Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][O:24]C3C=CC(OC)=CC=3)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)OC(C)(C)C)CCO2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepane-4-carboxylate (4.75 g) in acetonitrile (70 mL) and water (14 mL) was added ceric ammonium nitrate (16.18 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.36 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]=12>>[Cl:16][C:14]1[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]2=[C:10]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:15]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccnc1
Product: Cn1ncc2c(NCc3cccnc3)nc(Cl)nc21

Procedure:
Reaction of 3-aminomethylpyridine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-pyridin-3-ylmethyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[C:6]2=[O:25].[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:7]1[C:6](=[O:25])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][C:8]1([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)C(C)(C)O2
Yield: 99 %

Procedure:
A mixture of 7.3 g (0.0125) of the product of Example 110 and 700 mg 5% palladium on carbon in 200 mL ethyl acetate and 50 mL tetrahydrofuran was shaken in a Parr hydrogenator under 30 psi hydrogen for 3 hours. The mixture was filtered through Celite and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes yielded 6.8 g (99%) of the title product as an oil. NMR (CDCl3): δ1.38 (s, 3H); 1.47 (s, 3H); 2.20 (dd, 1H); 2.90 (m, 1H); 3.00 (dd, 1H); 3.60 (s, br, 2H); 3.78 (s, 3H). MS (Cl, NH3) m/e: 329 (M+ +18), 312 (M+ +1,2 100).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (3.95 g), N,N-diisopropylethylamine (1.79 mL), and morpholine (0.96 mL) in anhydrous DMF (149 mL) is heated at 65° C. for 1-2 h. The reaction is allowed to cool to room temperature, then poured into H2O (300 mL) to precipitate the product. The solid is filtered, adsorbed onto silica, and chromatographed (eluent 100% CH2Cl2 (0.5% CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1 L), 2% MeOH in CH2Cl2 (1L), 2.5% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 3.17 g (73%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[OH:38]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[OH:38])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2c(O)nc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2- isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[Br:19]Br>C(O)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([Br:19])[CH3:1])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Scheme X depicts the bromination of 4-benzyloxypropiophenone in acetic acid with bromine to yield 4'-(benzyloxy)-2-bromopropiophenone. When this reaction is complete, the mixture can be quenched with water. The resulting precipitate can be collected, washed with dilute acetic acid, water and heptane, and dried. ##STR38##
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)C)=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]>C(O)C.O>[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)Nc1ccc(-c2cccc(COC(C)(C)C)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Yield: 81.6 %

Procedure:
559 mg of sodium hydroxide in 2 ml of ethanol and 2 ml of water are placed in a round-bottomed flask containing 695 mg of N-[5-(3-tert-butoxymethylphenyl)pyridin-2-yl]acetamide. 1 ml of water and 1 ml of ethanol are added thereto and the mixture is heated at the reflux of the solvent for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up between dichloromethane and water and the organic phase is then separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 487 mg of compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1)([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].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>[F:28][C:4]1[CH:3]=[C:2]([S:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc(S)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C(C)C)cc4)cc3F)cc2)COC(C)(C)OC1
Yield: 122.9 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (170 mg) of Reference Example 10, 4-isopropylbenzenethiol (57 mg), diisopropylethylamine (98 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.8 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (11.2 mg) in 1,4-dioxane (1.5 mL) was heated under reflux for 9 hr under a nitrogen atmosphere. 4-Isopropylbenzenethiol (12 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (3.9 mg) and Xantphos (4.4 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.24 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(NC(=O)NCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc(N2CCNC2=O)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(2-chloroethyl)-3-(4-methoxyphenyl)urea (7.0 g, 30.6 mmol) in t-butanol (120 mL) was added potassium t-butoxide (6.4 g, 57.0 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 10 minutes, and then potassium t-butoxide (3.0 g, 26.7 mmol) was added. This solution was stirred for 10 minutes, and then potassium t-butoxide (4.3 g, 38.3 mmol) was added. The resulting solution was stirred for 16 hours at room temperature. The pH was adjusted to between 2 and 3 with 10% hydrochloric acid, and the solvent was evaporated under reduced pressure. To the residue were added water (100 mL) and ethyl acetate (100 mL), and stirred for 1 hour at room temperature. Resulting precipitates were filtered, washed with diethyl ether, and then dried under reduced pressure, to thereby yield 5.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:5][C@H:6]([C:13]([O:15]C)=[O:14])[NH:7]2.[OH-].[Na+]>CO>[C:13]([C@H:6]1[CH2:5][C@H:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:15])=[O:14]
Reactant: COC(=O)[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
Trans-5,7-dichloro-2,4-dimethoxycarbonyl-1,2,3,4-tetrahydroquinoline (1.13 g) was dissolved in 50% aqueous methanol (80 ml) and sodium hydroxide (0.16 g 1.1 molar equivalents) was added. The solution was stirred at room temperature for 4 h then concentrated in vacuo and redissolved in water (40 ml). The aqueous solution was washed with diethyl ether (2×20 ml) then acidified to pH 1 with 1N hydrochloric acid and extracted into diethyl ether (2×50 ml), dried (Na2SO4), filtered and the solvent evaporated to give an oil. This was purified by chromatography on silica gel with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane as eluent to give, as a colourless solid, trans-2-carboxy-5,7-dichloro-4-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.85 g, m.p. 160° C. dec); δ (360 MHz, DMSO), 1.91 (1H, ddd, J=13.4, 11.7 and 6.0 Hz, CHACHBHCCHD), 2.41 (1H, dm, J=13.4 Hz, CHACHBHCCHD), 3.65 (3H, s, CH3), 3.79 (1H, dd, J=11.7 and 3.2 Hz, CHACHBHCCHD), 3.96 (1H, dd, J=6.0 and 2.5 Hz, CHACHBHCCHD), 6.66 (1H, d, J=2.1 Hz. 6-H or 8-H), 6.83 (1H, d, J=2.1 Hz, 6-H or 8-H); m/e 303 (M+) 198 (M-H, CO2H, CO2Me); Found: C, 47.31; H, 3.70; N. 4.57. C12H11Cl2NO4 requires C, 47.39; H, 3.65; N, 4.61%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1C=C(C=CC=1)C#N.C1C=C(C=O)N=CC=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:20]#[N:19])[N:9]=1
Reactant: N#Cc1cccc(N)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: N#Cc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
By following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, except that 3-amino benzonitrile (709 mg, 6.0 mmol) and 2-pyridyl carboxaldehyde (642 mg, 6.0 mmol) were employed, 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile was obtained as an orange solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:25][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-[(2,2-Difluorocyclopropyemethyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2, 50 mg, 0.14 mmol, 1.0 equiv), and DIPEA (0.076 mL, 0.43 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and methanesulfonyl chloride (12.0 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 15-1 as a pale yellow oil. MS m/z (M+H): calculated=425.1456; observed=425.1465.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[SH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH2:18][C@@H:19]([CH3:29])[N:20]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:21][CH:22]=2)[N:16]=1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH:22]=[C:17]([C:15]2[N:16]=[C:12]([S:11][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:13][CH:14]=2)[CH2:18][C@H:19]1[CH3:29])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.58 ml, 0.58 mmol) was added at 0–5° C. to a solution of allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (172 mg, 0.58 mmol) in THF (2.0 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.21 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/4→1/3) to give allyl (4R,5S,6S)-3-[(4-{(2R)-1-[(allyloxy)carbonyl]-2-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (137 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH3:11])=[O:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([F:26])[C:24]=1F.Cl>CS(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH3:11])=[O:9])[N:3]=1
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: COC(=O)n1nc(O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 40 °C
Yield: 45.4 %

