Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]2[C:22](=[O:36])[CH:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:5][C:6]1[CH:7]=[C:8]([C:22]2([OH:36])[C:21]3[CH:37]=[CH:38][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=3[O:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Under nitrogen atmosphere 3-bromomagnesium phenyl trimethylsilyl ether was prepared from 3-bromophenyl trimethylsilyl ether (629 mg, 2.1 mmol) and magnesium turning (52 mg, 2.1 mmol) in dry tetrahydrofuran (1.5 ml) and then cooled to -78° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-benzopyran-4-one (250 mg, 0.7 mmol) dissolved in dry tetrahydrofuran (2 ml) was slowly added dropwise thereto and then stirred for one hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 283 mg (yield: 92%) of the title compound as a foam.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:5][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC(O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DL-2-hydroxystearic acid (3.0 g, 10 mmole) in 20 ml dry DMF was added potassium tert-butoxide (1.23 g, 11 mmole) and the mixture was stirred for one hour at 60° C. Benzyl bromide (2.14 g, 12.5 mmole) was added and the mixture was stirred for six hours at 80° C. The mixture was evaporated under reduced pressure and 100 ml ethyl acatate was added. The organic phase was separated and washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography. Yield: 3.3 g
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCOCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C23H21N5O3, 415.2.
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[CH2:3]1.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([NH:1][N:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CC1(C)CN(N)c2cc(C(F)(F)F)ccc2O1
Product: CC(=O)NN1CC(C)(C)Oc2ccc(C(F)(F)F)cc21
Yield: 63 %

Procedure:
Acetic acid (3 ml) was added to 123 mg of 4-amino-2,2-dimethyl-6-trifluoromethyl-1,4-benzoxazine, followed by refluxing for 1 hour. The acetic acid was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed first with a 1N aqueous solution of sodium hydroxide and then with water, and was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column, whereby 90 mg of Compound No. 2 were obtained (yield: 63%). EXAMPLE 2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CSc2cccc[n+]2[O-])cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CS(=O)c2cccc[n+]2[O-])cc1

Procedure:
The procedure employed is identical to that of Example 68 using 7 gm (0.028 mol) 2-(4-methoxyphenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 5.6 gm (0.028 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][C:11](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)CC1CC2CCCC(C1)N2C(=O)OC(C)(C)C

Procedure:
390 mg of 3-ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester are dissolved in 50 ml of EtOH and hydrogenated (50 bar, RT) in the presence of 100 mg of PtO2 as a catalyst. From the mixture obtained the catalyst is filtrated off and 3-ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of a mixture of the syn and anti isomers is obtained. 13C-NMR: 172.95, 172.88, 155.55, 154.44, 79.46, 79.42, 60.63, 47.40, 45.96, 45.88, 44.60, 43.77, 40.69, 37.01, 36.63, 32.24, 32.03, 31.40, 31.02, 29.61, 29.21, 29.17, 27.43, 20.60, 14.65, 14.07.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C(=O)(O)[O-].[Na+:29]>O.C(O)C>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O-:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Na+:29]
Reactant: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)OCC)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)[O-])oc12

Procedure:
The product of step (a) (6 g) was heated at 100° with sodium bicarbonate (1.55 g) in a mixture of water (50 ml) and ethanol (5 ml), for 4 hours. The ethanol was removed, in vacuo, and the remaining aqueous solution was filtered and cooled. The sodium salt (1.8 g) crystallised from this solution as orange needles.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH:7]([O:8][CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1>C(O)C>[ClH:1].[ClH:1].[NH2:2][C@H:3]1[C@H:7]([O:8][CH3:9])[CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1N
Agent: Cl
Solvent: CCO
Product: CO[C@@H]1CNC[C@H]1N

Procedure:
6.3 ml of 6N aqueous hydrochloric acid were added to a solution of 0.4 g (0.0019 mole) of 3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine [prepared as described in Step (3) above] dissolved in 20 ml of ethanol, and the mixture was heated under reflux for 1.5 hours, after which the solvent was removed by evaporation under reduced pressure. The residue was washed with a 1:9 by volume mixture of ethanol and ethyl acetate to give 0.34 g of trans-3-amino-4-methoxypyrrolidine dihydrochloride as a colorless powder, melting at 248°~258° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[NH:6][C:5](=O)[CH:4]([NH:17][C:18](=O)[CH2:19][O:20][CH3:21])[CH2:3]1>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[NH:6][CH2:5][CH:4]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:3]1
Reactant: COCC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Solvent: C1CCOC1
Product: COCCNC1CNc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 70 °C

