Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1)([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(I)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of the 7-chloro-2-iodothieno[3,2-b]pyridine (23) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), 2-fluoro-4-nitrophenol (3) (11.15 g, 71.1 mmol), K2CO3 (13.08 g, 94.8 mmol) in Ph2O (30 ml) was heated at 200° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with DCM and filtered; the filtrate was collected and then concentrated. The resultant solid was triturated with diethyl ether, to afford intermediate 24 (7.3 g, 74% yield), which was used directly in the next step with no additional purification. MS (m/z): 417.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22](O)=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N>ClCCl>[CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([NH2:30])=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[C:4]=2[N:3]=1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Product: Cc1nc2c3c(c(C(N)=O)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 64 h
Yield: 50.2 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 11.1 ml (5.6 mmol) Ammonia (0.5 M in dioxane) were added and the mixture was stirred for 24 h at room temperature. The precipitate was filtered off and dried in vacuo at 40° C. to afford 0.15 g (48%) of the title compound as a yellow solid. m.p. 264°-267° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[Cl:20][C:19]1[C:14]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:10])([F:9])[F:8])[N:4]=[CH:5]2)=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:18]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
To a solution of 0.50 g (3 m mol) of 5-methyl-4-trifluoromethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 133 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.62 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 8 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.48 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-trifluoromethylimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH3:11][O:12][CH2:13][C:14](O)=O>>[CH3:11][O:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: COCC(=O)O
Product: COCc1nc2c(C)cc(O)cc2[nH]1

Procedure:
0.55 g (4.00 mmol) 3,4-diamino-5-methyl-phenol and 1.57 mL (20.00 mmol) methoxy-acetic acid were stirred for 1 h at 120° C. Then the reaction mixture was evaporated down and further reacted as crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[F:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2cccc(F)c2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A 25 mL microwave vessel was charged with 1-bromo-3-nitrobenzene (XLVIII) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g, 3.3 mmol), potassium phosphate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane (15.0 mL), and water (3.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) was added, and the reaction was placed in a microwave reactor for 1 h at 95° C. An additional 3-fluorophenylboronic acid (0.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) were added, and the reaction was heated for another 1 h at 95° C. in a microwave reactor. The organic solvent was separated from the water and concentrated to a residue. The residue was then purified by flash chromatography using a 25 g Thomson normal phase silica gel cartridge (100% hexanes→1:99 EtOAc:hexanes) to afford 3′-fluoro-3-nitrobiphenyl (L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.48 (t, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78 (t, J=8 Hz, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), 7.32-7.28 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(OP([CH2:25][C:26]#[N:27])(=O)OCC)C.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[CH:25][C:26]#[N:27])[CH2:5][CH2:4]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4-Dimethylamino-4-phenyl-cyclohexanone (10.85 g, 50 mmole) and cyanomethanephosphonic acid diethyl ester (10.65 g, 12 mmole) were dissolved in DCM (100 ml). This solution was added dropwise with ice water cooling at a temperature of 5 to 10° C. with vigorous stirring to a solution of 40% aqueous NaOH (50 ml) and stirred for 2 h at RT. Working up was performed by combining the batch with ice (100 g). The organic phase was separated off. The aqueous phase was extracted with DCM (3×40 ml). The combined extracts were washed with saturated NaCl-solution (50 ml), dried over Na2SO4 and then evaporated. (4-Dimethylamino-4-phenylcyclohexylidene)acetonitrile was obtained as a yellow oil in a yield of 95% (11.4 g).
Reaction SMILES: ClC1C(=O)C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=CC=CC=2OC)(=O)=O)=CC=1.Cl[C:34]1[CH:35]=[C:36]([S:40]([N:43]=[C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47](=[O:54])[C:46](Cl)=[CH:45]2)(=[O:42])=[O:41])[S:37][C:38]=1Cl.[SH:56][CH2:57][CH2:58][C:59]([NH:61][CH:62]1[CH2:64][CH2:63]1)=[O:60]>>[CH:62]1([NH:61][C:59](=[O:60])[CH2:58][CH2:57][S:56][C:46]2[C:47](=[O:54])[C:48]3[C:53]([C:44](=[N:43][S:40]([C:36]4[S:37][CH:38]=[CH:34][CH:35]=4)(=[O:42])=[O:41])[CH:45]=2)=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:64][CH2:63]1
Reactant: O=C(CCS)NC1CC1
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Agent: COc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Product: O=C(CCSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O)NC1CC1

