Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[ClH:11].[N:12]([O-])=O.[Na+]>O>[Cl-:11].[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:8]#[N:12])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: NCc1ccc(Br)cc1
Reactant: Cl
Agent: C
Agent: [Na+]
Solvent: O
Product: N#[N+]Cc1ccc(Br)cc1
Product: [Cl-]
Reaction time: 0.25 h

Procedure:
This example shows another method for the preparation of a carbon black product of the present invention. A suspension of 0.676 g of 4-bromobenzyl amine, 0.60 g of concentrated HCl, 30 g of water and 10.22 g of the untreated carbon black used in Example 7 was prepared in an ice bath. An aqueous solution containing 0.269 g of sodium nitrite was added and the resulting suspension was stirred for 15 minutes, forming 4-bromophenylmethanediazonium chloride in situ, which reacted with the untreated carbon black. The product was filtered off, and was subjected to Soxhlet extraction with THF overnight. The resulting carbon black product contained 0.26% bromine, compared to <0.01% for the untreated carbon black product. This shows that 9% of the bromobenzyl groups used in the example became attached to the carbon black product. Therefore, the carbon black product had 0.031 mmol/g of attached bromobenzyl groups.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22].O>CS(C)=O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:19][CH2:20][CH2:21][OH:22])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2cccnc12
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCCCOc1cccc2cccnc12
Temperature: 70 °C

Procedure:
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tert-butoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was stirred for 1 hr at room temperature. 3-Chloro-1-propanol (24.0 g, 0.25 mole) was added and the solution was heated overnight at 70° C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80° C. overnight to give 35.67 g (70.3%) of light brown solid, m.p. 126°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14]OC(OC)N(C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][CH:14]=[CH:12]2
Reactant: COC(OC)N(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]ccc2c1C
Reaction time: 0.67 h

Procedure:
A solution of 1-methoxy-2,3-dimethyl-4-nitro-benzene (5.0 g), N,N-dimethylformamide dimethylacetal (7.4 mL) and triethylamine (0.10 mL) in 25 mL of N,N-dimethylformamide was heated to reflux for 3 days under nitrogen. The volatiles were removed in vacuo and the resulting residue was dissolved in 40 mL of a 1:1 mixture of methanol and tetrahydrofuran. Raney nickel (50% slurry in water, 1 mL) was added to the solution, then hydrazine hydrate (2.7 mL) was added dropwise and the mixture was stirred for 40 min under nitrogen. The reaction mixture was filtered through a bed of celite and the filtrate was reduced in vacuo. The product was purified by column chromatography (30% ethyl acetate in hexanes) to yield 1.5 g of pure 5-methoxy-4-methyl-indole.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Reactant: NCCO
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NCCO)s1
Yield: 35 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (29 mg, 35%) which was obtained as a white solid MS: m/e=359.1 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:31][CH2:30][CH:29]([CH3:32])[NH:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH:29]([CH3:32])[CH2:30][CH2:31][CH:27]1[CH3:26])=[O:13])[CH2:8]2
Reactant: CC1CCC(C)N1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC1CCC(C)N1c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2,5-Dimethyl-pyrrolidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamant-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2,5-dimethylpyrrolidine. Mass spectrum (ES) MH+=419.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].N1C=CC=CC=1.[S:15]([OH:35])([O:18][C:19]1[C:20]([CH3:34])=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[C:23]([C:29](OCC)=[O:30])=[CH:22]2)(=[O:17])=[O:16].O>CN(C)C=O>[S:15]([OH:35])([O:18][C:19]1[C:20]([CH3:34])=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[C:23]([C:29]([NH:7][C:6]([NH2:8])=[NH:5])=[O:30])=[CH:22]2)(=[O:16])=[O:17]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(C)c(OS(=O)(=O)O)ccc2n1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(OS(=O)(=O)O)ccc2c1cc(C(=O)NC(=N)N)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of sodium methoxide (4.28 g, 79.2 mmol), guanidine hydrochloride (7.58 g, 79.3 mmol) and N,N-dimethylformamide (70 ml) was stirred at room temperature for 1 hour, and then the insoluble material was filtered off. A solution of 2-ethoxycarbonyl-1,4-dimethyl-1H-indole-5-yl hydrogen sulfate pyridine salt (3.11 g, 7.92 mmol) in N,N-dimethylformamide (10 ml) was added to the filtrate, and the resulting mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction mixture, followed by washing with chloroform. Subsequently, chloroform and then 2N hydrochloric acid were added and the solid thus precipitated was collected by filtration and washed with methanol to obtain 2.12 g of 2-[[[amino(imino)-methyl]amino]carbonyl]-1,4-dimethyl-1H-indol-5-yl hydrogen sulfate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=[O:29])[NH:13][C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:31](N(CC)CC)C.C(N[C@@H](C(O)=O)C(C)C)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=[O:29])[NH:13][C:14]1[CH:19]=[C:18]([CH3:31])[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Br)ccc1NCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2ccccc2)c(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(2-benzylamino-5-bromo-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (250 mg, 0.9 mmol) and triethylamine (0.19 ml, 1.35 mmol) in dry DMF (5 ml), was added Boc-D-valine (290 mg, 1.35 mmol) followed by TBTU (290 mg, 0.9 mmol,). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: C(=O)C1C=CC=CC=1.[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[ClH:18].[CH3:19][NH2:20].C1(N)C(F)=C(F)C(F)=[C:23]([NH2:30])C=1F.Cl.Cl>>[ClH:9].[ClH:18].[CH3:23][NH:30][CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Cl:9])[CH2:19][NH2:20]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: O=Cc1ccccc1Cl
Reactant: CN
Agent: Cl
Solvent: O=Cc1ccccc1
Product: CNC(CN)c1ccccc1Cl

