Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:21][CH2:22][CH2:23][OH:24])[CH:12]=2)[S:6]1(=[O:18])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(O)c2)S1(=O)=O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(OCCCO)c2)S1(=O)=O
Yield: 88.4 %

Procedure:
A solution of 4.08-B (0.2 g, 0.7 mmol), 3-bromo-1-propanol (0.1 mL, 1.1 mmol), and potassium carbonate (147 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with 0.5 N HCl (50 mL) and brine (50 mL), dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 50% ethyl acetate/hexane) to yield 4.08-C as a white solid (0.21 g, 88%). 1H NMR (500 MHz, CDCl3): δ 7.42 (dd, J=7.8, 7.8 Hz, 1H), 7.36–7.34 (m, 1H), 7.30 (dd, J=2.0, 2.0 Hz, 1H), 7.11–7.09 (m, 1H), 6.63 (s, 1H), 4.18–4.12 (m, 2H), 3.90–3.86 (m, 2H), 2.10–2.05 (m, 2H), 1.73 (s, 9H); LCMS found for C16H22NO5S (M+H)+: m/z=340.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)CCC>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Fc1cccnc1Cl
Solvent: CCCCO
Product: CN1CCN(c2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (1.0 g, 8.5 mmol) and N-methyl piperazine (4.26 g, 42.5 mmol) in n-butanol, 50 ml, is stirred at reflux for 18 hours. After concentrating under reduced pressure at 50° C., the residue is partitioned between ethyl ether and 50% NaOH solution. The ethyl ether extract is washed with a saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The oily product is converted to the hydrogen fumarate salt, mp 148°-149° C., by treatment with fumaric acid in methanol and precipitation with ethyl ether.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[C:26](O)(=S)C(C)O.Cl[C:33]1[C:42](=O)[C:41]2[C:36](=CC=CC=2)/[C:35](=N/S(C2C=CC3C(=CC=CC=3)C=2)(=O)=O)/[CH:34]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][C:18]3[C:42](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:41]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24]
Reactant: CC(O)C(O)=S
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc3ccccc3c2)c2ccccc21
Product: CC(Sc1cc(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2c1O)C(=O)O

Procedure:
5.2.64 2-(1-hydroxy-4-(naphthalene-2-sulfonamido)naphthalen-2-ylthio)propanoic acid (14v) was prepared according to the procedure of procedure B for 10a except using thiolactic acid and (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)naphthalene-2-sulfonamide (12f), which afforded the title compound 51.3 mg (58.6%) as an off-white solid, m.p.: 176-178° C.
Reaction SMILES: N1CC[CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[C:18](=[O:20])[CH3:19])[C:11]([O:13]C)=[O:12].[CH:21](=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>C(O)C.O>[C:11]([C:10]1[CH:9]=[C:8]2[C:17]([C:18](=[O:20])[CH:19]=[C:21]([C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][CH:3]([CH3:4])[CH3:2])[O:7]2)=[CH:16][CH:15]=1)([OH:13])=[O:12]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(C(C)=O)c(O)c1
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccccc1-c1cc(=O)c2ccc(C(=O)O)cc2o1

