Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[CH2:44][CH2:43]1>ClCCl>[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][N:50]([C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=3)=[O:9])[CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:44]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)N2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (900 mg, 6 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (1.52 mg, 15 mmol), 1-hydroxybenzotriazole (891 mg, 6.6 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1.254 g, 6.6 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (1.259 g, 6.6 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 80%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.72-1.80 (m, 1H), 3.41-3.81 (m, 8H), 7.58-7.60 (d, J=8.0 Hz, 1H), 7.95-7.97 (d, J=8.0 Hz, 1H), 10.07 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>>[Cl:13][C:14]1[CH:15]=[C:16](/[CH:17]=[CH:11]/[C:10](=[O:12])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cccc(CC(C)=O)c1
Product: COc1cccc(CC(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 1-(3-methoxyphenyl)propan-2-one and 3,4-dichlorobenzaldehyde following the procedure outlined in Example 9.1 above. 1H NMR (CDCl3, δ): 7.56 (d, J=2.0 Hz, 1H) 7.48 (d, J=16.0 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 6.8(m, 3H), 6.73 (d, J=16.0 Hz, 1H), 3.88 (s, 2H), 3.79 (s, 3H). 13C NMR (CDCl3, δ): 196.5, 159.8, 140.4, 135.3, 134.4, 134.3, 133.1, 130.8, 129.8, 129.7, 127.3, 126.2, 121.7, 115.1, 112.5, 55.1, 48.7.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH:3]\[C:4](OC)=[O:5].C1C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CO>[CH3:1]/[C:2](/[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH:3]\[CH2:4][OH:5]
Reactant: C=C(C)CCC/C(C)=C/C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Solvent: CO
Product: C=C(C)CCC/C(C)=C/CO
Reaction time: 2 h

Procedure:
To a mixture of the foregoing dienoic ester (0.827 mmol) and 7.5 ml of benzene, under nitrogen, is added 1.5 ml of 1.78 M diisobutyl aluminum hydride (DIBAH). After about 2 hours, 1 ml more of DIBAH is added and the reaction continued to completion as checked by thin layer chromatography. The reaction is worked up by adding about 2 ml of methanol and dilute HCl. The aqueous layer is extracted with ether. Then the combined ether phases are washed with water and brine, dried over sodium sulfate and solvent evaporated to yield (E)-3,7-dimethyl-2,7-octadien-1-ol.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:22])[C:18]([F:21])([F:20])[F:19])[C:13]([N+:23]([O-:25])=[O:24])=[C:12]([F:26])[CH:11]=2)[CH2:5][S@@:4](=[O:27])[CH2:3]1.[CH3:28][C:29]1([CH3:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH:38]=O)[CH:36]=2)[CH2:31][O:30]1.CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>>[CH3:28][C:29]1([CH3:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]4[CH:15]=[C:14]([O:16][C@@H:17]([CH3:22])[C:18]([F:21])([F:19])[F:20])[C:13]([N+:23]([O-:25])=[O:24])=[C:12]([F:26])[CH:11]=4)[CH2:5][S@@:4](=[O:27])[CH2:3]3)[CH:36]=2)[CH2:31][O:30]1
Reactant: CC1(C)OCc2ccc(C=O)cc21
Reactant: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3ccc4c(c3)C(C)(C)OC4)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 1h, starting from (1R,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol (0.075 g, 0.19 mmol), 3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde (0.036 g, 0.203 mmol), NaOAc (0.032 g, 0.38 mmol) and NaBH3CN (0.013 g, 0.19 mmol) and was obtained as a light yellow foam after chromatographic purification on silica gel: TLC (EtOAc-MeOH 19:1) Rf=0.20; HPLC RtA=1.78 min; ESIMS [M+H]+=575; 1H NMR (400 MHz, CDCl3): δ 7.19 (m, 2H), 7.04 (s, 1H), 6.84 (s, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 4.76 (m, 1H), 4.25 (s broad, 1H), 3.94 (d, 1H), 3.76 (d, 1H), 3.53 (ddd, 1H), 3.37 (ddd, 1H), 2.8-3.15 (m, 5H), 2.14 (m, 2H), 1.52 (d, 3H), 1.48 (s, 6H).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Yield: 73.1 %

Procedure:
