Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[N:19]=[C:12]3[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:20])[N:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C1([O-])C=CC=CC=1.[Na+]>O1CCOCC1>[N:21]1([C:2]2[N:6]=[C:5]([CH:7]=[CH:8][C:9]3[N:19]=[C:12]4[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[N:11]4[N:10]=3)[N:4]([CH3:20])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(Br)nn3C)nc2n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc(C=Cc3nc(N4CCC4)nn3C)nc2n1
Yield: 27.3 %

Procedure:
A solution of 2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (59 mg, 177 μmol, Eq: 1.00) in dioxane (2.11 ml) was purged with argon, then azetidine (15.1 mg, 17.8 μl, 265 μmol, Eq: 1.5), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.17 mg, 14.1 μmol, Eq: 0.08), tris(dibenzylideneacetone)dipalladium chloroform complex (7.31 mg, 7.06 μmol, Eq: 0.04) and sodium phenolate (20.5 mg, 177 μmol, Eq: 1.00) were added. The vial was capped and irradiated at 140° C. for 60 minutes in the microwave oven. Chromatography afforded 2-[2-(5-azetidin-1-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (15 mg/27.4%) as a light yellow solid. MS: m/z=311.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37](NC(=O)C)[CH2:36][CH2:35]1>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:35][CH2:36][CH:37]([CH2:16][C:17]([NH2:18])=[O:23])[CH2:38][CH2:39]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(=O)NC1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: NC(=O)CC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-ylacetamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-Piperidin-4-yl-acetamide following General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][C@H:9]([C:15](O)=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].N=C=N>O>[NH2:8][C@H:9]([C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1)=[O:16])[CH2:10][CH2:11][C:12](=[O:13])[OH:14]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: Nc1ccncc1
Agent: N=C=N
Solvent: O
Product: Nc1ccnc(C(=O)[C@@H](N)CCC(=O)O)c1
Reaction time: 24 h

Procedure:
A mixture of 4-aminopyridine (5 mmol) and glutamic acid (5 mmol) is added to 0.1M carbodiimide [N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide or EDC] in distilled water adjusted to pH 4.5, such that the final volume is 200 ml. The reaction is performed for 24 hours at 4° C. The resulting glutamyl-4-aminopyridine conjugate is collected as an oil and purified to pharmaceutical purity.
Reaction SMILES: N.C([O:5][N:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:7](=[O:9])[CH3:8])(=O)C>CO>[N+:17]([C:13]1[CH:12]=[C:11]([CH2:10][N:6]([C:7](=[O:9])[CH3:8])[OH:5])[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: CC(=O)ON(Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: N
Solvent: CO
Product: CC(=O)N(O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
N-{(3-Nitrophenyl)methyl}acetohydroxamic acid can be obtained in the following manner: 22 cm3 of an 17N aqueous solution of ammonia are added at a temperature near to 25° C. to a solution of 3.55 g of N-acetoxy-N-{(3-nitrophenyl)methyl}acetamide in 120 cm3 of methanol. The reaction mixture is stirred for two hours at a temperature near to 25° C., and then concentrated under reduced pressure. The residue is dissolved in 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. 2.46 g of N-{(3-nitrophenyl)methyl}acetohydroxamic acid melting at 80° C. are thus obtained.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:1]=[N+:2]=[N-:3])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: [N-]=[N+]=Nc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1N=[N+]=[N-]
Yield: 46 %

Procedure:
Upon heating a solution of 7.3 g 2-azidobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 250°C (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:14](C(OCC)=O)C(OCC)=O)=[N:4][CH:5]=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.Cl>O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:4][C:3]=1[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(S(=O)(=O)N(C)C)cc1Br
Agent: Cl
Solvent: O
Product: Cc1ncc(S(=O)(=O)N(C)C)cc1Br
Yield: 86.1 %