Procedure:
A solution of N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide (0.138 g, 0.43 mmol) in THF (10 mL, 0.1 mol) was treated with 1 M of Borane-THF complex in THF (3 mL). The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched by the slow dropwise addition of methanol until all bubbling ceased, was concentrated, taken up in CH2Cl2 and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][NH2:32])[CH3:25]>CC(C)=O>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:25]
Reactant: CCN1CCC[C@H]1CN
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c(OC)cc1N
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: CCN1CCC[C@H]1CNC(=O)c1cc(S(=O)(=O)CC)c(N)cc1OC
Yield: 84.9 %

Procedure:
95 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid dissolved in 370 ml of acetone, in the presence of 37 g of trielthylamine, is treated with 40 g of ethyl chloroformate with 57 g of (S)-(−)-1-ethyl-2-aminomethylpyrrolidine. 115 g of (S)-(−)-N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamide is obtained (yield=84%).
Reaction SMILES: S(=O)(=O)(O)O.C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O)=O)C.[CH3:17][NH:18][C:19]([NH2:21])=[S:20]>>[SH:20][C:19]1[N:18]([CH3:17])[C:9](=[O:8])[C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[N:21]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=S(=O)(O)O
Product: Cn1c(S)nc2c(c1=O)CCC2
Temperature: 100 °C
Yield: 28 %

Procedure:
Five (5) drops of concentrated sulfuric acid were added to a mixture of 2-ethoxycarbonylcyclopentanone (31.2 g) and methylthiourea (18.0 g) and the mixture was heated at 100° C. for 2 days. The resulting precipitate was collected by filtration, rinsed with ethanol, and dried to provide the title compound as colorless powder (10.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH3:20])=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=N)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.32 g (11 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide in methylene chloride is added, at room temperature, 1.78 g (12 mmol) of trimethyloxonium tetrafluoroborate. After stirring overnight under nitrogen, the resulting solution is poured onto an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo affords methyl 2-(4-chlorophenyl)-3-methylbutanimidate.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23]C(O)=O)([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].[C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:32])[CH2:28][C:29]([O-])=[O:30]>O1CCCC1>[CH3:1][C:2]([C@@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:29](=[O:30])[CH2:28][C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:3]
Reactant: O=C([O-])CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 83.3 %

Procedure:
N,N'-Carbonyldiimidazole (540 mg) was added to a solution of [(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]acetic acid (1.06 g) in tetrahydrofuran (50 ml) at ambient temperature. After stirring for 7 hours at the same temperature, magnesium salt of mono-p-nitrobenzyl malonate (1.45 g) was added thereto, and the resultant mixture was stirred overnight at ambient temperature, The solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed in turn with 0.1N hydrochloric acid, water, saturated aqueous sodium chloride, aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, 5% aqueous citric acid, water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 2:1) to give formy substance, which was crystallized from a mixture of chloroform and diisopropyl ether, washed with diisopropyl ether and then dried in vacuo to give 4-nitrobenzyl 4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (1.31 g), mp 123°-125° C. (dec.).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[CH:3](OC)OC.[NH2:16][C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1>CC(C)=O>[Cl:23][C:22]1[C:17]2[N:18]([C:2]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=3)=[CH:3][N:16]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COC(OC)C(Br)c1ccnc(SC)n1
Reactant: Nc1nccnc1Cl
Solvent: CC(C)=O
Product: CSc1nccc(-c2cnc3c(Cl)nccn23)n1

Procedure:
Alternatively, intermediate 7 used in the synthesis of compounds of formula Ia can be prepared according to Schemes 2-4 below. 2-Methylsulfanyl-pyrimidine-4-carbaldehyde (8) can be condensed with (methoxymethyl)triphenylphosphonium chloride (Wittig reaction) to give 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine (9). Oxidation of (9) with N-bromosuccinimide in methanol provides 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (10). Condensation of (10) with 2-amino-3-chloropyrazine (1) in aqueous acid and a co-solvent such as acetone gives 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (11). Compound 11 can then be reacted with an appropriate amine (HNR1R2) either in excess or in the presence of another base, such as diisopropyl ethyl amine, in an appropriate solvent, such as ethanol or butanol, between room temperature to reflux to give the intermediate 7. Intermediate 7 can also be prepared via the ethyl homologs 9′ and 10′ according to Scheme 4 below. Compound 9′ (the ethyl homolog) can be prepared by the reaction ethyl ethynyl ether (13) with borane—tetrahydrofuran complex followed by palladium catalyzed coupling with 4-chloro-2-(methylthio)pyrimidine (12). Oxidation of 9′ with N-bromosuccinimide in ethanol provides the ethyl homolog 10′. Homolog 10′ can be converted to intermediate 7 in the same way as 10.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:14][OH:15]>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: NO
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)ccc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 5-cyano-2-hydroxy-benzoate (ASTATECH; 63806; 1 g; 5.64 mmol; 1 eq.) in EtOH (10 mL) was added hydroxylamine (50% in water) (1.69 mL; 28.22 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 30 min. While cooling to RT a white precipitate was formed. Solvents were removed to dryness and the white solids were washed with EtOH to afford title compound pure at 66% as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (d, J=2.2 Hz, 1H), 7.81 (dd, J=8.4, 2.2 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 5.82 (br s, 2H), 5.69 (br s, 1H), 3.91 (s, 3H). LC/MS (Method A): 210.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:17])[F:18])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)[C@@H](C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(C(=O)O)c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h

