1.80 (s, 3H), 1.51-1.69 (m, 5H), 1.19-1.49 (m, 4H). LCMS (ESI) m/z 475 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21]C)=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([OH:21])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
To a stirred solution of methyl 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)(ethyl)amino]-5-chloro-2-ethylbenzoate (156 mg, 0.36 mmol) in THF (4.0 ml) and MeOH (0.29 ml), was added a solution of 4M NaOH (aq) (2.7 ml, 10.7 mmol). The resulting solution was stirred at 50° C. for 17 hours. The reaction mixture was treated with 4M NaOH (aq) (0.5 ml, 2.0 mmol) and stirring was continued at 50° C. for 32 hours. The heat was removed and the reaction mixture was left to stir at room temperature for 65 hours. The reaction mixture was treated with 4M NaOH (aq) (1.0 ml, 4.0 mmol) and heated back up to 50° C. for 24 hours. The organic solvents were removed in-vacuo and the aqueous phase was treated with a solution of 0.5M citric acid (20 ml) to adjust the pH to 4/5. The product was extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with brine (30 ml), dried (MgSO4), filtered and concentrated in-vacuo and then further dried on the high vac line for 4 hours to give the title compound (142 mg, 92%) as a white solid and a mixture of cis/trans isomers. LC-MS 98%, 5.49 min (7 minute LC-MS method), m/z=425.1, 427.1. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:9][C:10]=2[CH:16]=1
Reactant: N#Cc1ccc2nc(CC3CCCCC3)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2nc(CC3CCCCC3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
Dissolve 2-cyclohexylmethyl-benzothiazole-6-carbonitrile (0.2 g, 0.55 mmol) in anhydrous THF (2 mL) and add slowly 1M lithium aluminum hydride in THF (0.82 mL, 0.82 mmol) at room temperature. Stir the reaction mixture at room temperature for 0.5 h. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify the residue by SCX chromatography to obtain the title compound as a yellow oil (0.1 g, 92%). MS (ES+) m/z: 260 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][O:4][C@@H:3]1[C@H:8]1[N:11]([Si](C)(C)C)[C:10](=[O:16])[C@@H:9]1[C@H:17]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH3:18].[CH2:24]([O:27][C:28]([N:30]1[CH2:34][CH:33]([S:35]S(C2C=CC=CC=2)(=O)=O)[CH2:32][N:31]1[C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[O:29])[CH:25]=[CH2:26].C1(S(=O)(SC)=O)C=CC=CC=1>>[CH2:24]([O:27][C:28]([N:30]1[CH2:34][CH:33]([S:35][CH:7]2[CH2:6][CH2:5][O:4][C@H:3]([C@H:8]3[NH:11][C:10](=[O:16])[C@@H:9]3[C@H:17]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH3:18])[C:2]2=[O:1])[CH2:32][N:31]1[C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[O:29])[CH:25]=[CH2:26]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N([Si](C)(C)C)[C@@H]1[C@H]1OCCCC1=O
Reactant: C=CCOC(=O)N1CC(SS(=O)(=O)c2ccccc2)CN1C(=O)OCC=C
Agent: CSS(=O)(=O)c1ccccc1
Product: C=CCOC(=O)N1CC(SC2CCO[C@H]([C@H]3NC(=O)[C@@H]3[C@@H](C)O[Si](C)(C)C)C2=O)CN1C(=O)OCC=C

Procedure:
(3S,4S)-4-[(2R)-3-Oxotetrahydropyran-2-yl]-1-(trimethylsilyl) -3-[(R)-1-(trimethylsilyloxy)ethyl]azetidin-2-one was reacted as in Reference Example 38 except that 1,2-bis(allyloxycarbonyl)-4-phenylsulfonylthiopyrazolidine was used in lieu of S-methyl benzenethiosulfonate to give (3S,4S)-4-[(2R)-4-[[1,2-bis(allyloxycarbonyl)pyrazolidin-4-yl]thio]-3-oxotetrahydropyran-2-yl]-3-[(R)-1-(trimethylsilyloxy)ethyl]azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>N1C=CC=CC=1.CC(N(C)C)=O.C(C#N)(C)=O>[NH2:20][CH2:19][CH2:18][CH2:17][N:16]([C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15])[S:51]([C:48]1[CH:49]=[CH:50][C:45]([CH3:44])=[CH:46][CH:47]=1)(=[O:53])=[O:52]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Agent: CC(=O)C#N
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)S(=O)(=O)c1ccc(C)cc1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A solution of 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (52.6 mg, 0.10 μmol) in pyridine (0.5 mL) was treated with respective sulfonyl chloride (in this case 4-methyl benzenesulfonyl chloride, 0.25M solution in DMA/AcCN (1:1), 0.5 mL, 0.125 μmol). The mixture was stirred at 45° C. for 24 h. Solvent was removed under reduced pressure. Residue was taken in MeOH (1.0 mL) and treated with hydrazine (0.25 mL). Reaction mixture was stirred at room temperature for 16 h and solvent removed under reduced pressure. The product was purified with reverse phase chromatography to give final product. Yield (10.4 mg, 20%). LCMS: m/e 551 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[CH3:26][CH:27]([SH:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH:27]([CH3:28])[CH3:26])[CH:7]=1)[CH3:2]
