Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:39])[C:34](=[O:38])[CH2:35][O:36][CH3:37])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:39])[C:34](=[O:38])[CH2:35][O:36][CH3:37])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: COCC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Product: COCC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 39 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-methoxy-N-methylacetamide to give the title compound in 39% yield; NMR spectrum (DMSO-d6, 373K) 1.20 (m, 3H), 2.80 (s, 3H), 3.10 (s, 3H), 3.90 (m, 2H), 4.20 (m, 1H), 4.50 (m, 1H), 5.10 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (t, 1H), 7.90 (t, 1H), 7.95 (s, 1H), 8.40 (s, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum F 522.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:27].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[N:12][C:11]=2[C:22]([NH2:27])=[O:24])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1 g) in methylene chloride (10 ml) was added ammonia-methanol solution (60 ml) which was prepared by bubbling an ammonia gas (14 g) into methanol (120 ml), and the mixture was stirred for hours at ambient temperature. After evaporating the solvent, the residue was recrystallized from methanol to give 4-(3-nitrophenyl)-6-phenyl-3-p-yridazinecarboxamide (0.78 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1CCCC1.O.CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2](=[O:1])[NH:3][CH:4]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Oc1ccc(O)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1ccc(Oc2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 2,5-dihydroxy-pyridine (4.65 g, 41.9 mmol), 4-fluoro-nitrobenzene (2.22 ml, 21 mmol) and Cs2CO3 (13.7 g, 41.9 mmol) in N-methyl-pyrrolidine (60 ml) is stirred for 18 h at 90° C. under N2-atmosphere. The reaction mixture is diluted with water and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with a NaHCO3 solution and brine, dried (Na2SO4) and partially concentrated. Thereby the title compound crystallizes and can be filtered off and washed with AcOEt: m.p.: 214-217° C.; 1H-NMR (DMSO-d6): 11.6 (s, HN), 8.22 (d, 2H), 7.57 (d, 1H), 7.43 (dd, 1H), 6.14 (d, 2H), 6.46 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>>[CH:37]([C:34]1[CH:33]=[CH:32][C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:26]=2)=[CH:36][CH:35]=1)([CH3:39])[CH3:38]
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3OC)[N:21]=[C:20]3[N:34]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[N:35]=[C:36]([CH3:37])[C:19]=23)=O)[C:10]([CH3:45])([CH3:44])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC.C1C[O:53][CH2:52]C1>>[CH2:1]([N:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([CH2:16][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:53][CH3:52])=[CH:26][CH:25]=3)[N:21]=[C:20]3[N:34]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[N:35]=[C:36]([CH3:37])[C:19]=23)[C:10]([CH3:45])([CH3:44])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2cc(C(=O)N3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)c(OC)c1
Agent: B
Solvent: CSC
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 96 %

Procedure:
To a solution of 1.54 g of (4-benzyl-2,2,5,5-tetramethyl-piperazin-1-yl)-[6-(4-methoxy-methoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone in 9 ml of dry THF 20 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 12 h. The reaction was quenched by the addition of 13 ml of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 1.44 g (96%) of the title compound.
Reaction SMILES: NC1N(C)N=[C:4]([C:8]2[N:9]([CH3:16])[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][N:12]=2)[C:3]=1[C:17]#N.CC1NC([N+]([O-])=O)=CN=1.S(OC)(OC)(=O)=O.CN1C([N+]([O-])=O)=CN=C1C.C(=O)[C:46]1[CH:51]=[CH:50]C=[CH:48][CH:47]=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[CH3:16][N:9]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][N:12]=[C:8]1[CH:4]=[CH:3][C:17]1[CH:50]=[CH:51][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1N
Agent: CC[O-]
Agent: Cc1ncc([N+](=O)[O-])[nH]1
Agent: Cc1ncc([N+](=O)[O-])n1C
Solvent: CCO
Solvent: c1ccccc1
Solvent: COS(=O)(=O)OC
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1ccccc1

Procedure:
An exemplary starting compound, 5-amino-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile, is readily synthesized starting from commercially-available 2-methyl-5-nitroimidazole. The 2-methyl-5-nitroimidazole is allowed to react with a suitable alkylating agent, such as dimethyl sulfate, in a suitable solvent, for example benzene, to yield the compound identified as 1,2-dimethyl-5-nitroimidazole. This latter compound is in turn allowed to react with benzaldehyde in the presence of a base, for example sodium ethoxide in absolute ethanol, to yield 1-methyl-5-nitro-2-styrylimidazole.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1ccc(Cl)c(C#N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1
Yield: 53.5 %

