Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:9]1[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:17][O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1)=[O:15]
Reactant: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCOc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCNC(CCOc2ccccc2)C1
Yield: 99.2 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-4-methoxycarbonyl-2-(2-phenoxyethyl)piperazine (D8) (1.4 g, 3.85 mmol) in dichloromethane (30 ml) and trifluoroacetic acid (5 ml) was stirred at 35° C. for 0.75 h. On cooling, the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and IN sodium hydroxide (50 ml each). The organic layer was dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless oil (1.01 g, 99%). Mass spectrum (AP+): Found 265 (MH+). C14H20N2O3 requires 264.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][C:22]([N:25]4[C@@H:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][O:27][C:26]4=[O:33])=[N:21][C:20]=23)=[CH:12][CH:11]=1)=[O:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl.CC#N.CCOC(C)=O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[O:6][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][C:22]([N:25]5[C@@H:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][O:27][C:26]5=[O:33])=[N:21][C:20]=34)=[CH:14][CH:15]=2)=[N:8][N:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NNC(=O)NCCO)cc3)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nnc(NCCO)o4)cc3)c2n1
Temperature: 50 °C
Yield: 35.9 %

Procedure:
To a suspension of (S)—N-(2-hydroxyethyl)-2-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoyl)hydrazinecarboxamide (14.4 mg, 0.031 mmol) in dichloromethane (1 mL) and MeCN (1 mL) was added PS-triphenylphosphine resin (0.054 g, 2.28 mmol/g, 0.123 mmol), triethylamine (44 μL, 0.308 mmol), and CCl4 (12 μL, 0.123 mmol), and the reaction mixture was heated to 50° C. for 4 hours. After the mixture was cooled at ambient temperature, the reaction mixture was treated with EtOAc, washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude was then purified by preparative plate silica gel chromatography (10% MeOH in dichloromethane) to afford 5 mg (35%) of (S)-3-(3-(4-(5-(2-hydroxyethylamino)-1,3,4-oxadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H), 8.43 (s, 1H), 8.08 (m, 3H), 7.92 (d, 2H), 4.96 (m, 1H), 4.44 (m, 2H), 3.94 (t, 2H), 3.65 (m, 2H), 2.88 (m, 1H), 1.09 (d, 3H), 0.95 (d, 3H); LCMS (APCI+) m/z 450.6 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]([CH3:26])[CH2:22][CH:23]([OH:25])[CH3:24])=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:38]([O:37][C:35](=[O:36])[CH2:34][O:25][CH:23]([CH3:24])[CH2:22][CH:21]([O:20][C:18]1[C:19]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=3)=[C:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:26])([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CC(C)O)c23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CC(C)OCC(=O)OC(C)(C)C)c23)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Add 4.8 ml of 11.25 N sodium hydroxide solution to a solution of 2.19 g (5.41 mmol) 4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}pentan-2-ol in 20 ml toluene. After adding 184 mg (0.54 mmol) tetra-n-butylammonium hydrogensulphate and 2.11 g (10.83 mmol) tert.-butyl bromoacetate, stir the reaction mixture for 15 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. aqueous sodium chloride solution, dry over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Take up the residue in ethyl acetate and purify by flash chromatography on silica gel (solvent: ethyl acetate/methanol 1:0, 5:1). 0.08 g (92% purity, 3% of theor.) of the desired product is obtained as a racemic mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:14]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=3[O:23][CH3:24])[CH2:13][CH2:12][CH2:11][C:10]2=[O:25])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=1[CH:14]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH:7]=2)[C:10](=[O:25])[CH2:11][CH2:12][CH2:13]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 1-((2-bromopyridin-4-yl)methyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one (43 mg; 0.10 mmol; compound corresponding to example 36), commercially available 2-(tributylstannyl)thiazole (144 mg; 0.38 mmol), and PdCl2(PPh3)2 (7.5 mg; 0.01 mmol) in anh. THF (3 ml) was heated to 75° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 410.00 g/mol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:9]=1[CH:10]=[CH:11][C:12]([OH:14])=O.[OH-].[Na+].[Cl-].[Li+].C(N(CC)CC)C.