Procedure:
To a DMSO (15 mL) solution of methyl 3-hydroxy-5-methylpyrazole-1-carboxylate (1.56 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) was added 3-chloro-4,5-difluorobenzotrifluoride (2.21 g, 10.0 mmol), and the mixture was stirred under heating at 40° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid (30 mL) and extracted with ethyl acetate. The organic layers combined were washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The thus-obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give a white solid of methyl 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxylate (1.60 g, yield: 45.4%). Melting point: 123˜125° C., 1H-NMR (CDCl3, TMS, ppm): δ2.55 (d, J=0.8 Hz, 3H), 3.94 (s, 3H), 5.87 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.0 Hz, JHF=9.4 Hz, 1H), 7.50˜7.60 (m, 1H).
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([C@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Crude product from example C4 is dissolved in dry DMF (180 mL). After addition of sodium azide (11.7 g; 180.0 mmol) the reaction mixture is stirred for three days at 60° C. After filtration the reaction mixture is concentrated under reduced pressure, diluted with dichloromethane, extracted with water, half saturated brine and dried over MgSO4. After column chromatography on silica gel (cyclohexane/AcOEt—9:1) 11.8 g of the title compound is obtained as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(N)ccc1OC
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A mixture of 4-methoxy-3-(2-methoxyethoxy)nitrobenzene (7 g, 30 mmol) and 10% palladium-on-charcoal catalyst (1.4 g) in ethyl acetate (70 ml) was stirred under hydrogen at 3.3 atmospheres pressure for 1 hour. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The solid residue was suspended in ethyl acetate, collected by filtration and dried under vacuum to give 4-methoxy-3-(2-methoxyethoxy)aniline (6.1 g, 100%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:26]1[CH:27]=[CH:28][O:24][CH:25]=1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccoc2)c1
Yield: 42.6 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.296 mmol), furan-3-boronic acid (47.9 mg, 0.428 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (47 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.88 (ddd, J=0.9, 1.5, 2.5 Hz, 1H), 7.53 (dd, J=2.5, 7.1 Hz, 1H), 7.50 (t, J=1.7 Hz, 1H), 7.31-7.23 (m, 1H), 7.08 (dd, J=8.6, 10.6 Hz, 1H), 6.76 (dt, J=0.8, 1.7 Hz, 1H), 5.22 (s, 1H), 4.62 (s, 1H), 3.40-2.11 (m, 6H), 2.02-0.87 (m, 5H), 1.59 (dd, J=11.6, 70.3 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 150.2, 143.9, 127.44, 127.36, 127.0, 126.1, 123.8, 116.6, 116.4, 71.5, 55.9, 55.0, 47.6, 46.7, 30.1, 29.9, 25.6, 24.8, 19.8 ppm. Purity: 96% UPLCMS (210 nm); retention time 0.85 min; (M+1) 372.9.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 1-bromo-3-chloro-4-fluorobenzene according to Procedure A. White solid: mp 211-212° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.92 (dd, 1H, J=7.13, 2.19 Hz), 7.71-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.49 (t, 1H, J=8.95 Hz), 6.96 (d, 1H, J=8.01 Hz), 1.67 (s, 6H), MS (EI) m/z 305 ([M+H]+, 20%); Anal. Calc. For C16H13ClFNO2: C, 62.86; H, 4.29; N, 4.58. Found: C, 62.52; H, 4.45; N, 4.42.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=2)[C:30](O)=[O:31])[CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][N:35]=[C:27]([N:24]4[CH2:23][CH2:22][O:21][CH2:26][CH2:25]4)[CH:28]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccnc(N2CCOCC2)c1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-morpholin-4-yl-iso-nicotinamide was prepared starting from intermediate D and 2-morpholinoisonicotinic acid. MS calcd. for C26H24ClN4O3 [(M+H)+] 475.2, obsd. 475.0.