Procedure:
3.77 g (crude, about 11.5 mmol) of ethyl (3R)-2-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 14 ml of methanol, 14 ml of THF and 5 ml of water, and 9.16 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at 40° C. for about 6 h. The mixture was then acidified with 1 N hydrochloric acid (pH about 2) and extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.94 g of the target compound as a crude product which could be used without further purification for subsequent reactions.
Reaction SMILES: Br.[C:2](=[O:5])(O)[O-].[Na+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CBr>C1CCCCC1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:2][OH:5]
Reactant: BrCCCCCCCCCCCCCCCBr
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCCBr
Temperature: 25 °C

Procedure:
Diol 22 (4.70 g, 19.2 mmol) was dissolved in cyclohexane (50 mL) and 48% HBr (2.4 mL, 21.2 mmol, 1.1 eq.) was added under vigorous stirring. The mixture was refluxed overnight. After cooling to r.t., saturated sodium bicarbonate solution (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4. After evaporation of the solvent the product was purified by column chromatography (silica gel, 27×4 cm, cyclohexane/ethyl acetate, 4:1→100% ethyl acetate) and isolated as a white solid. Yield: 3.39 g (58%). Traces of 1,15-dibromopentadecane were also found.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7]C)=[O:6].B(O)O.[F:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25](CC(C(O)(C)C)(C)O)=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=3)[C:5]([OH:7])=[O:6])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(O)C(C)(O)Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 81.8 %

Procedure:
A 100 mL round bottom flask was charged with methyl 2-chloro-6-methylisonicotinate (3 g, 16.2 mmol), 2-[4-(4-fluoro-phenoxy)-phenyl pinacol boronate (5.1 g, 16.2 mmol), sodium carbonate (3.43 g, 32.4 mmol), PdCl2(PPh3)2 (569 mg, 0.81 mmol), DME (10 mL), EtOH (5 mL), and water (10 mL). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was then diluted with EtOAc (200 mL) and washed with 1M aq. HCl (2×200 mL). The organic layer was dried over MgSO4 and concentrated to a thick brown paste. The paste was suspended in EtOH (25 mL) and treated with 2N aq. NaOH (50 mL) at room temperature for 18 h, at which time the hydrolysis was complete. The mixture was concentrated under reduced pressure, suspended in water (50 mL), acidified with 4N aq. HCl (75 mL), and extracted with EtOAc (2×300 mL). The combined organic layers were dried over MgSO4 and concentrated to provide 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid as a waxy brown solid (4.28 g, 13.25 mmol). 1H NMR (d6-DMSO): 8.15-8.09 (m, 2 H), 8.08-8.04 (s, 1 H), 7.67-7.63 (s, 1H), 7.32-7.24 (m, 2 H), 7.20-7.13 (m, 2 H), 7.11-7.05 (m, 2 H), 2.65-2.60 (s, 3 H). LCMS: m/z=324 [M+H+]+. Unless otherwise indicated all 1H NMR chemical shifts reported herein are denoted by the delta (δ) scale.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH:9][C:10]([O:12][CH2:13][CH2:14]Br)=[O:11])=[CH:7][CH:6]=[C:5]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:4]=1.N>CO>[NH2:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][O:12][C:10]2=[O:11])=[CH:7][CH:6]=[C:5]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:4]=1
Reactant: Nc1nc(NCc2ccc(F)cc2)ccc1NC(=O)OCCBr
Agent: Cl
Agent: N
Solvent: CO
Product: Nc1nc(NCc2ccc(F)cc2)ccc1N1CCOC1=O

Procedure:
A suspension of 50 g (0.12 Mol) of 2-amino-3-[(2-bromethoxy)-carbonylamino]-6-(4-fluoro-benzylamino)-pyridine hydrochloride in 200 ml of methanol is added to 250 ml of 10% ethanolic ammonia and the mixture is stirred for a total of 24 hours at room temperature under argon (with a further 100 ml of 10% ethanolic ammonia being added after 12 hours). The resultant crystalline compound is filtered under suction and dried in a vacuum at room temperature.