Procedure:
Diethyl {3-bromo-5-[(dimethylamino)sulfonyl]pyridin-2-yl}malonate (222 mg; 0.52 mmol) was treated with a 5 N solution of HCl in water (11 ml) and the resulting solution was refluxed for 6 h. The solvent was removed under reduced pressure, and the solid residue was carefully quenched with a saturated Na2CO3 solution in water. The resulting suspension was extracted with AcOEt. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (125 mg; 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: COc1ccc(CC#N)cc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 4-methoxyphenylacetonitrile (200 g, 1.36 mol) and tetrahydrofuran (500 mL). Cool to about −5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (2900 mL, 1 M in tetrahydrofuran, 2.90 mol). When the addition is complete warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−12° C.) solution of ethyl bromoacetate (459.9 g) in tetrahydrofuran (1800 mL) at such a rate that the temperature of the reaction mixture does not rise above about 15° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether and extract with water, 10% hydrochloric acid solution, and saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 175-185° C. at 1.0 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:10](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/C(OC(C)(C)C)=O)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[O:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8](=[O:9])[CH2:10][C@@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C(=C/c1ccccc1)C(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: O=C1C[C@H](c2ccccc2)Oc2ccccc21
Yield: 91.4 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxyphenylcarbonyl)-3-phenylprop-2-enoate (5) (65 mg, 0.2 mmol) and thiourea catalyst III (14 mg, 0.02 mmol) in 2.0 mL toluene for 36 h at −25° C. and p-toluenesulfonic acid (19 mg, 0.10 mmol) for 24 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 41 mg (92%) of 7 as a white solid in 94% ee. [α]D: +55.6 (EtOH, c=0.5). Analytical data match those reported in the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-phenyl ester (0.236 g, 0.5 mmol), 4-methoxycarbonylphenylboronic acid (0.134 g, 0.75 mmol), sodium carbonate (0.158 g, 1.5 mmol) in THF (20 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.029 g, 0.025 mmol), then raise the reaction temperature to 80° C., and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.22 g (95%) of the titled product. MS (m/z): 461 (M+).
Reaction SMILES: FC1C([O:8][C:9](=[O:28])[CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=C(F)C(F)=C(F)C=1F.COC(=O)CNC(=O)C1C=CC(OCC2C=CC=CC=2)=CC=1>[OH-].[Na+]>[C:21]1([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH2:10][C:9]([OH:28])=[O:8])=[O:27])=[CH:14][CH:15]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(CNC(=O)c1ccc(OCc2ccccc2)cc1)Oc1c(F)c(F)c(F)c(F)c1F
Agent: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 47 %

Procedure:
N-(4-(Phenylmethoxy)benzoyl)glycine pentafluorophenyl ester. N-(4-(Phenyl-methoxy)benzoyl)glycine methyl ester (14.75 g, 49.2 mmol) was boiled under reflux with methanolic sodium hydroxide (1M) (80 mL) for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in water and was acidified by addition of aqueous hydrochloric acid. The suspension was extracted with ethyl acetate. The extract was washed with saturated brine and was dried with anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine (6.59 g, 47%). Dicyclohexylcarbodiimide (720 mg, 3.5 mmol) was added to N-(4-(phenylmethoxy)benzoyl)glycine (100 g, 3.5 mmol) in dry tetrahydrofuran (100 mL) and the mixture was taken to 0° C. Pentafluorophenol (640 g, 3.5 mmol) was added dropwise and the mixture was stirred for 17 h at 0° C. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and was washed with saturated aqueous sodium hydrogen carbonate (2×75 mL), with aqueous sulphuric acid (10%) and with water. The solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine pentafluorophenyl ester (Intermediate B) (1.5 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (640 mg), lithium hydroxide monohydrate (363 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (9 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (592 mg, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 179–180° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>O1CCOCC1>[CH3:17][N:13]1[C:14]2=[CH:15][N:21]([C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (2.04 g, 6.05 mmol), (S)-dibenzyl 2-aminopentanedioate (commercially available) (4.53 g, 9.08 mmol) and triethylamine (3.37 mL, 24.20 mmol) were suspended in dioxane (30 mL) and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between DCM and 0.1M HCl(aq) and the phases separated. The organic phase was passed through a hydrophobic frit. Purification by chromatography on silica, eluting with 20-60% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11](=O)[C:12](C)=[CH:13]C(=O)[CH:15]=1.CC(OP(C1C=CC=CC=1)C1C=CC=CC=1)(CC=C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:15])([CH3:9])[CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1
Reactant: CC1=CC(=O)C=C(C)C1=O
Reactant: Oc1ccc(Cl)cc1
Agent: C=CCC(C)(C)OP(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=CCC(C)(C)Oc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 2 %