Acetic acid (4.1 ml) and zinc powder (3.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylate (2.6 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (150 ml) and ethyl acetate (75 ml), and then extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystallized by adding acetonitrile. The crystals were collected by filtration, washed with ether and dried to give colorless crystals of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid (1.4 g), mp 173° to 174° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[CH:12][CH:13]=[CH2:14])[CH3:2].[CH2:16]([O:18][C:19]([N:21]=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]1[CH:12]=[CH:13][CH2:14][N:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]1[C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH3:2]
Reactant: C=CC=Cc1ncccc1C(=O)OCC
Reactant: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C1C=CCN(C(=O)OCC)N1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9.8 g of 2-(1,3-butadienyl)nicotinic acid ethyl ester and 9.2 g of diethyl-azodicarboxylate are mixed with 30 ml of toluene and heated to 80° under nitrogen. After 1 hr a further 3 g of diethyl-azodicarboxylate are added and after 3 hrs a further 5 g. After a further 4 hrs the reaction mixture is allowed to cool to RT and stirred overnight. The solvent is removed by evaporation under vacuum and the resulting oil chromatographed on silica gel and eluted with ethylacetate/hexane to give the title compound as black oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][C:6]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][C:25]3N[CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=2)[CH:21]=1)([CH3:15])[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:5][C:6]([C:16]1[CH:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25](=[N:24][CH:23]=2)[N:1]([C:2]([NH2:4])=[O:3])[CH2:27][CH2:28][CH2:29]3)[CH:19]=[N:18][CH:17]=1)([CH3:15])[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: NC(N)=O
Reactant: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3)c1
Product: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1

Procedure:
The titled product is synthesized according to the procedure of Urea Formation Method II using 2-methyl-1-morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-one.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:13]=2)[N:8]=1>C1COCC1>[Cl:6][C:7]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)([OH:25])[CH:1]([CH3:3])[CH3:2])[CH:13]=2)[N:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)c1cncn1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 0.056 mL, 0.11 mmol) was added dropwise to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (35 mg, 0.092 mmol, Intermediate 2: step b) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture was stirred for 25 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA), then was converted to the free base (saturated aqueous NaHCO3/DCM extraction) and re-purified by flash column chromatography (silica gel, 25-70% acetone-EtOAc) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.99 (d, J=8.80 Hz, 1H), 7.62 (d, J=8.80 Hz, 1H), 7.46-7.57 (m, 3H), 7.32-7.39 (m, 2H), 7.28-7.32 (m, 1H), 7.18-7.25 (m, 1H), 3.29 (s, 3H), 2.65-2.76 (m, 1H), 1.24 (d, J=6.60 Hz, 3H), 0.72 (d, J=6.85 Hz, 3H); MS m/e 426.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])(=[O:4])=[O:3].[OH-].[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[CH3:1][S:2]([CH:5]([S:19]([CH3:18])(=[O:21])=[O:20])[S:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:8])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CS(=O)(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)C(S(C)(=O)=O)S(=O)(=O)Oc1ccccc1
Temperature: 2.5 °C
Yield: 80 %

Procedure:
