Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[S:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:8]=1.C(=O)([O-])O.[Na+].Cl.CN(C)CCCN=C=NCC.C(OC([N:49]1[CH:53]([C:54](O)=[O:55])[CH2:52][S:51][CH2:50]1)=O)(C)(C)C>CN(C)C=O.O.ClCCl>[ClH:1].[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:4]([CH2:3][NH:2][C:54]([CH:53]3[CH2:52][S:51][CH2:50][NH:49]3)=[O:55])[S:5][C:6]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Reactant: COc1ccc(-c2nc(CN)sc2-c2ccc(OC)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)C3CSCN3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
2-Aminomethyl-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.20 g) was added to a mixture of dichloromethane and saturated aqueous sodium hydrogencarbonate, and was extracted with dichloromethane. The separated organic layer was washed with water, and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and resulting residue was dissolved in dimethylformamide (25 ml). To the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.71 g) and 3-(tert-butyloxycarbonyl)-4-thiazolidinylcarboxylic acid (0.77 g), and stirred at ambient temperature for 2 hours. The mixture was poured into water, and extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of methanol and chloroform. The fractions containing the object compound were combined and evaporated in vacuo. The resulting residue (oil-compound) (1.10 g) was dissolved with dichloromethane (20 ml), and stirred at 2° C. To the reaction mixture was added 1,4-dioxan solution of 4N hydrogen chloride (10 ml), and stirred at ambient temperature for 1 hour. The resulting residue was evaporated in vacuo. The residue was added iso-propyl ether (50 ml) and stirred at 2° C. for 3 hours. The resulting precipitate was collected by filtration and washed with iso-propyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(4-thiazolidinylcarbonylaminomethyl)thiazole hydrochloride (0.45 g).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[F:49]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([Cl:39])=[C:41]([F:49])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
5-(tert-Butyl)-4′-chloro-3′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-chloro-3-fluorophenylboronic acid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][O:15][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To 0.5 g of N-acetylglucosamine, 5 mL of pyridine and 5 mL of N,N-dimethylformamide were added, and the mixture was heated to 70° C. under stirring, and 0.46 mL of n-octanoyl chloride was dropwise added, and the reaction was carried out for 4 hours. On completion of the reaction, the reaction was extracted with ethyl acetate and washed with 2 mol/L hydrochloric acid, and the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 170 mg of 2-acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose as a white crystal.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:12]([F:35])[CH:11]=1)[CH3:8])(C)(C)C.C(OC(=O)C(OC1C=CC(CNC(C2C(OC3C=CC4=NON=C4C=3)=NC=CC=2)=O)=C(F)C=1)C)(C)(C)C>>[F:35][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][NH:17][C:18]([C:20]1[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:19])[O:9][CH:7]([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.5) was prepared in a manner analogous to described in Example 3, substituting (+)-2-[3-fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid tert-butyl ester for the corresponding (±)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid tert-butyl ester material.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCCO3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc(OCC2CCCCO2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 62 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(tetrahydropyran-2-yl)methoxyphenyl]methanone (0.32 g, 0.66 mmol) was converted to the title compound by the procedure of Example 3 using 0.24 mL (3.31 mmol) of ethanethiol and 530 mg (3.97 mmol) of aluminum chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]O)[CH2:4][CH2:3]1.S(=O)(=O)(O)O.N.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH:6]2[N:5]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=32)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ncccc2CO)C(c2ccccc2)C1
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1CCN2c3ncccc3Cc3ccccc3C2C1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) is added to ˜5 mL of concentrated sulfuric acid. The resulting solution is mixed at 350° C. for 6 hours. After cooling, the reaction mixture is added to 25 g of ice under mixing and basified with a concentrated ammonia solution or sodium hydroxide solution to pH=10. The separated precipitate is extracted into methylene chloride and the extract is evaporated to dryness; 1.6 g of Mirtazapine is obtained (yield 95%).
Reaction SMILES: [I:1][C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:6](=O)[NH:7][CH:8]([CH3:10])[CH2:9][N:4]2[N:3]=1.B.C1COCC1.C(O)C>C1COCC1>[I:1][C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[CH2:6][NH:7][CH:8]([CH3:10])[CH2:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(I)nn2c1C(=O)NC(C)C2
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(I)nn2c1CNC(C)C2
Temperature: 70 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a solution of Intermediate 340B (4.0 g, 11.46 mmol) in THF (40 mL) was added BH3.THF (40.1 mL, 80 mmol, 1M in THF) and the reaction mixture was stirred at 70° C. for 16 h. Ethanol (10 mL) was added and the reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated to afford Intermediate 340C (1.9 g, 40% yield) as a pale brown liquid. MS(ES): m/z=336 [M+H]+. The crude compound was taken to the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:30])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCS(=O)(=O)O
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccccc1C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)NCCS(=O)(=O)O
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{2-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 minutes, the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][OH:27])=[N:17][S:16]2(=[O:42])=[O:41])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 72.2 %

