Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].N1C=CC=CC=1>ClCCl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:13][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)(=[O:11])=[O:10])[CH:34]=[CH:33][CH:32]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 106.3 %

Procedure:
Add 3-cyano-benzenesulfonyl chloride (673 mg, 3.34 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) and pyridine (0.98 mL) in dichloromethane (20 mL) at 0° C. Warm to room temperature. Partition the mixture between dichloromethane and 2N hydrochloric acid (60 mL). Wash the organic layer with saturated sodium bicarbonate and brine. Dry and concentrate to afford the title compound as an orange solid (1.65 g): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.47 (sextet, 2H), 2.55 (t, 2H), 2.57 (s, 3H), 5.19 (s, 2H), 6.62 (d, 1H), 7.05 (d, 1H), 7.14 (d, 1H), 7.23 (s, 1H), 7.29 (t, 1H), 7.73 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.07 (d, 1H) 8.12 (s, 1H), 10.55 (s, 1H), 12.86 (s, 1H).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CN1[CH2:18][CH2:17][N:16](C)C1=O.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.CCCCCC>[C:22]1([CH2:21][C:18]2([C:17]#[N:16])[CH2:6][CH2:5][CH2:7]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: ClCc1ccccc1
Reactant: CN1CCN(C)C1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC1(Cc2ccccc2)CCC1
Temperature: -60 °C
Yield: 75.9 %

Procedure:
To a solution under a flow of nitrogen and maintained at -30° C., of 82.3 ml (583 mmoles) of N,N-diisopropylamine in 600 ml of dried tetrahydrofuran, there is poured dropwise 364.4 ml (583 mmoles) of a 1.6M solution in hexane of n-butyllithium, then 83.4 ml of 1,3-dimethylimidazolidinone. The mixture is stirred 1/4 hour at -60° C. before cooling to -75° C. to add dropwise a mixture of 43.5 g (530 mmoles) of the compound prepared in example 27a and 500 ml of dried tetrahydrofuran. The mixture is stirred 1 hour at -75° C. and 67.1 g (530 mmoles) of benzyl chloride are added dropwise. The mixture is stirred 1 hour at -75° C. before pouring the reaction mixture over a ice-concentrated HCl mixture. The mixture is extracted with ether, and is washed with water until neutrality, before drying it over Na2SO4. After removing of the solvent under reduced pressure and distillation of the residue there is obtained 68.1 g (yield=75.9%) of a colorless liquid, which crystallizes at about -20° C. b.p.15 =140° C. (b.p.0.1 =118° according to Mousseron M., Jacquier R. and Fraisse R., Compt. Rend. Acad. Sci., Paris (1955), 241, 602-4).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:5]C1CCCCO1)[CH3:4].[H-].[Na+].CN(C)C=O.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:1][CH2:2][C@@H:3]([OH:5])[CH3:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)OC1CCCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](O)COCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) prepared according to the method of C. Malanga et al, Synthetic Communications, 12,(1), 67-70 (1982)) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in tetrahydrofuran (400 ml) (hereinafter abbreviated to THF), followed by adding dimethylformamide (hereinafter abbreviated to DMF) (200 ml), agitating the mixture for 2 hours, dropwise adding benzyl bromide (140.8 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, (S)-1-benzyloxy-2-tetrahydropyranyloxypropane, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture to 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing it with water, distilling off toluene, and distilling the residue to obtain (S)-1-benzyloxy-2-hydroxypropane (98 g)(b.p. 94.0° C./2.5 mmHg). A mixture of this (S)-1-benzyloxy-2-hydroxypropane (60 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (115.2 g). On the other hand, a solution of 4-hydroxy-4'-octyloxybiphenyl (50 g, 0.17 mol) in THF (200 ml) was dropwise added to a mixture of sodium hydride (8.5 g, 0.35 mol) with THF (100 ml), followed by dropwise adding a solution of the above (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (64.5 g)(0.20 mol) in DMF (100 ml), agitating the mixture at 60° C. for 4 hours, allowing the mixture to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH and further with water, drying over anhydrous magnesium sulfate, distilling off toluene, dissolving the residue in a mixture of ethanol (250 ml) with ethyl acetate (250 ml), adding Pd/C catalyst (10 g), agitating the mixture in hydrogen gas, filtering off the Pd/C, distilling off the solvent, and recrystallizing the residue from heptane (150 ml), to obtain (R)-4-(2'-hydroxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (m.p. 107.9° C.).
Reaction SMILES: ClCCl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.[CH3:13][O:14]C(Cl)Cl>[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: c1ccc2c(c1)CCO2
Reactant: COC(Cl)Cl
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 61555.6 %