[CH2:31]([C@H:38]1[CH2:42][O:41][C:40](=[O:43])[NH:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CN(C)C=O>[CH2:31]([C@H:38]1[CH2:42][O:41][C:40](=[O:43])[N:39]1[C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:8]=1[F:7])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(F)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Oxalyl chloride (19 mL, 216 mmol) in dichloromethane (50 mL) was added dropwise to an ice-cooled stirred suspension of 2,4-difluorocinnamic acid (20.0 g, 108 mmol) in dichloromethane (400 mL) and N,N-dimethylformamide (0.4 mL) over 0.5 hours (waste gases from the reaction were scrubbed with a solution of concentrated sodium hydroxide). Once addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then concentrated and azeotroped with dichloromethane (2×50 mL). The resulting acid chloride was redissolved in dichloromethane (50 mL) and this solution was added dropwise under nitrogen to a vigorously stirred suspension of lithium chloride (23.0 g, 540 mmol), triethylamine (76 mL, 540 mol) and (S)-(−)-4-benzyl-2-oxazolidinone (18.3 g, 103 mmol) in dichloromethane (400 mL) over 30 minutes. Once addition was complete, the reaction mixture was stirred at room temperature under nitrogen for 2.5 hours. The reaction mixture was diluted with dichloromethane (200 mL) and treated with a solution of 5% citric acid solution (500 mL). The organic layer was then separated and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane gave the crude product as an orange oil. The crude material was redissolved in dichloromethane (100 mL) and the resulting solution was passed through a plug of silica, eluting with dichloromethane. The filtrate (1 L) was finally concentrated to afford 30.8 g of the product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[CH2:2]([N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 87.9 %

Procedure:
To a stirring solution of 5-bromo-pentene (6.0 g, 0.040 mol) in DMF (30 mL) was added K2CO3 (4.7 g, 0.034 mol) and potassium phthalimide (6.21 g, 0.033 mmol) and the reaction mixture was heated at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The aqueous layer was then extracted with ethyl acetate (2×50 mL), and the combined organic layers were washed with 5% aq. NaHCO3 (2×20 mL), brine (30 mL) and dried over Na2SO4. Filtration and solvent evaporation gave an oil, which was purified by flash chromatography (silica gel/hexanes:ethyl acetate 0-35%) to yield the desired 2-(pent-4-enyl)-isoindoline-1,3-dione as a solid (6.36 g, 0.029 mmol, 72.5% yield): MS m/e [M+H]+ calcd 216.1. found 216.1; NMR (250 MHz, DMSO-d6) δ 7.79-7.95 (m, 4H), 5.70-5.91 (m, 1H), 4.90-5.11 (m, 2H), 3.58 (t, 2H), 1.98-2.10 (m, 2H), 1.59-1.78 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([N:25]([CH3:26])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (76 mg, 0.28 mmol, CAS RN 1271-19-8) was added to a solution of 6-chloro-N-methyl-4-o-tolylpyridin-3-amine (30 mg, 0.13 mmol, prepared as described in WO2005/002577) and DIPEA (50 μL, 0.29 mmol) in THF (1.5 mL). The reaction mixture was stirred overnight, filtered and all volatiles removed in vacuo. The desired product was isolated by flash chromatography on silica gel (25% EtOAc in n-hexane) as a waxy solid (48 mg, 79%). MS (ESI): m/z=472.9 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[C:16]1([CH2:15][CH2:14][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CN2CCNC[C@@H]2CCc2cccc3ccccc23)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1ccc2c(CC[C@H]3CNCCN3)cccc2c1
Reaction time: 5.5 h
Yield: 367.1 %

Procedure:
Dissolve (S)-1-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine (280 mg, 0.85 mmol) in ethanol (5 mL). Add ammonium formate (320 mg, 5.1 mmol) and palladium hydroxide (60 mg, 20 wt. % on carbon) and heat to reflux. After 5.5 h, filter the palladium hydroxide and concentrate the filtrate. Combine with Example 421 and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (5%) and 7N ammonia in methanol-methylene chloride (20%) as the eluent to give 750 mg (81%) of the title compound: mass spectrum (ion spray): m/z=241 (M+1). 1H NMR (DMSO-d6): 8.08 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.59–7.32 (m, 4H), 3.53 (br s, 2H), 3.22–3.09 (m, 1H), 3.08–2.98 (m, 1H), 2.98–2.73 (m, 3H), 2.71–2.53 (m, 3H), 2.31 (dd, 1H), 1.71–1.57 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([OH:20])[CH2:14][C:13]1([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.C(=O)(O)[O-].[Na+]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([O:20][CH2:23][CH:25]2[O:27][CH2:26]2)[CH2:14][C:13]1([CH3:21])[CH3:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Product: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Temperature: 30 °C