Procedure:
To detach the protecting group, 220 mg of [5-(3-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were dissolved in 4 ml of methanol and, after addition of 0.4 ml of concentrated hydrochloric acid, stirred at room temperature for 1.75 hours. The reaction solution was concentrated by rotary evaporation and coevaporated twice more with 10 ml of toluene, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (129 mg) with a molecular weight of 494.6 g/mol (C27H30N2O5S); MS (ESI): m/e=495 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O>CN(C=O)C>[C:8]1([S:14]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cccc1
Reaction time: 1 h

Procedure:
To a solution of 1H-pyrrole (5 g, 74.5 mmol) in DMF (50 mL) was added NaH (4.5 g, 110 mmol) portionwise at 0° C., and the mixture was stirred at this temperature for 1 hour. Benzenesulfonyl chloride (19.4 g, 110 mmol) was added, and the mixture was stirred at room temperature overnight, followed by a standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=100:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A solution of 1-bromo-4-chloro-2-nitrobenzene (13.92 g, 58.87 mmol) in MeOH (300 mL) was treated with water (50 mL), ammonium chloride (22.99 g, 429.8 mmol), and iron powder (325 mesh, 16.44 g, 294.4 mmol). The suspension was stirred at 23° C. After 18 hours, the suspension was filtered through celite. The filter cake was washed with MeOH (500 mL). The combined filtrate/washings were concentrated, partitioned in EtOAc/water (500 mL/200 mL), and the organic layer was separated. The aqueous layer was washed with EtOAc (2×200 mL). The organic layers were combined, washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo affording 11.51 g of 2-bromo-5-chlorobenzenamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:11]1([C:17]2[O:18][CH2:19][CH:20]([OH:29])[CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([O:29][CH:20]2[CH2:19][O:18][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:22][CH:21]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 72.6 %

Procedure:
3- Chlorophenyl isocyanate (0.8 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.2 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 7 hours 30 minutes and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 2 cm in diameter, collecting 15-cc fractions. Fractions 1 to 3, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume) are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (4RS, 5RS)-5-(3-chlorophenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 160° C., is obtained.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:7])[CH3:6]>O.C1COCC1>[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:6])[CH3:7]
Reactant: COC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.10 g, 4.17 mmol) in water (15 mL) was added to a solution of methyl 6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate (0.90 g, 1.67 mmol) in THF (30 mL). The mixture was allowed to stir at RT overnight. The THF was removed in vacuo and the resulting solution was partitioned between water (50 mL) and ethyl acetate (75 mL), then the ethyl acetate layer separated, washed with brine and dried (MgSO4). The aqueous layer was then taken to pH 7 by addition of 1N hydrochloric acid (5.2 mL) and extracted with ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (0.84 g).
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[CH:30][C:29]=1[CH3:39].Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:39])[CH:30]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(CC(C)(C)N)ccc1F
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: Cc1cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)ccc1F

Procedure:
1.10 g (3.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.50 g (2.8 mmol) of 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine are reacted and worked up analogously to the method for Example 8(d). White solid. Yield: 0.75 g (47%, hydrochloride); melting point 228° C.-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:20])[C:8]([N:12]3[S:16](=[O:18])(=[O:17])[NH:15][C:14](=[O:19])[CH2:13]3)=[CH:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+].Cl>CO.CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([O:20][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]([N:12]1[CH2:13][C:14](=[O:19])[NH:15][S:16]1(=[O:18])=[O:17])=[CH:9]2
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2O)S(=O)(=O)N1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CN(c2cc3cc(Br)ccc3cc2OC(=O)c2ccccc2)S(=O)(=O)N1
Reaction time: 0.02 h

