Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][C:36]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][S:22]([N:41]2[CH2:40][CH2:39][C:36]3([CH2:37][CH2:38][N:33]([C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)[CH2:34][CH2:35]3)[CH2:43][CH2:42]2)(=[O:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CCN(c4ccncc4)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (1.3 mmol, 1 eq) in MC (5 ml) was added to a solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (1.56 mmol, 1.2 eq) and DIPEA (5.2 eq) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was subsequently warmed to room temperature and stirred for 12 h. The reaction mixture was diluted with methylene chloride and washed with water and sat. sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel). Yield: 0.4 g (50%). MS, Rt=3.8 min, m/z=614.9 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.Cl.O.Cl.O1CCOCC1>O1CCOCC1>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {1-[2-(2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 164, 220 mg, 0.59 mmol) in dioxane (5 mL) was added a solution of HCl in dioxane (4M, 9 mL), followed by water (1 mL) and it was stirred at room temperature over night. An addition 5 mL of HCl/dioxane was added to the reaction. After 1 hr, the reaction was concentrated to dryness. The crude product was partitioned between 10% methanol/dichloromethane (50 mL) and 1M sodium hydroxide (50 mL). The aqueous phase was back extracted with 10% methanol/dichloromethane (50 mL) and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 170 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-chloroacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: Br[CH:2]=[C:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH:15]1[C:16]2[C:3](=[CH:2][C:25]3[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:29][CH:30]=3)[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: BrC=C1c2ccccc2Oc2ccccc21
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
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: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3Oc3ccccc32)c1
Temperature: 95 °C
Yield: 2.8 %

Procedure:
Mix 9-Bromomethylene-9H-xanthene (400 mg, 1.46 mmol), N-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (413 mg, 1.39 mmol), and Na2CO3 (2M/water, 1.74 mL, 3.48 mmol) in dioxane (10 mL) and sparge with nitrogen for 10 min. Add Pd(PPh3)4 (81 mg, 0.070 mmol), seal vial, and heat to 95° C. overnight. Concentrate and dilute with water (3 mL) and ethyl acetate (10 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 50 mL ethyl acetate. Purify on silica gel (20-40% ethyl acetate/hexanes), then re-purify by semi-prep reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA added) to afford 14 mg (3%) of the title compound as a yellow solid. MS [ES] 364 (M+H), 362 (M−H); HPLC shows 97% purity; 1H-NMR (CDCl3) δ 7.78 (d, 1H, J=7.5 Hz), 7.39-7.14 (m, 10H), 6.91 (s, 1H), 6.85 (t, 1H, J=7.5 Hz), 6.53 (s, 1H), 3.01 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])[CH3:4].S(Cl)([Cl:20])=O>>[CH3:2][N:3]([CH2:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:20])=[O:10])[CH3:4]
Reactant: CN(C)Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN(C)Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The mixture of 3-dimethylaminomethyl-2-nitrobenzoic acid hydrochloride (0.1 g) and thionylchloride (5 mL) was stirred at 80° C. for 3 hours. The solvent was removed and the residue was dried to obtain 3-dimethylamino methyl-2-nitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]#[N:17])[C:13]3[N:18]=[C:19]([CH:21]=[CH:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[NH:20][C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]#[N:17])[C:13]3[N:18]=[C:19]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[NH:20][C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:30]([F:33])([F:31])[F:32])[CH3:2]
Reactant: CCOc1ccc(-c2cc3[nH]c(C=CCN4CCOCC4)nc3c(C#N)n2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(-c2cc3[nH]c(CCCN4CCOCC4)nc3c(C#N)n2)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a flask containing a solution of 6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(3-morpholin-4-yl-propenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (16 mg) in ethanol was added 5% Pd/C (5 mg) and the vessel purged with hydrogen. The mixture was stirred for 1 h before filtration and purification by preparatice HPLC to afford the title compound. 1H NMR (MeOH) δ 8.32-8.25 (m, 2H) 8.17 (s, 1H) 7.30 (d, 1H) 4.24 (q, 2H) 4.20-3.84 (bm, 4H) 3.65-3.60 (bm, 2H) 3.40 (t, 2H) 3.22 (m, 4H) 2.40 (m, 2H) 1.45 (t, 3H) MS m/z 460.7 (m+1)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:10][C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[CH:14]=[CH:15][C:16](OCC)=[O:17])[CH2:8][CH3:9].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:10][C:11]1[CH:12]=[C:13]([CH2:14][CH2:15][CH2:16][OH:17])[CH:21]=[CH:22][CH:23]=1)[CH2:8][CH3:9]
Reactant: CCCOc1cccc(C=CC(=O)OCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCOc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To lithium aluminum hydride (7.58 g) suspended in diethyl ether (300 ml) was added dropwise at 0° C. a solution of ethyl 3-propoxycinnamate (24.0 g) in diethyl ether (100 ml) over a period of one hour. After the dropwise addition, the resulting mixture was stirred at room temperature for one hour. Water (7.6 ml), a 15% aqueous solution of sodium hydroxide (7.6 ml) and water (22 ml) were added to the reaction mixture, which was further stirred at room temperature for 0.5 hour. The reaction mixture was diluted with diethyl ether and was dried with anhydrous magnesium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 4:1) to obtain 3-(3-propoxyphenyl)-1-propanol (15.23 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:45][OH:46]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:45][OH:46])=[O:27])=[O:17]
Reactant: NO
Reactant: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid (424 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (224 mg, 51%) as a brown solid. LC-MS (m/z) 440 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.O=S(Cl)[Cl:14]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Product: Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) in 50 ml SOCl2 was heated at reflux for 30 min. Solvent was removed and the residue was dried in vacuo.