Reaction time: 16 h

Procedure:
100 g (2.5 mol) of sodium hydroxide are dissolved in 100 ml of water in a 750 ml sulfonation flask fitted with mechanical stirrer, thermometer, dropping funnel and condenser. 71.9 g (0.25 mol) of 1-octyloxy-2,2,6,6-tetramethyl-4-hydroxypiperidine and 16.1 g (0.05 mol) of tetrabutylammonium bromide are added at 20° C. The mixture is warmed to 30° C. with vigorous stirring. A solution of 277.5 g (3 mol) of epichlorohydrin and 71.9 g (0.25 mol) of 1-octyloxy-2,2,6,6-tetramethyl-4-hydroxypiperidine is then added dropwise at 35° C. over the course of 75 minutes. The reaction solution is stirred at room temperature for 16 hours and poured onto 1 kg of ice and 100 g of sodium bicarbonate. The organic phase is separated off. The water phase is extracted with ethyl acetate. The two organic phases are washed with sodium chloride-saturated water, dried over sodium sulfate and evaporated on a Rotavap.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[C:20]([F:24])[CH:21]=[C:22]3[NH:27][N:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Fc1cnc2c(-c3ccc(OCc4ccccc4)cc3)n[nH]c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (41 mg), hydrazine hydrate (31.5 mg) and 2-propanol (10 mL) was stirred at 90° C. for 12 h, treated with saturated NaHCO3 aqueous solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (32.0 mg).
Reaction SMILES: Cl.[C:2]([C:5]1[S:37][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:15]=3[O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH:19]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:18]3)[C:7]=2[C:6]=1[CH3:38])(=[O:4])[NH2:3].CO>O1CCOCC1>[F:36][C:33]1[CH:34]=[CH:35][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:38])=[C:5]([C:2]([NH2:3])=[O:4])[S:37][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][CH3:24])[CH2:18]2)[CH:32]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC(N(C)C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
220 μl 4 M HCl in dioxane was added to 0.093 g tert-butyl 3-(2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)cyclohexyl(methyl)carbamate (cpd. 17.3) in 4 ml dioxane. The reaction mixture was stirred for 1 h at rt when further aliquots of 4 M HCl in dioxane were added. methanol was added and the mixture stirred for 2 days at rt. The mixture was purified by chromatography (gradient: CH2Cl2→20% MeOH/CH2Cl2 using the Biotage SP4).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]Br)=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:16].[Ca+2].O.O1CCOCC1.Cl>O1CCOCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:16])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(CBr)c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(Cl)c(CO)c1=O

Procedure:
2-tert-butyl-4-bromomethyl-5-chloro 3(2H)-pyridazinone (2 g, 7.19 mmol) and calcium carbonate (3.5 gm) are added to a 1:1 mixture of dioxane water (40 ml). The mixture is refluxed for 6 hours after which 30 ml of 3N HCl solution is added to it. The solution is stirred for 10 minutes after which dioxane is removed under reduced pressure. The resulting solution is then extracted with dichloromethane and the dichloromethane layer is washed and dried. The crude obtained after concentration is purified by flash chromatography (ethyl acetate/hexanes:1:2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH2:21]O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH:20]=1)[CH2:21][O:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cc(Br)ccc1I
Reactant: COc1ccc2c(O)cccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3cc(Br)ccc3I)cccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To a solution of 6-methoxynaphthalen-1-ol (4.45 g, 25.6 mmol), (5-bromo-2-iodophenyl)methanol (8.0 g, 25.6 mmol) and triphenylphosphine (7.4 g, 28.2 mmol) in tetrahydrofuran (128 mL) at 0° C. was added diisopropyl azodicarboxylate (5.54 mL, 28.2 mmol). The reaction was allowed to warm to room temperature overnight. After 15 hours, more triphenylphosphine (1.3 g, 5 mmol) and diisopropyl azodicarboxylate (0.99 mL, 5 mmol) were added and the reaction was stirred at room temperature. After 24 hours, the reaction was concentrated and recrystallized from CH2Cl2 and hexanes to yield 1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene (7.82 g, 65%). The mother liquor was purified by flash column chromatography to yield more product (790 mg, 6.5%).