The above phenyl methylsulfonylmethanesulfonate (25 g, 0.1 mole) was dissolved in a solution of 75 mL of water and 8 g (0.1 mole) of 50% sodium hydroxide. The solution was cooled to 0-5° C. and treated with 11.4 g of methanesulfonyl chloride which was added dropwise over 45 min. The resulting slurry was filtered (starting material precipitates during the addition) and the solid (14.3 g after drying) was washed with 75 mL of water. The filtrate was treated with conc HCl until no more solid precipitated. The phenyl bis(methylsulfonyl)methanesulfonate product was filtered and washed with ice-water. After drying in a 60° C. vacuum oven the product (12.9 g, mp 154-156° C.) was recrystallized from ethyl acetate with a hot clarification to give 11.3 g, (34.4% conversion, 80% yield) of phenyl bis(methylsulfonyl)methanesulfonate as a white solid, mp 159-160° C. H1NMR: δ 7.36-7.44 (m, 5H); δ 2.65 (s, 6H). No major impurities were detected by HPLC-MS.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:34]=[CH:33][C:28]([CH:29]=[CH:30][CH2:31]O)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCOCC>C(#N)C>[N+:22]([C:25]1[CH:34]=[CH:33][C:28](/[CH:29]=[CH:30]/[CH2:31][Br:20])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(/C=C/CBr)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In 35 mL of dry acetonitrile under nitrogen atmosphere was added 7.3 g (27.9 mmole) of triphenylphosphine. To the solution was added dropwise over 15 minutes 4.31 g of bromine (27.0 mmole) while cooling the reaction mixture to maintain the temperature between 0°-10° C. The solution was allowed to warm to room temperature (about 22°-25° C.) and 5.0 g (27.9 mmole) of p-nitrocinnamyl alcohol (Pfaultz & Bauer Chemical Co.) was added as a slurry in 50 mL of acetonitrile which caused an exothermic reaction, temperature about 45° C. The resulting dark red solution was heated for one hour at 60° C. with stirring and then poured into 500 mL of ether. Triphenylphosphine oxide precipitated from the solution after standing overnight (about 16 hours). The solution was filtered and 15 g of flash silica gel was added to the solution, followed by solvent removal. The resulting powder matrix was applied to a 3 in.×8 in. (7.6 cm×20.3 cm) flash column and the desired product was eluted with hexane, followed by 20% ethyl acetate in hexane to yield 5.8 g (23.9 mmole) of the desired pure trans product in 86% yield (MP=75°-76° C., Rf =0.81, 60:40 ethyl acetate:n-hexane) and was further characterized by:
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from (4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. 1H NMR (400 MHz, CDCl3) δ1.63 (br. s, 4H), 1.83 (br. s, 4H), 2.34 (s, 3H), 2.46-2.52 (m, 6H), 3.28 (s, 2H), 5.40 (s, 1H), 5.50 (s, 2H), 6.74 (d, J=8.3 Hz, 2H), 6.98 (s, 1H), 7.94 (br. s, 1H), 10.83 (br. s, 1H) ppm; MS (APCI, m/z): 468 [M+H]+.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8](=[O:25])[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20](=O)N(C)C)=[CH:15][CH:14]=1)([CH3:11])[CH3:10])[CH3:6].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:38]COS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:10])([O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:38][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])=[CH:17][CH:18]=1)[CH3:11])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(=O)N(C)C)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 17.1 %

Procedure:
Freshly prepared NaOEt (from 50 mg (2.2 mmol) Na) was charged with 2-(4-dimethylcarbamoylsulfanyl-phenoxy)-2-methyl-propionic acid ethyl ester (420 mg, 1.35 mmol) and refluxed for 3 h. Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)-ethyl ester (572 mg, 2.2 mmol) was added and the mixture was refluxed for another 3 h. The reaction was cooled and concentrated. The residue was shaken with EtOAc/water. After a second water wash, the organic layer was dried (MgSO4) and concentrated to give 500 mg crude product. Purification by flash chromatography (15% EtOAc/hexane) provided the product (98 mg, 17%): Rf=0.32 in 15% EtOAc/hexane; MS m/e 426 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:17])=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][Br:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 4-methyl-2-phenyl-thiazole-5-carboxylic acid ethyl ester (5.04 g, 0.02 mol), N-bromosuccinimide (3.8 g, 0.02 mol) and benzoyl peroxide (247 mg, 1 mmol) in carbon tetrachloride (60 mL) was refluxed for 17 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (6.55 g): 1H NMR (CDCl3, 200 MHz): δ=7.94 (m, 2H), 7.44 (m, 3H), 7.03 (m, 