Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:37][CH:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[CH2:39]1.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C>[N:40]12[CH2:45][CH2:44][CH:43]([CH2:42][CH2:41]1)[CH:38]([NH:37][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:39]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccc(F)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid (0.100 g, 0.39 mmol) in acetonitrile (10 mL) was treated with DCC (0.089 g, 0.43 mmol) and the mixture stirred at room temperature for 1 h. After this time a thick granular precipitate had formed. 3-Aminoquinuclidine dihydrochloride (0.086 g, 0.43 mmol) and DMAP (0.010 g, 0.08 mmol) were then added to the reaction followed by the dropwise addition of triethylamine (0.10 g, 1.00 mmol) over 15 min. The reaction was then stirred at room temperature overnight. Subsequent concentration of the reaction mixture and purification of the resulting solid residue by column chromatography afforded 0.100 g (70% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide as a white solid: mp 185-187° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.46 (d, J=6.7 Hz, 1H), 8.24 (m, 2H), 7.95 (m, 1H), 7.70 (m, 1H), 7.51 (m, 3H), 4.06 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.74 (m, 4H), 1.96 (m, 2H), 1.64 (m, 2H), 1.44 (m, 1H); MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])[CH2:17][CH3:18]
Reactant: O=Cc1cccc(Br)n1
Reactant: CCC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 120 °C
Yield: 30.8 %

Procedure:
To a high-pressure tube was added 6-bromopicolinaldehyde (1, 2.00 g, 10.7 mmol), 1-(piperazin-1-yl)propan-1-one (18, 3.82 g, 26.9 mmol), potassium carbonate (6.69 g, 48.4 mmol) and anhydrous DMF (12 mL). The tube was sealed and the reaction mixture was heated at 120° C. for 17 h. The reaction suspension was poured into water (100 mL) and the mixture was brought to pH 7 using 2 N aq. HCl (20 mL). The solution was extracted with CH2Cl2 (3×100 mL), washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to a brown oil. The product was purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.815 g, 31%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 3.84-3.73 (m, 2H), 3.68-3.59 (m, 2H), 2.40 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15]3)[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1

Procedure:
Diethyl malonate (17.5 g; 110 mmole) was added to a solution of sodium metal (1.91 g; 83 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(5-indanyl)but-1-en-3-one (19.25 g; 103 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of two minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (30% solution, 50 ml) was added and the mixture was heated under reflux for a further 11/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one, was obtained as a white solid (18.70 g; 79.6%), mp 198° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:15]/[S:16]([CH2:19][S:20](/[CH:23]=[CH:24]/[C:3]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:2]=1[F:1])(=[O:22])=[O:21])(=[O:18])=[O:17]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: N#Cc1ccc(C=O)c(F)c1
Solvent: CC(=O)O
Product: N#Cc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(C#N)cc2F)c(F)c1
Yield: 72 %

Procedure:
A solution of 2-fluoro-4-cyanobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 72% yield. m.p. 268-270° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[CH2:18][S:17][C@H:6]1[O:7][C:8]1[C:9]2[N:10]([N:14]=[CH:15][N:16]=2)[CH:11]=[CH:12][CH:13]=1)(=O)C.N>CO>[O:7]([C:8]1[C:9]2[N:10]([N:14]=[CH:15][N:16]=2)[CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[S:17][CH2:18][C@@H:19]([OH:25])[C@H:20]([OH:21])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccn2ncnc12
Agent: N
Solvent: CO
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cccn3ncnc23)SC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture consisting of the product obtained in example 38, in 5 ml of a 7 M solution of ammonia in methanol, is stirred at ambient temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the crude product obtained is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture (97/3; v/v). The product obtained is washed with cold water and then filtered and dried. The desired product is obtained in the form of a white solid with a yield of 36%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH3:59])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH2:58][CH3:59])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)CCc2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)CCc2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-propan-1-one (181 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-191) as a pale brown powder (115 mg, 60%).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1>ClCCl>[OH:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([O:22][C@H:14]2[CH2:15][CH2:16][C@@:17]3([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]4[C@@H:19]3[CH2:20][CH2:21][C@@:4]3([CH3:5])[C@H:6]4[CH2:7][CH2:8][C:3]3=[N:1][OH:2])[CH2:13]2)=[O:44])=[CH:41][CH:40]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: O=C(O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc(O)cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 36 h
Yield: 45.7 %

Procedure:
17-Oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) was taken in anhydrous dichloromethane (30.0 ml). Dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) was added followed by p-hydroxybenzoic acid (0.23 g, 1.6 mmol). Reaction mixture was stirred at room temperature for 24-48 hr and completion of the reaction was monitored by TLC. The reaction mixture was filtered to remove precipitated dicyclohexylurea (DCU). Excess of solvent was removed under vacuum and the product was crystallized from ethyl acetate:petroleum ether (60:80) to yield 17-oximino-5-androsten-3β-yl 4-hydroxybenzoate (15) (0.31 g, 62.0%) mp 177-182° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([OH:19])=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([OH:19])=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3c(O)cccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3c(O)cccc3c2)cc1
Yield: 30 %