Procedure:
Following a procedure substantially the same as that described in Example 20, 8.0 g of 3-chloro-6-ethylthio-2-pyridinecarbonitrile was reacted with 8.2 g of 3,4-dichlorophenol in the presence of 5.6 g of t-BuOK in 60 ml of THF and 30 ml of DMSO. The reaction was allowed to proceed at boiling temperature for about 40 hours. The product, an oil, was purified by distillation on a Kugelrohr distillation apparatus, separated on a Water's Prep LC 500 instrument, and again distilled on a Kugelrohr apparatus to give about 7 g (54%) of the desired 3-(3,4-dichlorophenoxy)-6-ethylthio-2-pyridinecarbonitrile, having a boiling point (b.p.) of 160° C. at 0.01 mm Hg pressure.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:16][CH:17]([CH3:22])[O:18][CH:19]([CH3:21])[CH2:20]1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Reactant: CC1CC(O)(c2csc(S)c2)CC(C)O1
Product: CC1CC(O)(c2csc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CC(C)O1
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-hydroxy-4-(2-mercaptothien-4-yl)-2,6-dimethyltetrahydropyran to give 4-hydroxy-2,6-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 28% yield;
Reaction SMILES: [CH3:1][N:2]1[CH2:6][N:5]([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([OH:58])=O)[N:54]=1)=[O:48]>CC(C)=O>[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([NH:13][C@H:9]2[C@H:8]([S:7][N:5]3[CH2:6][N:2]([CH3:1])[N:3]=[N:4]3)[NH:11][C:10]2=[O:12])=[O:58])[N:54]=1)=[O:48]
Reactant: CN1CN(S[C@@H]2NC(=O)[C@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)N=N1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SN1CN(C)N=N1)c1csc(NC(=O)CCl)n1
Yield: 55.9 %

Procedure:
Following the procedure of Reference Example 66B, solution of 1.12 g of (3R,4S)-4-(1-methyl-1H-tetrazol-4-yl)thio-3-tritylamino-2-oxoazetidine in 5 ml of acetone, 0.491 g of p-toluenesulfonic acid monohydrate and 0.788 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid is treated to give 0.650 g of (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-4yl)thio-2oxoazetidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([C:20](O)=[O:21])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH:16][C:20]([C@H:18]([NH:17][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:19])=[O:21])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNc1ccc(Nc2cccc(Cl)c2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
(Step 1-iii) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (2.4 g, 10 mmol) was combined with Boc-D-Ala-OH (2.0 g, 10.5 mmol), HBTU (4.4 g, 11.6 mmol) in DMF and DIEA (2.0 mL (11.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and poured into ethyl acetate/saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, concentrated to an oil, and purified by silica gel column chromatography (EtOAc to 10% MeOH/EtOAc), to give the product, tert-butyl (R)-1-(6-(3-chlorophenylamino)pyridazin-3-ylaminocarbamoyl)ethylcarbamate (1.38 g, 3.4 mmol, 34%).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][NH:21][C:20]=3[N:19]=2)[C:11]1=[O:28])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([C@@H:6]([CH2:7][CH2:8][CH2:9][N:10]2[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[CH2:24][CH2:23][CH2:22][NH:21][C:20]=4[N:19]=3)[C:11]2=[O:28])[CH2:5][C:4]([OH:37])=[O:3])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NCc2ccc3c(n2)NCCC3)C[C@H]1C)c1ccc(OC)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@@H](CCCN2C(=O)[C@@H](NCc3ccc4c(n3)NCCC4)C[C@H]2C)CC(=O)O)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 4-9 (150 mg) in tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (60 mg) in water (6 mL) and the mixture was stirred for 16 h. The reaction mixture was then concentrated at reduced pressure and the resulting oil was purified by flash column chromatography (silica gel, 30:3:3 to 50:5:5% ethanol/ammonium hydroxide/water in ethyl acetate) to give 4-10 as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[NH:6][C:7]1[C:12]([CH2:13][NH:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1.[O-:22][CH2:23]C.[Na+].C(=O)(OCC)OCC>O1CCOCC1>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:6]2[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][N:14]([CH2:15][CH3:16])[C:23]2=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CCNCc1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(=O)OCC
Product: CCN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 96.5 %

Procedure:
To a mixture of 2.0 g of 2-(m-trifluoromethylanilino)-3-ethylaminomethylpyridine, 1.0 g of sodium ethoxide and 30 ml of dioxane was added dropwise 2.4 g of diethyl carbonate, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the dioxane was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was recrystallized from ether to yield 2.1 g of 1-(m-trifluoromethylphenyl)-3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 155° - 157° C.
Reaction SMILES: Cl[C:2]1[O:10][C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=1>C(O)(=O)C.[Zn]>[O:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Clc1cc2ncccc2o1
Agent: [Zn]
Solvent: CC(=O)O
Product: c1cnc2ccoc2c1

Procedure:
Chlorofuropyridine (7, 1.27 g, 8.27 mmol) is treated with zinc (3.23 g, 49.6 mmol) in acetic acid (20 ml) at refluxing temperature until the starting material disappears (˜4 hours). The reaction is filtered to remove solid. The filtrate is concentrated and the residue is dissolved in water. After basification with 1N sodium hydroxide, the mixture is extracted with methylene chloride. Evaporation leaves a yellow oil, which is purified with flash column chromatography on silica gel to give furopyridine as a yellow oil (8).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:24]1(=[O:34])[N:28]([CH2:14][C:15]2[S:19][C:18]3=[CH:20][N:21]=[CH:22][N:17]3[C:16]=2[CH3:23])[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(CO)sc2cncn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)sc2cncn12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 43.6 %