1H), 4.98 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H); MS: (+) m/z 326.0, 328.0 (M+1, 79Br/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)Nc1ccc(N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of N-(5-amino-pyridin-2-yl)-acetamide (2.05 g, 13.55 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 13.55 mmol, 1.0 equiv; commercially available) in conc. acetic acid (0.78 mL, 0.81 g, 13.55 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (3.45 g, 16.26 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (50:1→12:1). Recrystallization from diethylether provided 0.91 g (20%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.12-1.28 (m, 2H), 1.40 (s, 9H), 1.86 (d, J=12.3 Hz, 2H), 2.00 (s, 3H), 2.90 (br s, 2H), 3.39 (d, J=9.1 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 5.48 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 10.01 (s, 1H). MS (ESI): 335.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1.Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[CH2:22][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(O)C1
Reactant: N#Cc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-phenyl-piperidine-1-carboxylate [Example 2(a)] with 2-bromomethylbenzonitrile there was obtained tert-butyl (3RS,4RS)-3-(2-cyano-benzyloxy)-4-phenyl-piperidine-1-carboxylate as a colourless oil; MS: 393 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+]>O1CCOCC1.CO>[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][CH:13]5[CH2:17][CH2:16][O:15][CH2:14]5)[C:7](=[O:18])[C:6]5([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]5[C:4]=4[N:3]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC12COCCN1c1nc(Cl)ncc1N(CC1CCOC1)C2=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC12COCCN1c1nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc1N(CC1CCOC1)C2=O
Temperature: 100 °C
Yield: 15.4 %

Procedure:
2-Chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (390 mg, 1.151 mmol) PdCl2(dppf)-CH2Cl2 (188 mg, 0.230 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (417 mg, 1.381 mmol) and sodium 2-methylpropan-2-olate (1.5 ml, 1.151 mmol) were combined in 1,4-dioxane (3 ml). The suspension was heated by microwave irradiation at 100° C. for 30 minutes, the reaction was filtered, cooled, and purified by mass-triggered preparative HPLC using 22-25% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column). Product containing fractions were evaporated in vacuo to give a residue. The residue was dissolved in methanol for transfer. The solvent was removed under a stream of nitrogen gas to give 85 mg of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 0.48-0.57 (m, 2H) 0.71-0.79 (m, 2H) 1.73 (s, 3H) 1.73 (m, 1H) 2.02-2.14 (m, 1H) 2.61 (m, 1H) 2.68-2.80 (m, 1H) 3.55-3.65 (m, 2H) 3.68 (dd, J=12, 4 Hz, 1H) 3.71-3.81 (m, 3H) 3.84 (d, J=12 Hz, 2H) 3.91-4.05 (m, 2H) 4.08-4.21 (m, 2H) 4.75 (d, J=16 Hz, 1H) 7.67 (d, J=8 Hz, 2H) 8.03 (s, 1H) 8.11 (dd, J=8, 4 Hz, 2 H) [M+H] found 479.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][O:29]CC5C=CC=CC=5)[N:25]=[CH:24][N:23]=4)=[CH:20][C:15]=3[O:14][CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][OH:29])[N:25]=[CH:24][N:23]=4)=[CH:20][C:15]=3[O:14][CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1coc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1coc2cc(Oc3cc(CO)ncn3)ccc12
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 133 mg (0.256 mMol) 6-(6-benzyloxymethyl-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 13.3 ml CH2Cl2 is cooled in an icebath. 3.3 ml H3CSO3H are added and stirring is continued for 2.5 h at rt. The solution is poured into a vigorousely stirred mixture of 70 g ice and 70 ml sat. Na2CO3 solution. After 5 min, the mixture is extracted 3 times with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc/hexane 1:19→1:1→EtOAc) gives the title compound: m.p.: 181-182° C.; MS: [M+1]+=430; Anal.: C,H,N,F; 1H MNR (DMSO-d6): δ ppm 10.56 (s, HN), 8.85 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.72 (s, 1H), 7.63 (t, 1H), 7.47 (d, 1H), 7.27 (d, 1H), 7.06 (s, 1H), 5.67 (sb, HO), 4.55 (s, CH2).