Procedure:
The compound is prepared by reaction of 6-(4-methoxyphenyl)-1-naphthol (57 mg, 0.23 mol, 1 eq) with boron tribromide (2.3 ml, 2.28 mmol, 10 eq) according to method G. Purification by column chromatography with dichloromethane/2% methanol as the eluent yields the desired product in a yield of 30%, 16 mg.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[N:14][CH:13]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:18][C:16]2[CH:17]=[N:12][CH:13]=[N:14][CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1cncnc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and pyrimidin-5-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:21])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:5]([N:7]1[CH:13]2[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:6].[Cl-:22].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:22][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([F:1])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([F:21])[CH:14]=1
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2Cl)cc1F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4 ml of chloroform and 298 mg of zinc (II) chloride was stirred at 60° C. After 5 minutes, a mixture of 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at 60° C., and the resulting mixture was heated under reflux for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of N-(2-chlorocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 87 of the present invention) represented by the formula:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:2]1
Reactant: Nc1cc(F)ccn1
Reactant: O[C@H]1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(O[C@H]2CCOC2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-tetrahydrofuran-3-ol (707 mg, 8.03 mmol) was treated with KHMDS (1 M in THF, 5.89 ml, 5.89 mmol) and stirred at room temperature for 5 min. Then, the mixture was added to a solution of 4-fluoropyridin-2-amine (300 mg, 2.68 mmol) in THF (15 ml). The resulting brown solution was stirred for 16 h. KHMDS (1 M in THF, 2.68 ml, 2.68 mmol) was added to the reaction and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a pink solid. (UPLC-MS 3) tR 0.30 min; ESI-MS 181.1 [M+H]+.
Reaction SMILES: C(N1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.Cl.[NH2:18][C@H:19]([C:27]([NH2:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:7]1(=[O:16])[N:18]([C@@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]([NH2:29])=[O:28])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
By following the procedure of Example 19 but employing N-carbethoxyphthalimide and (S)-phenylalaninamide hydrochloride, there is obtained (S)-2-phthalimido-3-phenylpropionamide which can be recrystallized from ethanol to afford white crystals: mp 211-215° C.; 1H NMR (DMSO-d6)δ 7.92 (s, 5H, Ph), 7.72, 7.33 (2 s, 2H), 7.2-7.0 (m, 4H, Ar), 4.92 (dd, 1H, J=12, 4.5 Hz), 3.52 (dd, 1H, J=4.3, 13.9), 3.35 (dd, 1H, J=12, 13.9); 13C NMR (DMSO-d6)δ 169.6, 167.4, 137.7, 134.3, 131.2, 128.5, 128.1, 126.3, 122.9, 54.2, 33.7.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH:3]=[CH2:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH:6](=[N:5]/[CH2:1][CH2:2][CH:3]=[CH2:4])\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCCN
Reactant: O=Cc1ccccc1
Solvent: CO
Product: C=CCC/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of but-3-en-1-amine (580 mg, 8.16 mmol) in anhydrous MeOH (20 mL) was added a dozen molecular sieve beads. Benzaldehyde (865 mg, 8.16 mmol) was added dropwise. The mixture was stirred at rt for 18 hr, The reaction mixture was filtered, and the filtrate was concentrated to dryness to give (E)-N-benzylidenebut-3-en-1-amine (1.30 gm, 8.16 mmol, 99% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (s, 1H), 7.76-7.70 (m, 2H), 7.41 (dd, J=5.0, 1.8 Hz, 3H), 5.86 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.20-4.97 (m, 2H), 3.69 (td, J=7.2, 1.2 Hz, 2H), 2.47 (td, J=7.1, 1.1 Hz, 2H).
Reaction SMILES: Cl.CC(O)C.[F:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38][CH2:37]2)[CH:33]=[N:32][CH:31]=1.C(Cl)Cl>CO>[F:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][CH:39]([NH2:42])[CH2:40][CH2:41]2)[CH:33]=[N:32][CH:31]=1
Reactant: COc1cccc(-c2ccc3c(c2)c(-c2cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n2)nn3C2CCCCO2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: COc1cccc(-c2ccc3[nH]nc(-c4cncc(N5CCC(N)CC5)n4)c3c2)c1F
Temperature: 80 °C