Procedure:
Piperidine (200 m) was added to a solution consisting of methyl 3-hydroxy-4-acetyl-benzoate (15 g) and salicylaldehyde (15 g) in absolute ethanol (400 ml); the mixture was kept at reflux temperature for 40 hours. After cooling, acidification with hydrochloric acid and extraction with ethylacetate, the organic phase was washed with K2CO 3 5%, and with water, then evaporated to dryness. The residue, so obtained (11 g), was dissolved in n-amylic alcohol (200 ml) by adding SeO2 (11 g) and the solution was kept at reflux temperature for 18 hours. After cooling, the residue was filtered off and the amylic alcohol was distilled in a steam current: the residue of the distillation was recovered by extraction with chloroform, to give, after crystallisation from ethanol, 7-carbomethoxy-2'-hydroxy-flavone (6.3 g), which was reacted in dimethylformamide (30 ml) with 2-bromo-propane (3.5 g) and anhydrous potassium carbonate (4 g) at 70° C. for 18 hours. After cooling, the mixture was diluted with water (200 ml), and then filtered, so obtaining 7-carbomethoxy-2'-isopropoxy-flavone (7.9 g) which was subsequently hydroylsed by treatment with the stoichiometric quantity of a solution of potassium hydroxide 1% in ethanol 95% at reflux temperature for 30 minutes. After cooling, acidification with acetic acid, dilution with water, filtration, and subsequent crystallisation from ethanol, 7-carboxy-2'-isopropoxy-flavone (5.7 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12].[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc3oc(=O)n(C)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
5-[2-(2-Chloro-5-methoxy-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 192, step 1) was dissolved in DMF (15 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (55% in mineral oil, 72 mg). The mixture was stirred for 50 minutes at 0° C. Methyl iodide (0.104 mL) was added dropwise over a period of 10 minutes. Stirring was continued at 0° C. for 1.5 hours. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3) to give the title compound as a colorless gum (312 mg, 60%). MS (m/e)=346.1 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:60]4[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:58][CH2:59]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN1CCNCC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCN(CC(=O)Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added N-methoxyethyl piperazine (12.5 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 78% conversion to product. A further portion of N-methoxyethyl piperazine (12.5 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated 89% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamide (Example 10) as a light orange solid (45 mg, 73%): m/z 705 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO) δ: 1.27 (9H, s), 2.39 (3H, s), 2.46-2.48 (3H, m, obscured by DMSO), 2.57-2.50 (4H, m), 3.17 (2H, s), 3.23 (3H, s), 3.42 (2H, t), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65-7.55 (3H, m), 7.93 (1H, d), 8.36-8.30 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.92 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([O:17]C)=O)[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH:27][CH3:26])=[O:17])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CN
Product: CNC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
This compound was prepared from 1.48 g. (4.2 mmol) of the end product of Example 9 and mono-methylamine according to the procedure described above in Example 11. Recrystallization from acetone/ether/hexane gave the desired product, mp 170°-172°. An analytical sample was prepared by recrystallization from the same solvent system and isolated as colorless needles: mp 170°-172°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[CH3:17][Si:18]([CH3:27])([CH3:26])[C:19]#[C:20][C:21](OCC)=[O:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:21](=[O:22])[C:20]#[C:19][Si:18]([CH3:27])([CH3:26])[CH3:17])=[N:6][CH:7]=1
Reactant: Fc1cccc(F)c1Cc1ccc(Br)cn1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1ccc(Br)cn1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-(2,6-difluorobenzyl)pyridine (5.6 g) in THF was added ethyl 3-(trimethylsily)propynoate (4.2 mL) and LHMD (42 mL, 1N in THF) at −78° C. The mixture was warmed to 0° C. and stirred in additional 2 h. The reaction was complete by TLC and quenched with NH4Cl, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and condensed in vacuo. The crude compound was purified by silica gel (hexanes/methylene chloride) to give the desired product.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=1)[CH2:24][N:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:21]3[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=3)[CH2:24][N:25]3[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]3)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN(Cc2cccc(Br)c2)C1
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Product: COC(=O)C1CN(Cc2cccc(-c3cc4cc(Cc5ccccc5)ccc4o3)c2)C1

Procedure:
Synthesized according to Scheme B2, Step 2 and general procedure F from 5-benzylbenzofuran-2-ylboronic acid and methyl 1-(3-bromobenzyl)azetidine-3-carboxylate to give methyl 1-(3-(5-benzylbenzofuran-2-yl)benzyl)azetidine-3-carboxylate as a light yellow oil. MS (ESI) m/z: Calculated: 411.2; Observed: 412 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[CH:30]1([O:35][C:36]2[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([O:35][C:36]2[N:41]=[CH:40][C:39]([NH:42][C:18](=[O:19])[NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[CH2:9]4)=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(OC2CCCC2)nc1
Product: CC(=O)N(C)C1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)nc3)cc2)C1

Procedure:
N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then 6-cyclopentyloxypyridin-3-ylamine by method A. This resulted in the product with the molecular weight of 437.55 (C24H31N5O3); MS (ESI): 438 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(=O)N(CCO)N=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCOS(C)(=O)=O)N=Cc1ccccc1
Reaction time: 2 h

Procedure:
26.4 g. of the ethyl ester product from part (a) and 10 g. of triethylamine are dissolved in 200 ml. of methylene chloride. 11.4 g. of methylsulfonyl chloride dissolved in a small amount of methylene chloride are added dropwise at -20°. After two hours, 300 ml. of water are added to the reaction solution and this mixture is stirred for 10 minutes. The organic phase is dried (Na2SO4) and, after distilling off the solvent, a colorless oil is obtained which crystallizes upon scratching. Recrystallization from ethanol yields as a white powder [1-[2-[(methylsulfonyl)oxy]ethyl]-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 93°-95°.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])NC(=O)C(C)(C)C.[CH3:12][C:13]1[CH2:14][S:15](=[O:35])[C@@H:16]2[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:34])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20].[Br:36]N1C(=O)CCC1=O>ClCCl.[N+](C1C=CC=CC=1)([O-])=O>[Br:36][CH2:12][C:13]1[CH2:14][S:15](=[O:35])[C@@H:16]2[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:22](=[O:34])[N:17]2[C:18]=1[C:19]([O:21][Si:2]([CH3:11])([CH3:10])[CH3:1])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)N[Si](C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 44 %

