Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][C:5](=[O:8])[CH2:6][NH2:7])C.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47](O)=[O:48])=[N:43][N:44]=1>ClCCl>[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47]([NH:7][CH2:6][C:5]([OH:4])=[O:8])=[O:48])=[N:43][N:44]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(O)CNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Glycine ethyl ester hydrochloride (0.21 g, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 1.86 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol, 3.0) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL), and the mixture is stirred at room temperature for 18 hours. Purification by SGC (0-100% EtOAc/Hexanes) affords 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:31][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(-c2ncc[nH]2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccnc1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 1-{1-[4-(2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.0 g) and potassium carbonate (0.35 g) in dimethylformamide (10 ml) is added methyl iodide (0.16 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Further, to the mixture are added methyl iodide (0.16 ml) and potassium carbonate (0.3 g), and the mixture is stirred at room temperature for 8 hours. The mixture is poured into icewater, extracted with ethyl acetate, washed with water and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=25:1) and recrystallized from ethyl acetate to give 1-{1-[4-(1-methyl-2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.15 g) as colorless scales, m.p. 177°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:32])[C:18]([C:24]1[CH:25]=[CH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH2:33]([O:35][C:36](=[O:39])[CH2:37]Br)[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][O:16][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:32])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[F:15])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CC(c1ccc(Oc2ccc(F)c(O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 147, step 6, 5-{2-[2-chloro-4-(4-fluoro-3-hydroxy-phenoxy)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-1-methyl-1H-pyridin-2-one was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=558.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(CC)CC
Yield: 82.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.6 ml (0.025 mol) of diethylamine in 25 ml of DMF were reacted at room temperature for 16 hours affording a yellow semi-solid oil which was kugelrohr distilled at 80 Pa, pot temperature 102°-105° C., to give 4.63 g (82.3%) of product as a yellow solid; mp 31.5°-33° C.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CI
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Product: CC(C)CN1C(=O)CN=C(c2ccccc2)c2ccccc21