Procedure:
Similarly, by following the same procedure but using the corresponding benzaldehyde or substituted benzaldehyde as starting material in place of 2-chlorobenzaldehyde and the corresponding alkyl amine hydrochloride for methylamine hydrochloride the dihydrochloride salts of the following compounds are respectively prepared.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[CH2:7]([OH:10])[C:8]#[CH:9].C([O-])(=O)C.[NH4+:15]>C(O)C.[Cu](Cl)Cl>[NH2:15][CH:3]([C:9]#[C:8][CH2:7][OH:10])[C:2]([OH:6])=[O:5]
Reactant: C#CCO
Reactant: O=CC(=O)O
Reactant: [NH4+]
Agent: Cl[Cu]Cl
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Product: NC(C#CCO)C(=O)O

Procedure:
A mixture of glyoxylic acid monohydrate (23 g, 250 mmol), propargyl alcohol (16.8 g, 300 mmol), copper (II) chloride (3.2 g, 25 mmol) and ammonium acetate (49 g, 600 mmol) in ethanol (100 ml) is heated under reflux for 6 h. Then the reaction mixture is concentrated in vacuo, diluted with water (50 ml), acidified to pH 5 with 1N HCl and washed twice with ether (100 ml). Then the aqueous solution is poured on an ion exchange resin column (DOWEX 50, H+). The column is eluted with 1M ammonium hydroxide to give the title compound 2-amino-5-hydroxy-3-pentynoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:20](Cl)(=[O:22])=[O:21])[CH:6]=[C:7]([F:19])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12](F)[CH:11]=1)#[N:2].[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.N1C=CC=CC=1.C(Cl)[Cl:39]>O>[Cl:39][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]#[N:17])[O:9][C:8]1[C:7]([F:19])=[CH:6][C:5]([S:20]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Nc1ccc(F)cn1
Reactant: N#Cc1ccc(Oc2c(F)cc(S(=O)(=O)Cl)cc2C#N)cc1F
Reactant: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(Oc2c(F)cc(S(=O)(=O)Nc3ccc(F)cn3)cc2C#N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of 3-cyano-4-(4-cyano-3-fluorophenoxy)-5-fluorobenzene-1-sulfonyl chloride (Preparation 43, 27 mg, 0.153 mmol) in DCM (5 mL) was added 5-fluoro-2-aminopyridine (26 mg, 0.230 mmol) followed by pyridine (36 mg, 0.459 mmol, 0.037 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (20 mL) and water (30 mL). The organic layer was separated and the aqueous re-extracted with DCM (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography eluting with (acetonitrile/0.1% formic acid) and (water/0.1% formic acid), gradient 5% to 60% to afford the title compound as colourless solid (21 mg, 31%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][N:5]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([F:8])[CH:10]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCC(OC)OC)cc1F