Procedure:
Titanium chloride (28 ml) was dropwise added to a dichloromethane (100 ml) solution containing 2,3-dihydrobenzofuran (10.0 g, 83.2 mmols) and dichloromethyl methyl ether (11.3 ml, 0.125 mmols), while cooling with ice. The mixture was stirred for 1 hour, while still cooling with ice, and then water was added thereto. Dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel chromatography (hexane/ethyl acetate=1/1) to obtain 11.4 g (yield: 92%) of the target compound. This was oily.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:15].Cl>O.[Cu]Cl>[NH2:15][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: Cl[Cu]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (5.00 g, 24.8 mmol), ammonium hydroxide (25.0 ml) and copper (1) chloride (50 mg) is heated in a bomb at 125° for 20 hr and is then allowed to cool to 20°-25°. The solid residue is dissolved in water and the solution acidified with 3 N hydrochloric acid. The resultant mixture is filtered, washed, and dried to provide the 2-amino-3-nitrobenzoic acid, mp 201-203; IR (mineral oil) 3478, 3345, 2954, 2925, 2855, 1692, 1677, 1571, 1559, 1520, 1512, 1442, 1271, 1259, 1130 cm-1 ; NMR (300 MHz, CDCl3 -MeOD) 8.38, 8.30, 6.66; MS (EI) m/e 182, 164.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CO>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@@H]3O
Temperature: -78 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a solution of (-)-calanolide A (341 mg, 0.922 mmol) in anhydrous methylene chloride (5 mL) at -78° C. under N2 was added a solution of diethylamidosulfur trifluoride (DAST, 178 mg, 1.11 mmol) in methylene chloride (1 mL) and the resulting yellow solution stirred at -78° C. for 4 hours. The reaction was quenched with 0.5 mL methanol, then allowed to warm to room temperature. The solution was diluted with methylene chloride (20 mL), then washed with water (50 mL) and saturated brine (50 mL). After drying over magnesium sulfate, the solution was filtered and evaporated to provide a light yellow solid. TLC analysis (silica gel, 3% methanol in methylene chloride) showed two components, one fast-moving and one slow. The material was chromatographed through 80 g silica gel, eluting with 1% methanol in CH2Cl2, and the fractions containing the respective components combined and evaporated to afford 198 mg (61% yield) of compound 22 and 75.3 mg (22%) of (-)-calanolide B.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.CN([CH:25]=[O:26])C>>[Br:16][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]([CH:25]=[O:26])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: O=Cc1c2ccccc2c(Br)c2ccccc12
Temperature: 25 °C

Procedure:
This material was made from 9,10 dibromoanthracene (Eastman, 20 g, 60 mmol) modifying the procedure of R. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961). In this procedure, the reaction mixture was cooled to -78° before the nBuLi was added. The resulting mixture was warmed to RT over 1 H and then refluxed until the crystalline starting material disappeared. The mixture was then cooled to -78° again before the DMF was added (in one portion). The flask was warmed to RT and then quenched with 1M HBr (200 mL). The two-phase system was then extracted with CH2Cl2 (3×500 mL). The extracts combined, dried (MgSO4), filtered, and the solvent removed to give the crude material. This was purified by preparative HPLC using PhCH3 as the eluting solvent. After the solvent was removed 13.06 g (76%) of 10-bromo-9-anthracenecarbaldehyde mp 215°-216.5°, lit. mp 218°, P. Kuhn and H. Fischer, Chem. Ber. 94 3060 (1961)), (C, H, Br) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16]C)=[CH:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.Cl(O)(=O)(=O)=O.[CH2:34](Cl)Cl>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11](=[O:16])[CH2:12][C:13]([O:15][CH3:34])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: ClCCl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenoic acid (0.5 g), 35% aqueous perchloric acid (5 ml.) and methylene dichloride (5 ml.) is stirred at RT for 4 days. Then the solution is extracted with methylene dichloride. The combined extracts are washed, dried and evaporated. The residue is purified by prep. thin layer chromatography using 20% ethyl acetate/hexane to yield methyl 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3- oxopentanoate.
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]([CH3:27])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:30]=[C:31]1[O:35][CH:34]([O:36][CH2:37][CH2:38]C2C=CC=CC=2)[CH:33]([NH:45][C:46](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:47])[CH2:32]1>>[CH2:37]([O:36][CH:34]1[CH:33]([NH:45][C:46]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]2[CH:19]=[C:20]([CH3:27])[C:21]([O:25][CH3:26])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:47])[CH2:32][C:31](=[O:30])[O:35]1)[CH3:38]
Reactant: COc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(C)c(OC)c(C)c1
Yield: 81 %

