Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.[C:28](OC(=N)N(C(C)C)C(C)C)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:24][C:23]([C:5]1[N:4]2[C:26](=[O:27])[C@@H:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:17][C:18]1[NH:19][N:20]=[N:21][N:22]=1)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:25])([CH3:31])([CH3:30])[CH3:29]
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClCCl
Product: 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
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 21.8 g (0.05 mol) of 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml of methylene chloride is added over a 30 minute interval a solution of 30.0 g (0.15 mol) of O-t-butyldiisopropylpseudourea in 100 ml of methylene chloride. The mixture is stirred at ambient temperature for 72 hours. The precipitate is removed by filtration and the filtrate is evaporated to a residue which is taken up in 200 ml of benzene and filtered again. The filtrate is extraced with three 100 ml portions of cold 1N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase extracted with two 150 ml portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]1=[O:25]>C(Cl)(Cl)(Cl)Cl>[NH2:9][C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][C:28]=1[Br:8])[CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:15]1=[O:25]
Reactant: Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Br)cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Add NBS (7.82 g, 43.9 mmol) to a solution of 3-(3-amino-2,6-dichlorobenzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 50) (15.0 g, 43.9 mmol) in CCl4 (500 mL). Stir at room temp overnight. Filter the suspension. Concentrate the filtrate. Form a suspension in CH2Cl2 and filter. Dissolve the solid in CH2Cl2 and wash several times with water. Dry, filter and concentrate. Concentrate the filtrate. Purify the combined residue by a plug of silica gel eluting with a mixture of EtOAc and hexanes (20:80) to give the title compound (17.6 g, 96%): Mass spectrum (apci) m/z=421.1 (M+H).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+].C(O)C>O>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:22]\[NH:23][C:24]([NH2:26])=[O:25])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Yield: 74.7 %

Procedure:
A solution of 10.3 g of 1-(2-diisopropylaminoethyl)isatin, 5.1 g of semicarbazide hydrochloride and 3.7 g of sodium acetate in 150 ml of a mixture of ethanol and water (2:1) was stirred for 17 hours at room temperature. The yellow precipitates were collected by filtration and washed with aqueous ethanol. The filtrate and the washed the aqueous ethanol solution were combined and concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue. The yellow precipitates were collected by filtration and washed with dichloromethane. The yellow precipitates were combined and recrystallized from aqueous methanol to obtain 9.3 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 193°-196° C.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[OH:13][C:12](=[O:14])[CH2:11][N:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:4])[O:5][C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a cold (−20°) suspension of 60% NaH (120 g, 3.00 mol) in THF (700 mL) was added (30 min) a solution of Boc-glycine (175 g, 1.00 mol) in THF (300 mL). Thereafter, benzyl bromide was added to the mixture. After 15 min, the cooling bath was removed. The reaction mixture was stirred at room temperature for 1 h and then heated at reflux for 16 h. The reaction mixture was cooled to 0°. H2O (˜50 mL) was added dropwise over a 30 min period. After another 30 min, H2O (600 mL) was added. The mixture was washed with hexane (3×500 mL). 1N Aqueous HCl (1.3 L) was added slowly to the aqueous layer, followed by the addition of 4N aqueous HCl (300 mL). The aqueous solution was extracted with EtOAc (1.5 L) and then CH2C12 (3×500 mL). The combined organic layers were serially washed with H2O and brine, dried (MgSO4, Na2SO4, charcoal), filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (241 g, 91% yield) as a pale yellow solid: Mp 94-97°; 1H NMR (400 MHz, DMSO-d6) δ10.5 (broad s, 1H), 7.23-7.33 (m, 5H), 4.40 (s, 2H), 3.80, 3.72 (2s, 2H), 1.38, 1.35 (2s, 9H); MS (FAB) m/z 266 (MH)+; Anal. Calcd for C14H19NO4 (and accounting for water content, 0.58% w/w as determined by Karl Fisher analysis): C, 63.01; H, 7.26; N, 5.25. Found: C, 62.79; H, 7.14; N, 5.13.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:13]([C:21](OC)=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].[H][H]>C(O)C.[Ni]>[O:22]=[C:21]1[CH:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:4]2[N:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[CH2:1][NH:2]1
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1C#N
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1C(=O)NCc2cc(C(F)(F)F)cnc21
Yield: 99.4 %

Procedure:
To a solution of tert-butyl methyl [3-cyano-5-(trifluoromethyl)pyridin-2-yl]malonate (4.02 g, 11.7 mmol) in ethanol (60 mL) was added a slurry of Raney Nickel (0.60 g, 10 mmol). The mixture was placed on a Parr apparatus and hydrogenated under hydrogen at 40 psi overnight. The suspension was filtered through celite and the filtrate was evaporated in vaccuo to afford 3.68 g (99.6%) of the desired product as a yellow oil. LC-MS calculated for C14H15F3N2O3: (M+H)+317; found 217.1 (M−CO2tBu+H+1)+.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:35])[F:34])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:34])[F:35])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 767.6 %