Procedure:
To a solution of 5-(7-bromo-3-hydroxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (3) (0.998 g, 2.8 mmol) in MeOH is added KHCO3 (5.6 mL, 0.5M). To this salt in DMF (25 mL) at 0° C. is added potassium t-butoxide (2.94 mL, 1M). The reaction mixture is stirred for 1 min before benzoyl chloride (0.357 mL, 3.08 mmol) is added and the mixture is stirred for 1 min. Sat. NaHCO3 solution is added and it is acidified with 1 N HCl solution. The mixture is extracted with EtOAc, washed with brine and dried with Na2SO4. The organic layer is concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C>[NH2:12][C:11]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[N:10][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccc(Cl)cc2)c1N
Yield: 77.4 %

Procedure:
Reaction of p-chlorophenyl azide (7.48 g; 0.0487 mole) with ethyl cyanoacetate (5.5 g; 0.0487 mole) as described in example 1a gave 10.057 g (81%) of the triazole of mp (ethanol) 162-164° C. (lit mp 165-167° C.; Ger Offen No. 2,009,134[1970]) (Found; C, 49.78; H, 4.31; N, 21.15; C11H11CIN4O2 requires; C, 49.54; H, 4.16; N, 21.01%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 395.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=1.[CH:11]1([CH2:17]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.CN1CCN(C(N=NC(N2CCN(C)CC2)=O)=O)CC1>C1COCC1.O>[CH:11]1([CH2:17][O:1][C:2]2[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCC1CCCCC1
Reactant: CSc1snc(O)c1C#N
Agent: CN1CCN(C(=O)N=NC(=O)N2CCN(C)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1snc(OCC2CCCCC2)c1C#N
Reaction time: 72 h
Yield: 46.9 %

Procedure:
3-hydroxy-5-methylsulfanyl-isothiazole-4-carbonitrile (10 g, 58 mmol) is dissolved in anhydrous THF (200 mL). Cyclohexylmethanol (11 mL, 87.1 mmol) and diphenyl-2-pyridyl-phosphine (30.5 g, 116 mmol) are added to the solution. Diazenedicarboxylic acid bis(N′-methylpiperazide) (32.7 g, 116 mmol) is slurried in anhydrous THF (200 mL) and added dropwise over 1 hour to the reaction. The reaction is stirred at room temp. for 3 days and then diluted with water and extracted with EtOAc (100 mL×3). The combined organics are then dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography (20% EtOAc/hexane) followed by a second chromatography (10% EtOAc/hexane) provides 3 (7.3 g, 52%). 1H NMR (d6 DMSO): δ 4.18 (2H, d, J=6.3 Hz), 2.76 (3H, s), 1.64–1.81 (6H, m), 1.16–1.27 (3H, m), 1.00–1.13 (2H, m).
Reaction SMILES: C[CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C(C)CCC)[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:19]C(C1CC1)=O.C([Mg]Br)CC.[Br-].Br.BrCCCC(C)CCC.C(C(C)=O)=C.C(P(CCCC)CCCC)CCC>O=[Pt]=O.CO>[CH3:19][CH:10]([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CCCC(C)CCCCCC(C)CCCC(C)=O
Reactant: CC(=O)C1CC1
Agent: O=[Pt]=O
Agent: Br
Agent: C=CC(C)=O
Solvent: CO
Product: CCCC(C)CCCCCC(C)=O

Procedure:
The novel synthesis of racemic 6,12-dimethylpentadecan-2-one is shown in FIG. 4 and described in detail below in Example 2. Briefly, the synthesis of racemic 6,12-dimethylpentadecan-2-one was initiated by the reaction of methylcyclopropyl ketone with n-propylmagnesium bromide. The intermediate tertiary carbinol was isomerized to the homoallylic bromide (1) with hydrobromic acid. The allic bromide (1) was reduced to 1-bromo-4-methylheptane (2) by hydrogenation with PtO2. The saturated bromide (2) was converted to the corresponding organocopper reagent which was reacted with methyl vinyl ketone in the presence of tri-n-butyl phosphine to produce 8-methylundecan-2-one (3). A Wittig reaction between the C-12 methylketone (3) and ethylene ketal pentan-2-one phosphonium salt (4), produced a mixture of the Z and E isomers of the ethylene ketal of 6,12-dimethyl-(5) (15% yield). The unsaturated ethylene ketals were hydrogenated and then subjected to acid hydrolysis to produce 6,12-dimethylpentadecan-2-one (7). The final product was purified by high-performance liquid chomatography (HPLC) and GLC.