Procedure:
Prepared from 1-[2-(4-methoxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 174 mg (81% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.04 (t, 0.45H), 1.27 (t, 2.55H), 1.34-1.45 (m, 3H), 1.95-2.45 (m, 10H), 2.78-2.84 (m, H), 3.60-3.90 (m, 8H), 4.50-4.70 (m, 2H), 4.90-4.94 (m, H), 5.45 (d, 0.85H), 5.61 (d, 0.15H), 6.99 (d, H), 7.15 (d, H), 7.45 (s, 2H); retention time on analytical HPLC: 10.09 min; LC-MS: m/z=476 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14].C1(=O)NC(=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]2[CH2:12][CH2:13][O:14][CH2:2][C:3]=2[CH:8]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCO)c(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C1CCC(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)COCC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 2-[2-(hydroxymethyl)-4-nitrophenyl]ethanol (Step 1, 1.65 g, 8.37 mmol), succinimide (829 mg, 8.37 mmol) and triphenylphosphine (2.46 g, 9.37 mmol) in dry THF at 0° C. under N2 is treated with diethyl azodicarboxylate (1.50 mL, 9.54 mmol) dropwise over 5 mins, and the resulting mixture is stirred at 0° C. for 4 hrs and then concentrated under reduced pressure. The residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with EtOAc/heptane (10/90), and those fractions with an Rf=0.60 by TLC (EtOAc/hexane, 50/50) are pooled and concentrated to give 995 mg (66%) of the title compound as a white solid, mp 96-98° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl.[CH2:18]([CH2:25][NH:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCCCCC.C(OCC)C>[CH2:18]([CH2:25][NH:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[OH:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1c2ccccc2CCC1CNCCc1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccc(C(F)(F)F)cc2)c2ccccc2CCC1CNCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cooled (−78° C.), stirred mixture of n-butyllithium in hexane (1.6 M, 34.7 cm3) and diethyl ether (25 cm3) was added 4-bromobenzotrifluoride (7.8 g). After a further 15 min, 2-(N-benzylmethylamino)methyl-3,4-dihydro-2H-naphthalen-1-one hydrochloride (prepared using methods described in Process 1) was added portion-wise. The reaction mixture was then stirred for 1 h before being allowed to warm to room temperature and then water (50 cm3) was added. The organic layer was separated and washed with water (50 cm3). It was then extracted with hydrochloric acid (2 M, 50 cm3) and the acidic aqueous portion was basified with solid sodium carbonate and extracted with dichloromethane (100 cm3). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to afford the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:39]=[O:40])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:40][CH3:39])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNS(C)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: O=[Pb]=O
Solvent: ClCCCl
Solvent: c1ccccc1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.18 g (2.4 mmol) of 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution water and a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>O1CCOCC1.CCCCCC>[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: BrCCCCCCN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(CCCCCCN2CCCCC2)c2ccccc21
Temperature: 70 °C

Procedure:
To a suspension of 33.2 g (0.157 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 875 ml of anhydrous dioxan, 173 ml (approx. 0.45 mol) of a 2.6 molar solution of n-butyl-lithium in n-hexane was added dropwise at ambient temperature and the resulting mixture was then stirred for another hour at the same temperature. It was then heated to 70° C. and at a reaction temperature of not more than 75° C. 83.0 g (0.034 mol) of 1-bromo6-(1-piperidinyl)hexane were added dropwise, then to complete the reaction the mixture was stirred for a further 4 hours at 80° C. After cooling, the solvent was distilled off in a water jet vacuum, the residue was adjusted to pH 7 with dilute aqueous hydrochloric acid and the mixture was then filtered. The filtrate was made alkaline with concentrated aqueous potassium hydroxide solution and extracted exhaustively with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and then evaporated down and the residue remaining was digested with 100 ml of boiling diethyl ether and filtered while hot. The residue remaining after the ether had been removed was purified by chromatography on silica gel (Macherey-Nagel, 0.2-0.5 mm) using dichloromethane/methanol/cyclohexane/ethyl acetate/conc. ammonia 59/7.5/7.5/25/1 (v/v/v/v/v) as eluant. By evaporating the desired fractions and subsequently recrystallising from acetonitrile, a colourless crystalline product with a m.p. of 131° to 132° C. was obtained in a yield of 11.29 g (19% of theory). The hydrochloride melted at 223° C. (ethanol).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.C(Cl)(C([Cl:20])=O)=O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([Cl:20])=[O:15])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4-carboxylic acid (5.5 g, 34.7 mmol) and (COCl)2 (12 mL) in DCM (100 mL). The mixture was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure to give crude 6-chloropyrimidine-4-carbonyl chloride (6.0 g, yield: 97.7%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:21])#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][N:24]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=2[F:21])=[N:24][CH:25]=1)[CH3:31]
Reactant: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Reactant: CCOc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C#Cc2ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2F)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-ethynyl-3-fluorophenoxy)-1-methylethyl]carbamate (9.36 g), 2-bromo-5-ethoxypyridine (5.86 g), bis(triphenylphosphine)palladium(II) dichloride (2.04 g), cuprous iodide (0.552 g), triethylamine (6.06 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.00 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:21]([CH:17]3[CH2:20][CH2:19][CH2:18]3)=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)C1CCC1
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 110 mg (0.90 mmol) cyclobutanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.