Procedure:
1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52, 3232-3239, incorporated herein by reference) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11]
Reactant: C#Cc1cccc(C)c1C
Reactant: COc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2cccc(C)c2C)SC(/C=C\c2cccc(C)c2C)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,3-dimethylphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dimethylstyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:7]([C:6]1[N:5]([CH3:9])[N:4]=[C:3]([CH3:10])[C:2]=1[NH:1][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])#[N:8]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nn(C)c(C#N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C#N)c1NC(=O)C(C)C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of 24 g (0.176 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole and 28 ml of triethylamine in 200 ml of chloroform is treated dropwise with 19.3 g (0.18 mol) of isobutyryl chloride and stirred overnight. The mixture is stirred with 100 ml of saturated sodium bicarbonate solution, the organic layer is separated and evaporated in vacuo. The residue is crystallized from ethyl acetate to give 30 g (83%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl)isobutyramide. This amide (30 g, 0.0146, mol) is added in portions to a solution of 7.1 g (0.017 mol) sodium hydroxide in 250 ml of water containing 36 ml of 30% hydrogen peroxide at 80° C. After stirring at 80° C. overnight, the solution is cooled and acidified with glacial acetic acid to give 23 g (74%) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 264°-266° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[N:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:10]=2[CH:11]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Fc1ccc2nnn(CCCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
1-(4-chlorobutyl)-6-fluoro-1H-benzotriazole (8.2 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.3 g compound (I-32) with a yield of 65.7%. ESI-MS [M+H]+: m/z 422.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])=[CH:61][CH:60]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:62]2[CH:63]=[CH:64][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[C:66]1=[O:73])=[O:71]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.098 g; 0.425 mmol), PyBOP (0.332 g; 0.638 mmol), N,N-diisopropylethylamine (0.220 mL; 1.28 mmol) and 1-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (42%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:30]1[C:34]([CH:35]=O)=[N:33][N:32]=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[NH:33][N:32]=[N:31][N:30]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1nnn[nH]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
In 1,2-dichloroethane (14 ml)/acetic acid (7 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution were added tetrazole-5-carbaldehyde (0.31 g) and sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=15:1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.67 g).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:23][CH:22]=1)[CH3:19]
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-ethoxybenzene boronic acid: MS (ESI) m/z 337 [M+H]+, 1H-NMR (CDCl3) δ 7.43 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 4.08 (2H, q, J=6.9 Hz), 3.91-3.89 (2H, m), 2.93 (2H, t, J=6.6 Hz), 2.31 (3H, s), 2.28 (3H, s), 1.45 (3H, t, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10]OC(OC)OC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[N:1]=[CH:10][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(OC)OC
Reactant: Cc1cccc(N)c1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,3-diaminotoluene (1.00 g, 8.2 mmol) in CH2Cl2 (82 mL) was added trimethylorthoformate (4.5 mL, 41 mmol) and trifluoroacetic acid (0.32 mL, 4.1 mmol) and the mixture stirred at room temperature for 24 h after which the reaction mixture was diluted with CH2Cl2 (200 mL), and washed consecutively with saturated aqueous NaHCO3 (40 mL) and H2O (40 mL). The aqueous layers were reextracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated to a rusty brown solid (1.07 g, 97%). 1H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.23–7.18 (m, 1H), 7.10 (d, 1H, J=7.5 Hz), 2.64 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.O.[CH3:17][O:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:17][O:18][C:19]1[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncccc1-c1nccnc1Oc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added 4-(3-chloropyrazin-2-yloxy)aniline (1.0591 g, 4.78 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine hydrate, trans-dichlorobis(triphenylphosphine) palladium (II) (0.268 g, 0.382 mmol), and sodium carbonate (2.53 g, 23.89 mmol) in DME (7.65 mL) and water (1.911 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 15 min. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 4(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z:295.2.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH2:26])[CH:20]=1.C(=O)(O)[O-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH:26][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=2)[CH:20]=1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C(C)(C)C)cc2)c1
Yield: 102 %

Procedure:
(4-tert-butyl-phenoxy)-acetic acid (200 mg, 0.96 mmol) and 3-amino-4-hydroxy-benzoic acid methyl ester (240.7 mg, 1.44 mmol) were dissolved in PPSE (3 mL), and reacted for 2.5 h at 140° C. After saturated sodium bicarbonate aqueous solution was added, organic phase was washed with 10% HCl and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give 3-[2-(4-tert-butyl-phenoxy)-acetyl-amino]-4-hydroxy-benzoic acid methyl ester as an orange solid (350 mg, 89% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5](=[O:14])[N:4]2[C@H:15]([C:19]([OH:21])=O)[CH2:16][CH2:17][CH2:18][N:3]12.C(OC([NH:28][C@H:29]([CH:38]([OH:50])[C:39]1[O:40][C:41]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:42]=2[N:43]=1)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=O)C=C.C(NC1C(=O)N2C(C(NC(C(O)COCC3C(Cl)=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1>>[Cl:49][C:45]1[CH:46]=[C:47]([Cl:48])[C:41]2[O:40][C:39]([CH:38]([OH:50])[CH:29]([NH:28][C:19]([CH:15]3[N:4]4[C:5](=[O:14])[CH:6]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:7][CH2:8][C:2](=[O:1])[N:3]4[CH2:18][CH2:17][CH2:16]3)=[O:21])[CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[N:43][C:42]=2[CH:44]=1
Reactant: CS(=O)(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Reactant: C=CCOC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc2cc(Cl)cc(Cl)c2o1
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NS(C)(=O)=O)C(=O)N12)C(O)c1nc2cc(Cl)cc(Cl)c2o1