Procedure:
5.2.43 N-cyclopropyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13h) was prepared according to the procedure for 13d except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N-cyclopropylpropanamide which afforded the title compound 20 mg (37%) as a yellow solid, m.p.: ° C.
Reaction SMILES: C([C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CC(C)=O>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:19][CH2:20][O:21][CH3:22])=[CH:3][C:8]=1[CH3:9]
Reactant: CCc1c(O)ccc(Cl)c1C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(Cl)c(C)c1

Procedure:
To a solution of ethyl 4-chloro-3-methylphenol (1 eq.) in acetone (0.2 M) was added potassium carbonate (5 eq.) and 1-bromo-2-methoxyethane (1.3 eq.). The resulting suspension was refluxed for 25 h. The insolubles were removed via filtration and the filtrate was concentrated in vacuo to furnish the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=1)[C:22]#[N:23]>O1CCOCC1.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>[CH2:35]([O:34][C:31]1[N:30]=[CH:29][C:28]([O:27][C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:33][CH:32]=1)[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)COc1ccc(Oc2ccc(C#N)cc2Br)cn1
Reactant: COc1ncccc1B(O)O
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+]
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1ccc(OCC(C)C)nc1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
Potassium carbonate (0.239 g, 1.73 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.162 g, 0.950 mmol) were added to a solution of 3-bromo-4-[(6-isobutoxypyridin-3-yl)oxy]benzonitrile (Preparation 6, 0.300 g, 0.864 mmol) in dioxane (10 mL). The reaction was degassed three times. Tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) was added and the mixture was degassed three times more. The mixture was heated at 60° C. for 24 hours, then allowed to cool to room temperature and filtered through arbocel, washing with DCM/MeOH (1/1, 50 mL). The combined filtrates were concentrated in vacuo. The residue was absorbed onto silica and purified by silica gel chromatography (Biotage®, SNAP cartridge 50 g, gradient from 5 to 10% EtOAc in heptane 6, then 10% EtOAc in Heptane) to yield the title compound as a solid (0.257 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
Methanesulfonyl chloride (144 mg, 1.27 mmol) was added to a solution of 4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg, 1.15 mmol) and pyridine (255 mg, 2.52 mmol) in CH2Cl2 (10 mL) at 0° C. The solution was warmed to room temperature and was stirred for 24 h. EtOAc was added and the organic solution was washed with HCl (1N, 2×) followed by brine. The organic solution was dried (Na2SO4), filtered, and concentrated to yield the title compound as a white solid (240 mg). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, 2H), 6.90 (dd, 2H), 4.77 (m, 1H), 4.15 (t, 2H), 3.88 (s, 3H), 3.58 (m, 2H), 3.02 (s, 3H); MS 274 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].CO.[OH-].[Na+].Cl>O>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
10 g (31.6 mmol) of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester, 100 ml of methanol and 31 ml of a 10 M NaOH solution are introduced, in order, into a 250 ml three-necked flask. The mixture is stirred at 80° C. for 30 minutes. After returning to room temperature, the reaction medium is poured over water and acidified with a 1 N HCl solution. The precipitate is filtered off. It is taken up in heptane. After filtering and drying, 9 g of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid are obtained in the form of a beige powder (yield=98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH:7]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[CH:18][CH:19]=2)=[O:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)c2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
[3-(3-Bromo-benzoylamino)-phenyl]-acetic acid ethyl ester (203 mg, 0.56 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude residue was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Clc1ccncn1
Product: C[C@@H](c1ccc(-c2ccncn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-chloropyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.167, m/z=374; 1H NMR (CDCl3) 1.06 (s, 3H), 1.11 (s, 3H), 1.49 (d, 3H), 2.11 (s, 1H), 2.17 (s, 2H), 2.21 (m, 1H), 2.35 (m, 1H), 2.80 (m, 1H), 5.66 (m, 1H), 7.02 (d, 2H), 7.21-7.36 (m, 5H), 7.54 (d, 1H), 7.78 (d, 2H), 8.68 (d, 1H), 9.16 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C:10]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:20][CH2:19][CH2:18][O:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)OCCO1
Yield: 58.4 %