Procedure:
Under an argon atmosphere at room temperature, 0.705 ml of diethyl azodicarboxylate was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 505 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole, 662 mg of phthalimide and 1180 mg of triphenylphosphine, and the mixture was then stirred at room temperature for 4.5 hours. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 389.3 mg of 2-phthalimidomethyl-3-methylimidazo[5,1-b]thiazole as a lemon crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:22][C@@H:23]3[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@@H:34]([O:35]C(=O)C)[C@H:29]([O:30]C(=O)C)[C@H:24]3[O:25]C(=O)C)=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[CH:5][CH:4]=1.C[O-].[Na+]>CO>[C@@H:23]1([O:22][C:11]2[C:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:14]([CH3:15])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=2)[O:40][C@H:39]([CH2:41][OH:42])[C@@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(-c3ccccc3)c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(-c3ccccc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To a solution of 4-[(4-methoxyphenyl)methyl]-5-methyl-1-phenyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.38 g) in methanol (5 mL) was added sodium methoxide (28% methanol solution, 0.12 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.32 g).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:61](#[N:64])[CH:62]=[CH2:63]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:63]=[CH:62][C:61]#[N:64])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:29]([CH3:31])[CH3:30])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CC#N)ccc1OCc1ccccc1)C(C)C
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (13.87 g, 28.87 mmol) (prepared as described in WO 94/11337, Example 1) in DMF (140 mL) was added triethylamin (5.00 mL, 36.10 mmol), Pd(OAc)2 (0.32 g, 1.44 mmol), tri(o-tolyl)phosphine (1.76 g, 5.77 mmol) and acrylonitrile (2.39 mL, 36.10 mmol). The reaction mixture was stirred overnight at 115° C. in a sealed flask equipped with a reflux condenser under nitrogen atmosphere. The resulting mixture was concentrated, and the residue was dissolved in diethyl ether, washed with aqueous 2 M sodium hydroxide and water. The organic phase was dried (MgSO4) where after petroleum ether was added to the organic phase and a precipitate was formed. Recrystallisation from ethanol yielded 5.50 g (42%). 1H NMR (CDCl3) δ0.90 (s, 6H), 0.95 (s, 6H), 2.15 (q, 2H), 2.35 (q, 2H), 2.95 (m, 2H), 4.40 (t, 1H), 5.05 (s, 2H), 5.70 (d, 1H), 6.85 (d, 1H), 7.10-7.50 (m, 13H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([C:15]#[CH:16])=[C:13]([O:17][C:18](=[O:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH2:15][CH3:16])=[C:13]([O:17][C:18](=[O:20])[CH3:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: C#Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Yield: 98.7 %

Procedure:
To a solution of (4-acetoxy-3-ethynyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (50 mg) in methanol was added 10% palladium on carbon (10 mg). The resulting mixture was hydrogenated under 40 psi of hydrogen for 2 hours and filtered. The filtrate was concentrated in vacuo to afford (4-acetoxy-3-ethyl-6-fluoro-naphthalen-2-yl)acetic acid methyl ester (50 mg) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][NH:15][C:14]=3[CH:19]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(OCC)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:28](=[O:29])[CH2:27][CH2:26][Cl:25])[C:14]=3[CH:19]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCCO2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCCl)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
To a solution of 6-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.530 g, 1.90 mmol) in 5 mL ethyl acetate was added 2 mL saturated aqueous sodium bicarbonate. The mixture was stirred rapidly and cooled to 0° C., and 3-chloro-propionyl chloride (0.219 mL, 2.30 mmol) was added dropwise over 2 minutes. Stirring was continued for 20 minutes, and 20 mL ethyl acetate was added to the reaction mixture. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to give 0.689 g (99%) of 1-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-chloro-propan-1-one as an orange-white solid. MS: 367 (M+H)+.
Reaction SMILES: ClCl.[CH3:3][S:4][CH3:5].[C:6]12([O:16][C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(Cl)Cl>[C:6]12([O:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:21])=[C:22]([CH2:3][S:4][CH3:5])[CH:23]=3)[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: CSC
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N
Temperature: 25 °C

Procedure:
To 6.2 g. (0.088 mole) of chlorine in 240 ml. of CH2Cl2 in one-liter 3-neck flask cooled to -70° to -73° was added dropwise with stirring a cold (~ -70° ) solution of 5.7 g. (0.092 mole) of dimethyl sulfide in 20 ml. of CH2Cl2. The solution was stirred for several minutes, and then a solution of 21.4 g. (0.088 mole) of 4-(1-adamantyloxy)-aniline and 8.9 g. (0.088 mole) of triethylamine in 400 ml. of CH2Cl2 cooled either to -70° or to -40° to -50° was added dropwise rapidly. Then the mixture was either stirred at -70° and gradually allowed to warm to room temperature during four hours and then cooled again to -65° or it was stirred at -70° for 2 hours followed in either case by the addition of 51.8 g. of 25% sodium methoxide in methanol solution, removal of the cold bath, and stirring at room temperature for 12 to 18 hours.