Procedure:
355.9 mg (2.06 mmoles) of N-trimethylsilyl-2,2-dimethylpropanamide were added to a suspension of 426.0 mg (1.22 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in a mixture of 40 ml of dichloromethane and 2 ml of nitrobenzene and the mixture obtained was refluxed for one hour. The clear solution obtained was cooled in an ice-bath and bromination was carried out in half an hour using 336.6 mg (1.89 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 44% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:18][CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:23])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17].[BH4-].[Na+].C(O)(=O)C>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:18][CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:23])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[OH:17]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 96.5 %

Procedure:
Dissolve dl-3-methoxy-6-methyl- 13-ethylgona-1,3,5(10)-trien-17-one (7.0 g) in methanol (300 cc) and treat with sodium borohydride (3.0 g). After spontaneous reflux ceases, make acid with 50% aqueous acetic acid (20 cc). Pour into brine, extract with acid and isolate the dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-1,3,5(10)-triene (6.8 g), m.p. 158°-160°C, λmax. KBr 3.05, 6.45 μ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]2[O:20][C:21]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:22][C:18]=2[CH:17]=1>CO>[N:1]1([CH2:15][C:16]2[CH:28]=[CH:27][C:19]3[O:20][C:21]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:22][C:18]=3[CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1cc2cc(CN3CCOCC3)ccc2o1

Procedure:
A stirred solution of morpholine and triethylamine in methanol is treated with 5-bromomethyl-2-sulfamoylbenzo[b]furan to give the subject compound.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.F[C:29](F)(F)[C:30](O)=O>ClCCl>[CH2:24]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=1)[CH2:25][CH2:26][CH2:27][CH2:22][CH2:29][CH3:30]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 2-aminopyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=85:15 to 40:60) to give the title compound as a white solid.
Reaction SMILES: N1C2OC3C=CC=CC=3NCC=2C=CC=1.BrC1C=C(F)C=CC=1C(Cl)=O.[Br:27][C:28]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36].[Na].[CH3:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1>>[Br:27][C:28]1[CH:33]=[C:32]([N:56]2[CH:57]=[CH:58][C:54]([CH3:53])=[N:55]2)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Oc2ccccc21
Agent: O=C(Cl)c1ccc(F)cc1Br
Agent: [Na]
Agent: c1cnc2c(c1)CNc1ccccc1O2
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Oc4ccccc43)c(Br)c2)n1

Procedure:
The title compound may be prepared in a manner analogous to that of the 2-chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][1,5]benzoxazepine of Example 16, Step A, with 2-bromo-4-fluorobenzoyl chloride of Example 3, Step A. Subsequent reaction of the intermediate (2-bromo-4-fluoro-phenyl)-(11H-5-oxa-4,10-diaza-dibenzo[a,d] cyclohepten-10-yl)-methanone with the sodium salt of 3-methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[I:19]I.O>C1COCC1>[I:19][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(I)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 1.00 g (4.22 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 10 ml of dry THF at -78° was added dropwise 4.5 ml (1.4M in pentane, 6.3 mmol, Aldrich) of t-butyllithium solution over 10 minutes. The reaction mixture was stirred at -78° for 30 minutes then at 0° for 15 minutes. The resulting yellow solution was re-cooled to 31 78° then 1.20 g (4.72 mmol, Aldrich) of iodine was added in one portion. The reaction mixture was warmed to room temperature, stirred for 1 hour then added to 50 ml of H2O and extracted with 50 ml of ethyl acetate. The organic extract was washed with an additional 50 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was recrystallized (EtOAc/petroleum ether) to afford 805 mg (67%) of title compound as pale yellow flakes, m.p. 142°-143°.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[NH:4][N:3]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1
Reactant: O=Cc1c(Br)n[nH]c1Br
Reactant: C=COCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(C)n1nc(Br)c(C=O)c1Br
Temperature: 20 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
1 g (3.94 mmol) of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde, 1.5 mL (16 mmol) of ethyl vinyl ether and 3 drops of concentrated 12 N hydrochloric acid are introduced with stirring into 30 mL of toluene at a temperature in the region of 20° C. The reaction mixture is stirred for 15 hours at a temperature in the region of 20° C., followed by addition of 1.5 mL (16 mmol) of ethyl vinyl ether, and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then diluted with 20 mL of toluene and washed with twice 30 mL of saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.19 g of 3,5-dibromo-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxaldehyde in the form of a yellow oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.10 (t, J=7.5 Hz: 3H); 1.64 (d, J=6.5 Hz: 3H); 3.31 (mt: 1H); 3.51 (mt: 1H); 5.88 (q, J=6.5 Hz: 1H); 9.73 (s: 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CNCC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of tert-butyl 4-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.35 g, 0.82 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (2.83 M, 5 mL) and the reaction mixture was stirred at rt for 16 h then added water (10 mL). The resulting mixture was adjusted to pH=8 with a saturated Na2CO3 aqueous solution, then extracted with DCM (20 mL×3). The combined organic layers were washed with brine dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.13 g, 48.5%).