Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[C:13]2[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c2c1NCCN2
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Compound 468A (0.037 g, 0.18 mmol) was dissolved in a mixture of ethyl acetate (1.0 mL)/ethanol (1.0 mL) and 10% Pd/C (0.050 g) was added. Hydrogen was then introduced via a balloon. After 2 h, the reaction was purged with nitrogen and filtered through Celite, rinsing with ethyl acetate. Concentration in vacuo gave 0.029 g (90%) of compound 469A as a red oil, which was taken on without further purification. HPLC: 97% at 3.217 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([S:30]([O-:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.[Na+]>>[F:29][C:27]1[CH:26]=[C:25]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([F:22])[CH:28]=1
Reactant: O=S([O-])c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc3c2C1
Yield: 50 %

Procedure:
The product of Example 29, step B and sodium 3,5-difluorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(3,5-difluorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (191 mg, 50%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.82 (dd, J=8.4, 1.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.49-7.45 (m, 2H), 7.02-6.94 (m, 1H), 4.59 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91-2.84 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C1(P([C:34]2[CH:39]=[CH:38]C=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([Mg]Br)CC1.Cl>O1CCCC1.Cl[Ni]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:38]2[CH2:39][CH2:34]2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(Br)ccc1Cl
Agent: Cl[Ni]Cl
Agent: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-1-chloro-2-methoxy-benzene (1.45 g, 6.55 mmol) in dry tetrahydrofuran (10 ml), was added {1,3-bis (diphenylphosphino)-propane} dichloronickel (II) and cyclopropylmagnesium bromide (46 ml, 0.5 M in tetrahydrofuran, 23 mmols) at room temperature. The solution was stirred at room temperature for 2 hours, and then heated at 65° C. for 48 hours. Aqueous hydrochloric acid solution (1 N, 20 mL) was added, and the mixture was then cooled to room temperature and stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% ethyl acetate in hexane) to yield 1-chloro-4-cyclopropyl-2-methoxy-benzene as yellow oily residue (0.81 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.Cl.CN(C)[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:16]1([C:14]2[CH:13]=[CH:12][C:3]3[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=3[N:1]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: NC1=CC(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2nc(-c3ccccc3)ccc21
Temperature: 25 °C
Yield: 26.4 %

Procedure:
3-Aminocyclohexenone (5.55 g, 50 mmol) and 3-dimethylaminopropiophenone hydrochloride (10.65 g, 50 mmol) were suspended in glacial acetic acid (15 mL) and heated at reflux for 1 h. The mixture was cooled to room temperature and cautiously poured into 20% aqueous sodium carbonate. After gas evolution ceased the residue was extracted with chloroform, dried over anhydrous sodium carbonate, filtered and evaporated. Purification by chromatography on silica gel using 1:1 chloroform/dichloromethane as eluant provided 2.95 g (26%) of 2-phenyl-7,8-dihydroquinolin-5(6H)-one as an off-white solid, mp 128°-130° C.; 1H NMR (CDCl3) δ8.32 (d, 1H), 8.05 (dd, 2H), 7.66 (d, 2H), 7.55-7.42 (m,3H), 3.21 (t, 2H), 2.72 (t, 2H), 2.22 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(Br)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Yield: 51.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.52 g (11.1 mmol) of 3-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.01 g (yield 37%) of Compound 161 as pale green plates.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC=C(c1ccccc1)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC=C(c1ccccc1)c1ccccc1)OCC
Yield: 108.2 %

Procedure:
A mixture of 40.8 g (0.155 mol) of 3,3-diphenylallyl chloride (11a) and 94.48 g (0.569 mol) of triethyl phosphite was stirred with refluxing for 24 hours. The disappearance of the 3,3-diphenylallyl chloride (11a) was ascertained, before the reaction was terminated. After cooling, the reaction mixture was distilled with a Claisen flask equipped with a vigreux to obtain 55.39 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:14]([OH:17])CO)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:8]([C:6]1[C:5]([O:11][CH2:12][CH3:13])=[C:4]([C:3]([CH3:18])=[C:2]([Cl:1])[CH:7]=1)[CH:14]=[O:17])(=[O:10])[CH3:9]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1C=O
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 1-[5-chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone (0.64 g, 2.3 mmol) in tetrahydrofuran (18 mL) and water (11 mL) was added acetic acid (35 μL, 0.61 mmol) and sodium periodate (1.50 g, 7.04 mmol) at 0° C. After stirring for 30 min, the reaction mixture was diluted with water, and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.58 g, 100%). LCMS calculated for C12H14ClO3 (M+H)+: m/z=241.1; Found: 241.1.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CCOC(=O)c1csc(-n2cccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(-n2cccc2)n1
Yield: 69 %

Procedure:
In substantially the same manner as in Reference Example 77, ethyl 2-(1-pyrrolyl)-4-thiazolecarboxylate was reduced by lithium aluminum hydride to give 2-(1-pyrrolyl)-4-thiazolylmethanol. The yield was 69%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 111-113° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:19]>>[ClH:19].[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: O=C(O)c1ccc(C2CCNCC2)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A mixture of 4-(1-acetylpiperidin-4-yl)benzoic acid described in Production Example 1-10 (4.50 g, 18.2 mmol) and 5 M hydrochloric acid (50 mL, 250 mmol) was stirred under nitrogen atmosphere at 140° C. for 18 hours. The mixture was cooled to room temperature and then the product was collected by filteration and washed with water to obtain the title compound (3.77 g, 86%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Cl[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][CH2:34][CH3:35])=[CH:28][N:27]=1>>[CH2:34]([O:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[N:27][CH:28]=1)[CH3:35]
Reactant: CCOCc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Product: CCOCc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(OC(C)C)cc4)ccc32)nc1