Reaction SMILES: ClC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.Cl[S:30]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([Br:42])[CH:40]=2)[N:35]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])[C:34]=1[C:52]([O:54][CH2:55][CH3:56])=[O:53])(=[O:32])=[O:31].Cl.CN.C(O)(=O)C(O)=O.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72]>>[CH2:55]([O:54][C:52]([C:34]1[N:35]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])[C:36]2[C:41]([C:33]=1[S:30]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])(=[O:32])=[O:31])=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=2)=[O:53])[CH3:56]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCN
Agent: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CCOC(=O)c1c(S(=O)(=O)NCCCCC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-bromo-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with tert-butyl 5-aminopentanoate oxalic acid salt, the title compound was obtained after flash chromatography through silica gel (100% dicloromethane). ESI+ MS: 587 [M-CH2═CMe2]+.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCOC(C)=O.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([Cl:1])[CH:3]([NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:4]1
Reactant: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1Cl)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOP(=O)(NC1CN(c2ccncc2N)CCC1Cl)OCC
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of diethyl 4-chloro-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate (1.0 equiv.) in degassed EtOAc (0.1M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen atmosphere for 18 h. Filtered and concentrated the filtrate to yield diethyl 1-(3-aminopyridin-4-yl)-4-chloropiperidin-3-ylphosphoramidate in 83% yield. LCMS (m/z): 363.1 (MH+), Rf=1.89 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: BrCc1cccnc1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: Br
Product: Cc1oc(-c2ccc(OCc3cccnc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 57 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) and 3-(bromomethyl)pyridine hydrobromide. MS (m/e): 378.3 (M+1)
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]([O:17][N:18]=[C:19]([C:50]1[N:51]=[C:52]([NH2:56])[S:53][C:54]=1[Cl:55])[C:20]([NH:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([O:34]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12)=[O:21])[CH3:16])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH:15]([O:17][N:18]=[C:19]([C:50]1[N:51]=[C:52]([NH2:56])[S:53][C:54]=1[Cl:55])[C:20]([NH:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12)=[O:21])[CH3:16])([OH:14])=[O:12]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)OC(C)(C)C)c3nc(N)sc3Cl)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)O)c3nc(N)sc3Cl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
Trifluoroacetic acid (6.4 ml) was added to a solution of benzhydryl 7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g) in methylene chloride (3.0 ml) and anisole (1.6 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 1.5 hours. To the reaction mixture was added diisopropyl ether (50 ml), and the precipitates were collected by filtration and added to a mixture of water and ethyl acetate. After adjusting to pH 7.5 with 10% aqueous sodium hydroxide, the separated aqueous layer was adjusted to pH 2.2 with 10% hydrochloric acid and then saturated with sodium chloride, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 7-[2-(1-carboxyethoxyimino)-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]#[CH:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].Cl[C:24]1[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=1>C(N(CC)CC)C.C(#N)C.C(OCC)(=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]#[C:19][C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6]
Reactant: C#CC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)c1)(C3)C2
Reactant: Cc1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cncc(C#CC23CC4CC(C2)CC(NC(=O)c2cccc(Cl)c2)(C4)C3)n1
Temperature: 70 °C
Yield: 38.9 %

Procedure:
To a stirred mixture of intermediate 8, 3-chloro-N-(3-ethynyl-adamantan-1-yl)-benzamide (60 mg, 0.19 mmol) and 2-chloro-6-methylpyrazine (60 mg, 0.47 mmol) in triethylamine (0.5 mL) and acetonitrile (2 mL) was added Pd(PPh3)4 (3 mg, 0.02 mmol), followed by an addition of CuI (3 mg, 0.016 mmol). After heated at 70° C. for three hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (50 mL) and brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by Prep HPLC to give 30 mg (38%) of the title compound, 3-chloro-N-[3-(6-methyl-pyrazin-2-ylethynyl)-adamantan-1-yl]-benzamide. 1H NMR (500 MHz, CDCl3): δ 8.57 (brs, 1H), 7.69 (t, J=2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 5.78 (s, 1H), 2.57 (s, 3H), 2.40 (s, 2H), 2.25 (s, 2H), 2.17-2.15 (m, 2H), 2.06-1.96 (m, 6H), 1.73-1.70 (m, 2H); ESI-MS m/z: 406 (M+H)+.