Procedure:
was prepared from the acid 212b and (3S,4RS) t-butyl N-(allyloxycarbonyl)-3-amino-4-hydroxy-4-(5,7-dichlorobenzoxazol-2-yl)butanoate (204) by an analogous method as that used for compound 215e to afford a mixture of diastereomers (460 mg, 70%) as a glass: IR (film) 3325, 1725, 1664, 1453, 1399, 1373, 1327, 1274, 1256, 1155; 1H NMR (CDCl3) δ7.57 (1H, m), 7.36 (2H, m), 6.06 (1H, t), 5.29 (2H, m), 4.79 (1H, m), 4.47 (1H, m), 3.23 (1H, m), 2.97 and 2.94(3H combined, 2×s), 2.9-2.4 (4H, m), 2.30 (1H, m), 1.96 (4H, m), 1.41 and 1.37 (9H combined, 2×s). MS ES Da/e 660 (M−1)− Cl35 100%, 662 (M−1) Cl37.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][O:30][NH2:31].CC([O-])=O.[Na+]>CCO>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[C:9]([C:1](=[N:31][O:30][CH2:29][C:28]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:26]([Cl:25])[CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOCc1ccc(Cl)c(Cl)c1)c1ccccc1)C(F)(F)F
Yield: 51 %

Procedure:
A solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (710 mg, 1.95 mmol), O-(3,4-dichlorobenzyl)hydroxylamine hydrochloride (468 .mg, 2.05 mmol) and anhydrous NaOAc (168 mg, 2.05 mmol) in EtOH (50 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2) and the solvent removed under reduced pressure. An isomeric mixture of E- and Z-oxime ether derivatives was obtained, which were separated by radial thin layer chromatography (eluting with CH2Cl2/PE, 7.5:92.5 to 1:5). The major isomer was obtained as a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{4-chloro-2-[(3,4-dichlorobenzyloxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 87 (535 mg, 51%), as pale yellow crystals. M.p. 87-88° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.18, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.55-7.40, m, 5H; 7.34-7.14, m, 4H; 6.88, d, J=2.2 Hz, 1H; 5.09, s, 2H. The minor isomer was obtained as a pale yellow solid (315 mg, 30%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][C@@H:42]([C@H:44]([C@H:46]([C@@H:48]([CH2:50][OH:51])[OH:49])[OH:47])[OH:45])[OH:43]>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S:5]([CH2:4][CH2:3][CH2:2][N:40]([CH3:39])[CH2:41][C@H:42]([OH:43])[C@@H:44]([OH:45])[C@@H:46]([OH:47])[C@H:48]([OH:49])[CH2:50][OH:51])(=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: CNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN(C)C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 1-deoxy-1-(methylamino)-D-galactitol were converted to the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19](Br)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].C(N(CC)CC)C.[C:29]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])#[CH:30]>[Cu]I.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.C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:30]#[C:29][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(N)cc(Br)c1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCCOCCNC(=O)c1cc(N)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 65 °C

Procedure:
To a 10 L flask under nitrogen was added the product from step (ii) above (700 g, 1.93 mol) and THF (5.59 L). This was followed by the addition of CuI (19.2 g, 0.1 mol), triethylamine (1.29 L, 9.27 mol) and ethynyltriisopropylsilane (389 g, 2.13 mol). The reaction was degassed and purged with nitrogen three times. Pd(PPh3)4 (125.5 g, 0.198 mol) was added and the reaction degassed and purged with nitrogen. The reaction was heated to 65° C. overnight, after which LC indicated 91% product and <1% starting material. The reaction mixture was concentrated in vacuo, then the residue was taken up in ethyl acetate (2 L) and put through a silica plug (2 kg), eluting with additional ethyl acetate (30 L). The product-containing fractions were concentrated in vacuo, then the crude product was dissolved in TBME (5 L) and extracted with 6 N HCl (5 L). The aqueous HCl phase was washed with TBME (2×5 L), before being basified with 6 N NaOH to pH 9-10. The product was then extracted with TBME (2×5 L), the organics were dried, filtered and concentrated in vacuo to give 635 g of the sub-title compound with a purity of >95% by 1H NMR (excluding solvents).