Reactant: CC(C)S
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1

Procedure:
[3-(2-Bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester was treated with 2-propanethiol as described in Example 21, Step 8 to provide [4-chloro-3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester as described in Example 21, Step 9. Treatment of the amine with pivaloyl chloride as described in Example 21, Step 10 provided {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38].CO>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-dimethyoxybenzoyl chloride (0.6 g, 2.8 mmol). The mixture was stirred at room temperature overnight followed by the addition of MeOH (1 mL). The reaction mixture was then washed with water (40 mL), 1N HCl (2×40 mL), and brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl-methyl]-3,4-dimethoxy-benzamide as a white solid (0.8 g, 79%): mp, 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.2 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.51-2.59 (m, 2H), 2.64 (m, 1H), 3.81 (s, 6H), 4.94 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.51-7.58 (m, 2H), 7.83-7.70 (m, 3H), 9.02 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.22, 48.86, 55.53, 55.60, 110.67, 110.92, 120.56, 121.80, 126.10, 127.05, 131.50, 133.06, 134.77, 139.66, 148.28, 151.44, 166.09, 166.96, 167.57, 169.83, 172.74. Anal Calcd for C23H21N3O7+0.2H2O: C, 60.71; H, 4.74; N, 9.23. Found: C, 60.39; H, 4.51; N, 8.99.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:22][N:23]1[CH:27]2[CH2:28][C:29]([CH2:31][CH:24]1[CH2:25][CH2:26]2)=O>[Zn].Cl[Ti](Cl)(Cl)Cl.C1COCC1>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:29]2[CH2:28][CH:27]3[N:23]([CH3:22])[CH:24]([CH2:25][CH2:26]3)[CH2:31]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(=C2CC3CCC(C2)N3C)c2ccccc2)cc1
Yield: 31 %

Procedure:
A 100 mL dry THF slurry of 18.6 g (284 mmol) zinc powder and 15.6 mL (142 mmol) TiCl4 was stirred and allowed to reflux for 2 h under Ar. The reaction was allowed to cool then a 20 mL THF solution of 10 g (35.5 mmol) N,N-diethyl-4-benzoylbenzamide and 5 g (35.5 mmol) tropinone was added slowly. Once the addition was complete, the reaction was allowed to reflux for 3 h, cooled, then quenched with 10% K2CO3 in H2O. The resulting slurry was partitioned between water and Et2O. The organic fraction was washed with brine, dried over MgSO4, filtered, and concentrated. The remaining yellow oil was absorbed onto silica gel then purified by flash chromatography eluted with 10% 0.5 M NH3 in MeOH 90% CH2Cl2 to produce the product N,N-diethyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenyl methyl] benzamide (4.27 g, 11 mmol). The HCl salt was precipitated from Et2O after the addition of ethereal HCl; mp 145-147° C. MS m/z (MH+) 389. 1H NMR 300 MHz (DMSO-d6) δ 7.2-7.45 (m, 9H), 3.8-3.9 (m, 2H), 3.15-3.25 (m, 2H), 2.75-2.95 (m, 4H), 2.65 (s, 3H), 2.25-2.4 (m, 2H), 2.15-2.25 (m, 2H), 1.75-1.9 (m, 2H), 0.95-1.2 (m, 6H). Anal calc C26H32N2O.HCl (3% H2O): C, 71.21; H, 7.93; N, 6.39. Found: C, 71.16; H, 7.95; N, 6.27.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:37]([S:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:10]4[S:11][C:7]([CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:33][CH2:32]1)(=[O:36])=[O:35])[CH3:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COCCNCc1ccc(B(O)O)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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCOC)s4)cc23)CC1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give impure title compound. The impure title compound was repurified using the HPLC and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide to give 15 mg of the title compound (15%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (4.0 mL, 52 mmol) was added slowly to a 0° C. solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (10.0 g, 43.7 mmol) and diisopropylethylamine (7.3 mL, 52 mmol) in dichloromethane (100 mL) with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture was extracted with water (4×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a clear oil which crystallized upon standing. Mp:60°-63° C. MSCI:252(MH+, base). 1H NMR(300 MHz, CDCl3 /TMS, δ): 4.3(br t,2H), 4.1(br d,2H), 3.0(S,3H), 2.7(br t,2H), 1.7-1.1(m,16H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]C)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 7 h