Procedure:
A solution of tert-butyl ((3S)-1-{4-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}pyrrolidin-3-yl)carbamate (0.05 g, 0.085 mmol) in 1 mL CH2Cl2 was treated with 0.1 mL of trifluoroacetic acid and stirred at ambient temperature overnight. Then the reaction mixture was partitioned with extra CH2Cl2 and saturated NaHCO3. The organic phase was isolated and dried (Na2SO4). The sovent was evaporated and the residue treated with excess HCl in diethyl ether. The solids were collected and dried to give 0.32 g of the title compound as the HCl salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[P:23](=O)([OH:26])([OH:25])[OH:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[P:23]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)([OH:26])([OH:25])=[O:24]
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Reactant: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1Nc2ccc(OP(=O)(O)O)cc2C1=Cc1ccnc2ccccc12
Temperature: 60 °C
Yield: 50 %

Procedure:
A mixture of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) and phosphoric acid 85% (13 g) and phosphorous pentoxide (10 g) was heated for 2 h at 60° C. The usual work-up gave the title compound in about 50% yield.
Reaction SMILES: [Na].CO.[CH2:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]1[O:7][CH2:6]1.[C:17](O)(=[O:19])C>>[CH2:9]([O:8][CH2:4][CH:5]([CH2:6][O:19][CH3:17])[OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCCCCOCC1CO1
Reactant: CC(=O)O
Agent: [Na]
Solvent: CO
Product: COCC(O)COCCCCCC(C)C
Temperature: 25 °C

Procedure:
Sodium metal (2.3 g; 0.1 mole) is dissolved in methanol (160 g; 5 moles). The solution is heated to reflux and treated dropwise over 2 hours with isooctyl glycidyl ether (186 g; 1 mole). After complete addition, the reaction mixture is maintained under reflux conditions for a further 6 hours. After cooling to ambient temperature, the reaction mixture is treated with acetic acid (5.8 g; 0.1 mole) and then the excess solvent is removed under vacuum. The oily residue is treated with water (250 ml) and then extracted with ether (250 ml). The ether extract is dried over MgSO4, filtered and evaporated. The residue is distilled under vacuum to yield 1-isooctyl-3-methyl glycerol, as a colourless oil, bp 75°-80° C./0.07 mbar, yield 145.6 g (67%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[CH:7]=1.C[S-:16].[Na+]>CC(N(C)C)=O>[F:12][C:11]([F:14])([F:13])[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([SH:16])=[CH:7][N:6]2[CH:8]=1
Reactant: FC(F)(F)c1cn2cc(Br)ccc2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cn2cc(S)ccc2n1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
A mixture of 6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (500 mg, 1.89 mmol) (for the synthesis, see WO2005111047) and sodium thiomethoxide (400 mg, 5.67 mmol) in dimethylacetamide (5 ml) was heated to 150° C. for 90 minutes under a nitrogen atmosphere. The resultant mixture was cooled down to room temperature and partitioned between ethyl acetate and an aqueous solution of ammonium chloride. The aqueous phase was extracted with more ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a red oil (251 mg, 61% yield). MS (ES+) 219, (ES+) 217.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:51]([O:57][CH2:58]I)(=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:58][O:57][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4COCO4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2COCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 76.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (71 mg) as prepared in Example 35(b) was reacted with iodomethyl pivalate (68 mg) similarly to Example 28 for the esterification reaction. The resulting reaction solution was post-treated and the produced compound was recovered and purified similarly to Example 28 to give the titled compound (43 mg; 51%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.CCOCC>O1CCCC1>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:3][C:2](=[NH:4])[NH2:1])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: NC(N)=S
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC(=N)N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.8 %