Procedure:
2-(tert-Butyldimethylsilanyloxy)-1-phenylethanone (8.0 g, 32 mmol), ethylene glycol (1.99 g, 32 mmol), and p-toluenesulfonic acid (50 mg) was suspended in benzene (50 ml). The mixture was stirred under reflux for 5 hours. The solvent was evaporated under reduced pressure. The residue was treated with water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to give tert-butyldimethyl-(2-phenyl-[1,3]dioxolan-2-yl-methoxy)silane (5.5 g, 18.7 mmol, 58%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:52])[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[S:16][CH:17]=1)C>ClCCl>[CH3:8][O:10][C:11](=[O:52])[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:40])([CH3:41])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[S:16][CH:17]=1
Reactant: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)OC)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Trifluoroacetic acid (0.15 mL) was added to a solution of {2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic acid ethyl ester (Example 63-(1); 20.7 mg, 0.0318 mmol) in dichloromethane (0.75 mL) at room temperature, and the mixture was stirred at room temperature for one hour and 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (15.9 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:12](=[O:13])[N:11]2[C@@H:7]1[CH2:8][C:9]([S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])([CH3:5])[CH3:4].P([O-])([O-])(O)=O.[K+:39].[K+].O.C(O)C>O1CCOCC1.[Pt](=O)=O>[CH3:1][O:2][C:3]([C@H:6]1[C:12](=[O:13])[N:11]2[C@@H:7]1[CH2:8][C:9]([S:27][C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)=[C:10]2[C:14]([O-:16])=[O:15])([CH3:5])[CH3:4].[K+:39]
Reactant: COC(C)(C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COC(C)(C)[C@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccncc3)C[C@H]12
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzyl (5R, 6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (371.0 mg) and platinum (IV) oxide (123.7 mg) in a mixture of dioxane (44.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (23.7 ml), water (5.98 ml) and ethanol (3.71 ml) was shaken for an hour under a hydrogen atmosphere (50 psi) at ambient temperature. The reaction mixture was filtered using super cell. The filter cake was washed with water, and the combined filtrates were concentrated. The residual aqueous layer was washed three times with diethyl ether at 0° C. and concentrated. After addition of potassium chloride (9 g), the resultant aqueous solution (180 ml) was chromatographed on non-ionic adsorption resin "Diaion HP-20 AG" (24×300 mm) eluting successively with water (420 ml), 5% aqueous isopropyl alcohol (420 ml) and 10% aqueous isopropyl alcohol (420 ml). The fractions, whose UV spectrum showed λ max 303 nm, were collected, concentrated and lyophilized to give potassium (5R, 6S)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (208.7 mg) as a white powder.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](=O)[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[CH2:31][NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=Cc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccccc1CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 53.7 %

Procedure:
Using General Procedure B: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (147 mg, 0.37 mmol) and salicylaldehyde (0.04 mL, 0.38 mmol) in CH2Cl2 (5 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the resultant mixture was stirred at room temperature for 16 hours. Purification of the crude material by radial chromatography on silica gel gel (2 mm plate, 75:1:1 CH2Cl2/MeOH/NH4OH) afforded the free amine (100 mg, 54%) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]3[C:45](=[O:46])[C:44]4[N:36]([C:37]5[C@@H:38]6[CH2:47][C@H:41]([C:42]=5[CH:43]=4)[CH2:40][CH2:39]6)[CH2:35][CH2:34]3)[C:28]=2[CH:48]=[O:49])=[CH:3]1.[BH4-].[Na+]>CO>[OH:49][CH2:48][C:28]1[C:29]([N:33]2[CH2:34][CH2:35][N:36]3[C:37]4[C@@H:38]5[CH2:47][CH:41]([C:42]=4[CH:43]=[C:44]3[C:45]2=[O:46])[CH2:40][CH2:39]5)=[N:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][CH:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@H]5CC[C@@H]6C5)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5[C@H]5CCC6C5)C4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 171a (90 mg, 0.136 mmol) in methanol (10 mL) was added NaBH4 (26 mg, 0.7 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. It was quenched with water (30 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 171 (35 mg, 31.5%) as light yellow solid. MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.47 (s, 1H), 7.38 (dd, J=2.5, 9.0 Hz 1H), 7.34 (d, J=5.0 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 6.51 (s, 1H), 4.97 (t, J=4.5 Hz, 1H), 4.58-4.54 (m, 2H), 4.50-4.37 (m, 4H), 4.30-4.24 (m, 2H), 3.86-3.84 (m, 1H), 3.69-3.67 (m, 1H), 3.60 (s, 3H), 3.47 (s, 1H), 3.42-3.37 (m, 1H), 3.30 (s, 2H), 3.10-3.07 (m, 1H), 2.95-2.92 (m, 1H), 2.36-2.29 (m, 3H), 2.21-2.16 (m, 1H), 1.88-1.754 (m, 3H), 1.60-1.58 (m, 1H), 1.08-1.05 (m, 1H), 0.98-0.96 (m, 1H), 0.93 (d, J=6.0 Hz, 3H).