Yield: 46.4 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) and sodium bicarbonate (1.8 g) in water (40 ml) was stirred at 40° to 45° C. for 7 hours. The reaction mixture was adjusted to pH 5.0 with acetic acid. This solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling, The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([NH:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=[CH:30][CH:31]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}aniline (70 mg) in dichloromethane (10 ml) were added pyridine (1 ml) and MsCl (0.032 ml). After stirred for 2 hours at the room temperature, the mixture was partitioned between ethyl acetate and water and the organic layer was washed with 1N-HCl, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with ether to afford (S)-N-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}phenyl}-methanesulfonamide (0.05 g).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[O:7])[CH:2]=1.[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][OH:22])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[N:3]1([C:6]([O:22][CH2:21][CH2:20][NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:23])=[O:7])[CH:2]=[CH:1][N:5]=[CH:4]1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of CDI (218 mg, 1.30 mmol) in DCM (4 mL) was added a solution of tert-butyl(2-hydroxyethyl)carbamate (0.22 mL, 1.37 mmol) in DCM (1 mL). After stirring at rt for 1 h, the reaction mixture was used directly in DCM for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13](N)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.N([O-])=O.[Na+].[FH:29]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13]([F:29])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccnc2N)CC1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-amino-pyridin-3-yl)-cyclohexanecarboxylic acid ethyl ester (0.25 g, 1.0 mmol) in 70% hydrogen fluoride in pyridine (2.4 ml, 92 mmol) was added solid sodium nitrite (0.076 g, 1.1 mmol) at 0-5° C. The cooling bath was removed after 30 minutes and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was partitioned between an ice-water mixture (50 ml) and tert-butyl methyl ether (50 ml). The organic layer was collected. The aqueous layer was extracted with one 100-ml portion of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gives the title compound (0.11 g, 44%) as light yellow oil. MS m/e: 252 ([M+H]+)
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:17][CH2:18][OH:19])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][CH2:17][CH2:18][OH:19]
Reactant: O=C(OCc1ccccc1)N1CCCC1C=CCO
Agent: [Pd]
Solvent: CCO
Product: OCCCC1CCCN1
Temperature: 35 °C
Yield: 94.2 %

Procedure:
0.73 g of (±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propen-1-ol was dissolved in 7 ml of ethanol and, after adding 200 mg of 5% palladium-carbon, the mixture was heated to 35° C. and hydrogenated at atmospheric pressure for 8 hours. A catalyst was removed by filtering the reaction solution and the filtrate was concentrated under reduced pressure to obtain 0.34 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[Si:22]([O:29][C@H:30]([CH3:56])[CH2:31][CH2:32][CH2:33][C:34](=[O:55])/[CH:35]=[CH:36]/[C@H:37]1[CH2:41][CH2:40][C:39](=[O:42])[N:38]1[CH2:43][CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1COCC1>[Si:22]([O:29][C@H:30]([CH3:56])[CH2:31][CH2:32][CH2:33][C@@H:34]([OH:55])/[CH:35]=[CH:36]/[C@H:37]1[CH2:41][CH2:40][C:39](=[O:42])[N:38]1[CH2:43][CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2/C=C/C(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2/C=C/[C@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of (S)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene, 0.4 mL, 0.4 mmol) in anhydrous THF (10 mL) at 0° C. was added Borane-THF complex (1.0 M, 0.4 mL, 0.4 mmol) dropwise. The mixture was stirred for 15 minutes. Methyl 4-{2-[(2R)-2((1E,7R)-7-{[tert-butyl(dimethyl)silyl]oxy}-3-oxooct-1-enyl)-5-oxopyrrolidin-1-yl}ethyl}benzoate (200 mg, 0.4 mmol) in THF (1 mL) was added dropwise. The mixture was stirred for 3 hours. The mixture was quenched with addition of 1 mL of the saturated ammonia chloride and was dilute with EtOAc (20 mL). The organic layer was washed with brine (3×5 mL), dried over MgSO4. The residue was used for the next reaction without purification.