Procedure:
To a mixture of thiourea (3.8 g, 50.0 mmol) in tetrahydrofuran (30 mL) was added dropwise 4-methoxybenzyl chloride (8.0 g, 51.1 mmol) and the reaction mixture was stirred at room temperature for 2 h before heating to reflux for 4 h. After the reaction was stirred at room temperature for 18 h the product was isolated from ether to yield the title compound (11.46 g). Electrospray MSm /z 197 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].Cl>O>[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
Pyridine (5 mL) was added to a mixture of 4-trifluoromethylbenzenesulfonyl chloride (0.73 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) and stirred at room temperature. After 20 hours, the mixture was added to water (50 mL), acidified with 2N HCl, and stirred for an hour. The precipitate was filtered off, rinsed with water, and dried to afford the product (1.2 g); m.p. 197-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].C(O)C.O>>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCSc2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
Hydrolysis of the foregoing ester with potassium hydroxide/ethanol/water in analogy to Example 57 gave p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoic acid, melting point 274°-276° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])[CH3:26]
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 21 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (approx. 27 mmol; crude material from the previous step) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (3.3 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 1.50 g (21%) of the title compound as a colorless oil. (+)-APCI-MS: 264 (MH−).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1.C([O-])(=O)C.[K+].O1CCOCC1>CS(C)=O>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-c1ccccn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2ccccn2)c1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To 2-(5-bromo-2-fluorophenyl)pyridine (544 mg, 2.16 mmol) and bis(neopentyl glycolato)diboron (585 mg, 2.60 mmol) under nitrogen was added dry potassium acetate (450 mg, 4.58 mmol), anhydrous dioxane (8 mL) and DMSO (1 mL). The mixture was degassed with nitrogen, and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (50 mg, 3 mol %) was added. After stirring at 85° C. under nitrogen for 15 h, the mixture was cooled to room temperature, and sodium hydroxide solution (20 mL of a 1 M solution) was added. The mixture was stirred for 10 min, and was then extracted twice with diethyl ether. The combined ether extractions were washed with water, then the combined aqueous layers were filtered through a glass fibre filter paper. The pH of the filtrate was adjusted to 6 by the addition of 2 N hydrochloric acid-precipitating a white solid. This was collected by filtration, washed with water and dried in vacuo at 60° C., and was found to be 4-fluoro-3-(pyridin-2-yl)phenylboronic acid (455 mg, 97%). δH (400 MHz, DMSO) 7.30 (1H, dd, J 8.2, 11.7), 7.41 (1H, m), 7.77 (1H, m), 7.90 (2H, m), 8.16 (2H, s), 8.36 (1H, dd, J 1.6, 8.6), 8.72 (1H, m); MS (ES+) 218.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH2:15][CH3:16]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:15][CH3:16]
Reactant: CCCO
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Product: CCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-propanol and the suspension is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 15 ml of n-propanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:3 yields E-2-amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 161°-162°.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:8]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[S:15]1[CH:16]=[CH:17][C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:14]1
Reactant: COC(CCOc1cccc(-c2ccsc2)c1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCOc1cccc(-c2ccsc2)c1
Reaction time: 4 h
Yield: 72.9 %

Procedure:
0.46 g of the resulting ether compound was dissolved in 5 ml of tetrahydrofuran, and 2 ml of 2N hydrochloric acid was added. The mixture was allowed to stand at room temperature for 4 hours, and then the solution was made basic with an aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, and the extract was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1→10/1] to give 0.28 g of 3-[3-(3-thienyl)phenoxy]propanal as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][C:13]1[S:14][C:15]2[C:21]([Cl:22])=[C:20]([Cl:23])[CH:19]=[C:18]([S:24][C:25]#[N:26])[C:16]=2[N:17]=1>CN(C)C=O>[Cl:23][C:20]1[CH:19]=[C:18]([S:24][C:25]#[N:26])[C:16]2[N:17]=[C:13]([NH:12][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:11])[S:14][C:15]=2[C:21]=1[Cl:22]
Reactant: N#CSc1cc(Cl)c(Cl)c2sc(N)nc12
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: N#CSc1cc(Cl)c(Cl)c2sc(NC(=O)Nc3ccc(Cl)c(Cl)c3)nc12

Procedure:
3,4-Dichlorophenyl isocyanate (18.8 g., 0.10 mole) was added in portions to a solution of 27.6 g. (0.10 mole) of 2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 200 ml. of dimethylformamide. The solution was heated at 110° for 5 hours with stirring and cooled at 0° overnight. The solid was collected by filtration to give 28 g. (60%) of product. Two recrystallizations from ethanol gave 13 g. (28%) of analytical material, m.p. 313°-320° (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29]C2CCCC2C=CC(C(O)=O)=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:18][C:19]1([CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][S:29][CH:16]2[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[CH3:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: CCOC(=O)c1ccc(CCCC=O)c(C)c1
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c(C)c1

Procedure:
This compound is prepared by the method described in Example 2, Step B, except that an equivalent quantity of ethyl 3-methyl-4-(4-oxobutyl)benzoate is substituted for the ethyl 4-(4-oxobutyl)benzoate of Example 2, Step B. The title compound is obtained as a viscous, yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[C:20]([Cl:19])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(NCc2cc(F)c(F)c(F)c2)c1
Solvent: ClCCl
Product: O=C(Cl)N(Cc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 124.5 %

Procedure:
To a solution of 3.4 g (13.30 mmol) of 3-fluorophenyl-(3,4,5-trifluorobenzyl)amine (Intermediate I-8) in 25 ml of methylene chloride, cooled at −10° C., was added slowly with stirring a solution of 2.0 g (6.70 mmol) of triphosgene in 15 ml of methylene chloride. The reaction was allowed to warm to room temperature and stirred for 17 hours at this temperature. After this time the solid formed during the process was filtered and the filtrate was concentrated in vacuo. The obtained residue was treated with n-hexane at −25° C. The soluble part was separated and filtrated. The filtrate was concentrated in vacuo to dryness to give 2.65 g (62.8%) of the tide product as an oil. The structure was confirmed by 1H-NMR.