Reaction SMILES: BrC1C=C[C:5]([OH:36])=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.C(C1C(=O)[NH:42][C:43](=[O:53])[N:44]([C:46]2[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=2)C=1)(=O)C.[OH-].[K+]>C(O)C>[Cl:52][C:47]1[C:46]([N:44]2[CH:7]=[C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[C:5](=[O:36])[NH:42][C:43]2=[O:53])=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cn(-c2cccnc2Cl)c(=O)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cn(-c5cccnc5Cl)c(=O)[nH]c4=O)ccc3c1)n2C1CCCCC1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-acetyl-1-(2-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound 45 mg, 31% yield). MS: 593.17 (M+H+); HPLC Procedure A, retention time=10.02 min.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:16]1[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([OH:39])[CH:35]=2)[CH:30]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[OH-].[Na+]>CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1.CO>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:16]1[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH2:2][C:3]3[NH:7][N:6]=[N:5][N:4]=3)[CH:35]=2)[CH:30]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCc1nnn[nH]1
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 17 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Pyridinium p-toluenesulfonate (0.16 kg, 0.64 mol) was added to a solution of 5-chloromethyl-1H-tetrazole (2.37 kg, 20.0 mol) and 3,4-dihydro-3H-pyran (2.83 kg, 33.6 mol) in acetone (20 L) and the resultant solution was heated at 45° C. for 3 hours. Additional 3,4-dihydro-3H-pyran (1.46 kg, 17.4 mol) was added and heating was continued for 2 hours. 1-benzyl-2-(6-hydroxynaphthalen-2-yl)-3-pentyl-1H-indole (7.0 kg, 16.7 mol) was added and the solution was stirred at 17° C. Cesium carbonate (6.77 kg, 20.8 mol) was then added. The temperature of the suspension was adjusted to 60° C. and heating was continued for 3 hours, at which time HPLC analysis showed 100% conversion. Toluene (55 L) was added and acetone was removed by atmospheric distillation. The mixture was heated to 100° C. to provide 35 L of residual volume. After cooling the residue to 20° C., a solution of 1 N hydrochloric acid (28.6 L) was added, the mixture was stirred for 30 minutes, and the layers were separated. The upper organic layer was treated with a mixture of concentrated hydrochloric acid (8.3 kg, 84.2 mol) and methanol (28 L) at 20° C. for 30 minutes, the time necessary to complete hydrolysis, followed by dilution with toluene (58 L). A 1 N sodium hydroxide solution (35 L) was added, which changed the pH to 4. The layers were separated and the upper organic layer was washed with a 17% sodium chloride solution (35 L) at 40° C. The toluene layer was slowly cooled to −3° C. (crystallization begins at 21° C.) while being stirred for 1 hour. The suspension was then filtered, and the cake was washed with cold toluene (−3° C., 40 L) to yield, after drying, 6.4 kg (76.4% yield) of the title compound as an off-white solid with 99.26% ar. HPLC purity.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.Cl[C:13]1[N:22]=[C:21]([NH:23][C:24]2[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:13]1[N:22]=[C:21]([NH:23][C:24]2[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(Oc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)c1

Procedure:
Sodium hydride (45 mg, 1.12 mmol) in THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6 mmol) and the reaction mixture is stirred until effervescence ceases. The THF is removed in vacuo and the above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (150 mg, 0.51 mmol)) is added. The reaction mixture is stirred at 100° C. for 20 h, then poured into aqueous K2CO3 and stirred for 2 h at room temperature. The solid that forms is collected and re-crystallized from ethanol to give the product [2-(3-methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.