Procedure:
To a cooled (0° C.), stirred mixture of 4-chloro-phenol (4.34 g) and 2,6-dimethylbenzoquinone (4.60 g) was added dropwise a solution of (2-methyl-pent-4-en-2-oxy)diphenylphosphine (8.0 g) in dichloroethane (20 ml). The mixture was then heated at 95° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give 1-chloro-4-(1,1-dimethyl-but-3-enyloxy)-benzene (0.14 g, 2%) as a colourless oil. MS (EI): 171.1 ([{37Cl}M−C3H5−]+), 1691 ([{35Cl}M−C3H5]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[IH:11]>C(Cl)Cl>[I:11][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CSc1cc(Cl)nc(C)n1
Reactant: I
Solvent: ClCCl
Product: CSc1cc(I)nc(C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
A mixture of 4-chloro-2-methyl-6-(methylthio)pyrimidine (5.3 g, 30.3 mmol) and hydriodic acid (67% solution, 5.71 mL, 76 mmol, Alfea Aesar, Avocado, Lancaster) in DCM (20 mL) was stirred at room temperature for 20 h and filtered. The collected solid was washed with DCM and then suspended in saturated NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give 4-iodo-2-methyl-6-(methylthio)pyrimidine (7.3 g, 27.4 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H); 2.62 (s, 3H); 2.52 (s, 3H). m/z (ESI, +ve ion) 266 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=[O:28]>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:27]([OH:28])[C:26]4[S:25][CH:24]=[N:23][C:22]=4[CH3:21])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: Cc1ncsc1C=O
Product: COC(=O)c1nc2n(c1C(O)c1scnc1C)CCOc1cc(F)c(Br)cc1-2

Procedure:
methyl 10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with 4-methylthiazole-5-carboxaldehyde to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester, (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (416 mg, 4.12 mmol), benzoyl chloride(144 μl, 1.24 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. MS-ES: m/z 456.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1Cc1ccccc1

Procedure:
A solution of 2-[4-benzyloxy-2-(hydroxy-phenyl-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester (1.67 g, 3.97 mmol maximum) in ethanol (50 mL) was treated with 5% Pd/C (0.42 g) and hydrogen (60 psi, room temperature, 18 h). The mixture was filtered and concentrated to a viscous colorless oil (1.15 g, 91%): 1H NMR (400 MHz, CDCl3) δ1.32 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 3.99 (s, 2H), 4.30 (q, 2H, J=7.0 Hz), 4.93 (brs, 1H), 6.58-6.66 (m, 3H), 7.22-7.34 (m, 5H); MS (ES) m/e 315 [M+1].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([Cl:36])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)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>[Cl:28][C:29]1[CH:34]=[C:33]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)[CH:32]=[C:31]([Cl:36])[N:30]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Temperature: 80 °C
Yield: 89.5 %

Procedure:
A suspension of 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (4.63 g, 12.1 mmol), 2,6-dichloro-4-iodopyridine (3.00 g, 11.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.308 g, 0.438 mmol) and sodium carbonate (1M, 8.76 mL, 8.76 mmol) in 1,2-dimethoxyethane/ethanol/water (7:2:3) (30 mL) was degassed and heated at 80° C. overnight. After cooling, the suspension was diluted with ethyl acetate, filtered, washed with ethyl acetate and water, and oven-dried to give 3.98 g (90%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: ClCc1cccc(Br)c1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reaction time: 8 h

Procedure:
3-bromobenzyl chloride (shown by the formula (vi)) and triethyl phosphite were put in a three-necked flask equipped with a reflux condenser, to which toluene was added and heated with stirring for 8 hours under reflux. The mixture was purified by the common method, to obtain diethyl 3-bromobenzylphosphonate (shown by the formula (vii)).