Procedure:
To a 5 mL conical microwave vial was added potassium phosphate (Aldrich, 129 mg, 0.61 mmol), PdCl2AmPhos (17.1 mg, 0.02 mmol), tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 135 mg, 0.24 mmol), and 2-fluoro-3-methoxyphenylboronic acid (Frontier Scientific, 45.3 mg, 0.27 mmol) which was sealed, evacuated and back-filled with N2 3×. Dioxane (2.0 mL) and water (0.4 mL) were added and the resulting mixture was heated at 150° C. for 30 min with microwave irradiation. After the reaction mixtures were filtered, the crude reaction mixture was concentrated under reduced pressure. The dark brown residue was dissolved with DMSO, filtered, and purified by HPLC (5% 0.1% TFA in water to 95% 0.1% TFA in ACN over 20 min) to give tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 53.5%). MS (ESI, pos. ion) m/z: 603 (M+1). A mixture of 5N HCl in IPA (25.9 μL, 0.13 mmol), tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 0.13 mmol), DCM (1.3 mL) and MeOH (1.3 mL) was heated at 80° C. for 30 min with stirring. The resulting reaction mixture was cooled to RT and concentrated to a yellow solid. The above solid was stirred with a 1:1 mixture of DCM:MeOH and applied to a pre-washed (10 mL MeOH) column of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The compound was released with 30 mL of MeOH (with 2M NH3) to yield the title compound product as a yellow oil. MS (ESI, pos. ion) m/z: 419 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:36]([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (100 mg, 0.30 mmol) in DCM (4 ml) and triethylamine (65.8 μl, 0.90 mmol), was added phenylmethanesulfonyl chloride (68.6 mg, 0.36 mmol). The reaction was stirred at RT for 13 hours. DCM was evaporated, and the crude was taken up with EtOAc and washed 1M Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylmethylsulfonamido)-acetate (74 mg; 59.5% yield).
Reaction SMILES: OC1N=CC=CC=1C(N)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:34]=[CH:35][CH:36]=1)[O:15][C:16]1[N:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][OH:23])=O>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:34]=[CH:35][CH:36]=1)[O:15][C:16]1[C:17]([C:18]2[O:23][CH2:22][C@@H:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:20]=2)=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C(N[C@@H](CO)c1ccccc1)c1cccnc1Oc1cccc(Cl)c1
Agent: NC(=O)c1cccnc1O
Product: Clc1cccc(Oc2ncccc2C2=N[C@H](c3ccccc3)CO2)c1

Procedure:
The compound of Example 129 was prepared according to the procedure of Example 128 substituting the corresponding hydroxy nicotinamide for (R)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nicotinamide. The duration of reaction was between 1 and 24 hours.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[C:31]([OH:40])(=[O:39])[C@@H:32]([C@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33]>[Pd].C(O)C>[C:31]([OH:40])(=[O:39])[C@@H:32]([C@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33].[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[CH3:23])[CH3:30]
Reactant: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Agent: [Pd]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
A 250 mL Parr bottle was charged with 0.14 g of 10% palladium on carbon (50% water) and covered with 20 mL ethanol. 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (1.42 g, 3.45 mmol) was dissolved in 50 mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50 psi for 2 h. The catalyst was filtered through a celite plug. The filter cake was washed with 150 mL ethanol and the filtrated concentrated under reduced pressure. The resultant oil was taken up in 20 mL hot ethanol to which was added L-tartaric acid (518 mg, 3.45 mmol) in 10 mL hot ethanol. The solution was allowed to stir 24 h at ambient temperature. The white crystalline precipitate was collected by filtration to yield 730 mg (50%) of (2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt as a white crystalline solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]1([O-])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:1]1([C:7]2=[N:8][NH:9][C:10](=[O:12])/[C:11]/2=[C:14]2\[NH:13][C:22]3[C:17]([CH:16]=[CH:15]\2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)=NN1
Reactant: [O-][n+]1cccc2ccccc21
Product: O=C1NN=C(c2ccccc2)/C1=C1\C=Cc2ccccc2N1

Procedure:
The title compound was synthesized using 3-phenyl-1H-pyrazol-5(4H)-one and quinoline N-oxide according to the procedure described in Example 23. 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.21 (d, J=9.09 Hz, 1H) 7.50-7.60 (m, 7H) 7.82 (t, J=7.71 Hz, 1H) 7.93 (t, J=6.82 Hz, 2H) 8.33 (d, J=8.84 Hz, 1H); ESI-MS: m/z calc'd for C18H13N3O 287.32. found 288.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.[Na:30].C(C(CCCC)C(O)=[O:35])C.C(C(CC)C(O)=O)C>C(O)(=O)C.CC(C)=O.C(O)C.O>[C:27]([OH:29])(=[O:28])[CH:18]([CH3:19])[OH:35].[CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.[Na:30]
Reactant: CCCCC(CC)C(=O)O
Agent: CCC(CC)C(=O)O
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)C(=O)O

Procedure:
The Cefuroxime-but-salt may be reacted in appropriate solvent, e.g. water in combination with a water-miscible solvent, e.g. ethanol and/or acetone, in the presence of an appropriate source of sodium, e.g. the sodium salt of a carboxylic acid, such as ethyl hexanoic acid, diethylacetic acid, acetic acid; lactic acid, to form cefuroxime in the form of a sodium salt which is isolated from the reaction mixture.