Procedure:
2,2-Dimethoxyethylamine (13.85 ml, 0.13 mol) is added to a solution of 3-fluoro-4-methoxybenzaldehyde (20 g, 0.13 mol) in toluene (200 ml). The resulting solution is flushed with nitrogen gas and then heated overnight under reflux in a Dean-Stark apparatus. The solvent is then removed under reduced pressure to yield (2,2-dimethoxy-ethyl)-[1-(3-fluoro-4-methoxy-phenyl)-methylene]-amine. This intermediate (31 g, 0.13 mol) is dissolved in ethylacetate and acetic anhydride (13 g, 0.13 mol) added. Platinum oxide (0.3 g) is then added, under a blanket of nitrogen, and the resulting mixture is stirred under a hydrogen atmosphere until uptake is complete. Filtration, washing with saturated aqueous NaHCO3 (3×100 ml), brine and water, drying over, MgSO4 and concentration then gives N-(2,2dimethoxy-ethyl)-N-(3-fluoro-4-methoxy-benzyl)-acetamide. This intermediate (38.9 g, ca 0.13 mol) is dissolved in anhydrous CH2Cl2 and then added slowly over 20 mins to a stirred mixture of A1C13 (90 g) and CH2Cl2 under an atmosphere of nitrogen. The total volume of CH2Cl2 is 250 ml. The mixture is stirred for a further 10 mins at room temperature and is then cooled with an ice bath during the addition of aqueous 40% NaOH. The mixture is further diluted with water (250 ml), filtered through glass wool, the organic phase separated and the aqueous phase further extracted with CH2Cl2 (2×200 ml). Drying over MgSO4 and evaporation under reduced pressure yields a crude oil which is purified by flash silica chromatography (eluant: 1% methanol in CH2 Cl2) to give as one of the products 1-(7-fluoro-6-methoxy-1H-isoquinolin-2-yl)-ethanone. This intermediate (0.60 g, 2.7 mmol) is mixed with glyoxylic acid (0.325 g, 3.5 mmol) and water (10 ml) and the resulting mixture is stirred at room temperature for 20 min. Concentrated hydrochloric acid (10 ml) is then added and the mixture heated to reflux for 1 h. Concentration and purification by preparative HPLC gives (7-fluoro-6-methoxy-isoquinolin-4-yll)-acetic acid, [MH]+ 236.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[C:66]([O:71][C:72]([F:75])([F:74])[F:73])[CH:65]=1>C(Cl)Cl>[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:36])=[C:66]([O:71][C:72]([F:73])([F:74])[F:75])[CH:65]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(I)cc1OC(F)(F)F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(I)cc2OC(F)(F)F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (5 ml) to give a clear solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 30 minutes. 4-Iodo-2-(trifluoromethoxy) aniline (136 mg, 447 μmol, Eq: 1.3) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc/Hexanes) to give the desired product as a white solid. 255 mg. (ES+) m/z Calcd: [(M+)+]: 752. found: 752.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:11])=[O:10]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A solution of 2,6-dibromobenzenesulfonyl chloride (4.7 g, 14.0 mmol) in tetrahydrofuran (20 mL) was treated with potassium carbonate (5.8 g, 42 mmol) and t-butyl amine (1.2 g, 16.8 mmol). The resulting mixture was stirred at ambient temperature over 18 h then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,6-dibromo-N-(1,1-dimethylethyl)benzenesulfonamide (4.5 g, 87%) as the white solid, which was used without further purification. 1H NMR (CD3OD): δ1.22 (s, 9H), 7.22 (t, 1H), 7.85 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.50 g), ethyl 3-(4-hydroxyphenyl)propionate (0.31 g), anhydrous potassium carbonate (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.38 g, 51%) of ethyl 3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 19 (50 mg) and triethylmethanetricarboxylate (0.073 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.344 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.068 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (48 mg). LC/MS MH+ 505, Rt 3.41 min (5 minute run).
Reaction SMILES: C[O:2][C:3]([CH:5]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1CCn2c(nc3ccccc32)S1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCn2c(nc3ccccc32)S1
Yield: 54.5 %

Procedure:
To a solution of 2.48 g (10 m mole) of 3,4-dihydro-2-methoxycarbonyl-2H-(1,3)-thiazino-[3,2-a]benzimidazole in dry tetrahydrofuran (50 ml) was added dropwise 0.5 g of lithium aluminum hydride devided in small pieces, with stirring under ice cooling condition. After thirty minutes, the resultant complex was decomposed by the addition of hydrated tetrahydro furan and subjected to filtration. Subsequent to drying the filtrate over anhydrous magnesium sulfate, tetrahydrofuran was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 1.2 g (yield: 54.5%) of the intended product, m.p. 112°-113° C.; IR νmaxKBr cm-1 : 3500-3000, 1430; Anal. Calcd. for C11H12N2OS: C, 59.98; H, 5.49; N, 12.72; S, 14.55; Found: C, 59.71; H, 5.61, N, 12.99; S, 14.15.
Reaction SMILES: [I-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:13](#[N:15])C>>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:13]#[N:15])=[O:7]
Reactant: CC#N
Reactant: O=C(Cl)c1ccccc1Br
Agent: [I-]
Agent: [Na+]
Product: N#CC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The reaction was carried out under Argon. Cuprous cyanide (6.52 g, 72.8 mmol) and anhydrous sodium iodide (20.25 g, 135 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with o-bromo benzoyl chloride (15.0 g, 68 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resulting precipitate was filtered off. Concentration of the filtrate under reduced pressure gave a yellow solid. Recrystallisation from 60°-80° C. b.p.t. petroleum ether afforded o-bromo benzoyl cyanide as yellow crystals (7.14 g, 50%), melting point 64° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18](F)[C:17]=1[N+:24]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:27](O)C>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:27])=[CH:18][C:17]=1[NH2:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)c1cc2c(Oc3ccc(C)cc3N)cccc2[nH]1
Reaction time: 2 h

Procedure:
138 (570 mg, 1.675 mmol) is dissolved in 150 ml of ethanol and, after addition of Pd—C (200 mg), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.