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36]S(C3C=CC(C)=CC=3)(=O)=O)[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:33]2=[O:58])=[C:29](\[OH:31])/[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N12CCCCC1C=NCCC2.C(O)(=O)C>COCCOC.C(Cl)Cl>[C:13]1([CH:19]([O:26][C:27]([C:28]2[N:32]3[C:33](=[O:58])[C@@H:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@H:35]3[S:36][CH2:30][C:29]=2[OH:31])=[O:59])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: COCCOC
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 ml of bis-trimethylsilyl-acetamide (0.508 mmol) is added to a solution of 301 mg (0.462 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester in 3 ml of 1,2-dimethoxyethane under a nitrogen atmosphere, and the mixture is stirred for one hour at room temperature. The solution is completely concentrated by evaporation and the oily residue is dried for one hour under a high vacuum. The silylated crude product is taken up in 3 ml of dried 1,2-diethoxyethane and after cooling to 0° C. 0.075 ml (0.508 mmol) of 1,5-diazabicyclo [5.4.0]undec-5-ene is added. After 6 hours' reaction time at 0° C. under a nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture is diluted with methylene chloride. The methylene chloride solution is washed successively with dilute sulphuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride and the combined organic phases are dried with sodium sulphate, concentrated in vacuo and dried under a high vacuum. Crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained. An excess of a solution of diazomethane in ether is added to the solution of the crude product in chloroform at 0° C. and the mixture is left to stand for 5 minutes at 0° C. It is then concentrated completely and the residue is chromatographed on silica gel, as in Example 2. 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; Rf value=0.19 (silica gel; toluene/ethyl acetate, 3:1); melting point 120° C. (from ether), IR spectrum (in CHCl3); 3,310, 1,775, 1,710, 1,690 and 1,600 cm-1, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6](I)=[CH:5]2.C(C1CCCCC1=O)(=O)C(C)C.[CH3:35][C@H:36]1[NH:41][C:40](=[O:42])[CH2:39][O:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:41]1[C@H:36]([CH3:35])[CH2:37][O:38][CH2:39][C:40]1=[O:42])=[CH:5]2
Reactant: C[C@@H]1COCC(=O)N1
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2N2C(=O)COC[C@H]2C)cc1
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (0.25 g, 0.533 mmol, prepared as in Example 1, Step 1-2), 2-isobutyrylcyclohexanone (0.018 g, 0.107 mmol), (R)-5-methylmorpholin-3-one (0.92 g, 7.99 mmol), copper(I) iodide (5.07 mg, 0.027 mmol), and cesium carbonate (0.35 g, 1.066 mmol) in DMF (5 mL) was heated at 125° C. for 10 min. Some product was observed but mostly starting material. The mixture was heated again at 125° C. for 10 min more. This process was repeated 7× until the starting material was completely consumed. The reaction was brought to RT, poured into water (20 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a light yellow solid as (R)-4-(6-bromo-2-(4-methoxybenzylamino)quinolin-3-yl)-5-methylmorpholin-3-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].C(=O)(OC(Cl)(Cl)Cl)[O:8][C:9](Cl)(Cl)[Cl:10].N1C=CC=CC=1>CCOCC>[Cl:10][C:9]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:8]
Reactant: COCC(C)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COCC(C)OC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml (10.2 mmol) of 1-methoxy-2-propanol (Fluka, Buchs, Switzerland) is injected slowly into an ice-cold solution of 916 mg (1.1 equivalent) of bis(trichloromethyl) carbonate (triphosgene; Fluka, Buchs, Switzerland) in 35 ml of ether using a syringe. At the same time, 1 ml (1.2 equivalents) of pyridine in 5 ml of ether is added dropwise from a dropping funnel. After the addition has ended, the mixture is left to stir at RT for a further 60 min. The reaction mixture is filtered through wadding and the solvent is carefully evaporated off (35° C. waterbath). The oily residue (title compound) is subjected to further processing without any purification. 1H-NMR (200 MHz; CDCl3)=inter alia 5.05/m (1H); 3.30/s (3H); 1.27/d (3H).