Procedure:
The title compound was prepared in accordance with Example 10 using 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester and 2-chloro-5-(ethoxymethyl)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]O>C(Cl)(Cl)Cl>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: CO
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitrobenzofuran-2-carboxylic acid (10 g) was dissolved in methanol (200 mL) and chloroform (100 mL), and the mixture was cooled to 0° C. Under stirring conditions was bubbled HCl gas until the solution was saturated. The reaction mixture was stirred at room temperature overnight, and white solid was formed. The precipitate was collected by filtration to afford 9.5 g of the title compound.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[CH3:23][O:24][C:25]1[C:34]2[N:29]([C:30](=[O:52])[N:31]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](B4OC(C)(C)C(C)(C)O4)[C:37]=3[CH3:51])[C:32](=[O:35])[CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:31]2[C:32](=[O:35])[CH:33]=[C:34]4[C:25]([O:24][CH3:23])=[CH:26][CH:27]=[CH:28][N:29]4[C:30]2=[O:52])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: COc1cccn2c(=O)n(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3C)c(=O)cc12
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1cccn2c(=O)n(-c3cccc(-c4c(Cl)cc(C(N)=O)c5[nH]c6cc(C(C)(C)O)ccc6c45)c3C)c(=O)cc12
Temperature: 60 °C
Reaction time: 0.01 h
Yield: 46.1 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 3] (0.051 g, 0.135 mmol), 5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 32] (0.050 g, 0.122 mmol) and Cs2CO3 (0.080 g, 0.245 mmol) in THF (2 mL) and water (0.5 mL) was bubbled with nitrogen for 2 min, then was treated with PdCl2(dppf) DCM adduct (5.0 mg, 6.12 μmol). Bubbling with nitrogen was continued for 30 sec and the reaction vessel was sealed. The mixture was heated at 60° C. overnight. The cooled mixture was diluted with DCM and MeOH, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give 3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (32.8 mg, 44% yield). Mass spectrum m/z 583 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.51-11.47 (m, 1H), 8.27 (br. s., 1H), 8.14 (d, J=1.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.59 (br. s., 1H), 7.55-7.45 (m, 3H), 7.30-7.25 (m, 1H), 7.03-6.97 (m, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.56 (q, J=7.6 Hz, 1H), 5.90 (s, 1H), 4.98 (s, 1H), 3.91 (s, 3H), 1.69 (s, 3H), 1.45-1.42 (m, 6H).
Reaction SMILES: [SH:1][CH2:2][C:3]#[N:4].O[CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2>FC(F)(F)C(O)=O.C(Cl)Cl.C(OCC)(=O)C>[C:3]([CH2:2][S:1][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2)#[N:4]
Reactant: N#CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Yield: 48.2 %

Procedure:
Under ice cooling and stirring, 0.44 g of mercaptoacetonitrile was added to 2.22 g of 11-hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 45 dissolved in a mixed solution of 20 ml of trifluoroacetic acid and 10 ml of methylene chloride and the mixture was stirred at the same temperature for 1.5 hours. The residue obtained by condensing the reaction mixture under reduced pressure was dissolved in ethyl acetate and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over anhydrous sodium sulfate. The viscous residue obtained by removing the solvent was crystallized from diethyl ether to obtain 1.23 g of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]1[CH2:44][CH2:43]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O1CCCC1.CCCCCC>[CH:42]1([N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=4)[CH2:31][CH2:32][CH2:33][CH2:34]3)[N:15]=2)=[O:13])[CH2:44][CH2:43]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (325) (100 mg, 0.16 mmol) in tetrahydrofuran was added 1N HCl (5 ml) at room temperature and stirring was continued for 30 min wile silica thin layer chromatography was performed (60% ethyl acetate in hexane; Rf=0.4). After completion of the reaction, solid NaHCO3 was added to the reaction mixture which was basified up to about pH 8 and extracted with ethyl acetate (3×30 mL). The combined extracts were dried and concentrated to get 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (326) as a brown sticky mass. This was used in the next step without purification.
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[CH2:14][CH2:15][CH2:16][CH3:17])(=O)C.Cl.[OH-].[Na+]>C(O)C>[CH2:14]([CH:6]1[C:5](=[O:4])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1oc2ccccc2c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1Oc2ccccc2C1=O
Temperature: 25 °C

Procedure:
4.6 g of 3-acetoxy-2-(n-butyl)benzofuran were dissolved in 20 ml of ethanol in a 100 ml flask, and 20 ml 6N hydrochloric acid were added. The mixture was heated to reflux for 4 hours. After cooling to room temperature, the pH was adjusted to 4 to 6 with sodium hydroxide, and the ethanol was distilled off. This was followed by extraction with dichloromethane. Drying of the combined organic phases over sodium sulphate and removal of the solvent resulted in 2.8 g (76% of theory) of 2-(n-butyl)-3(2H)-benzofuranone as yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]([OH:26])[C@@H:10]([C:23]([OH:25])=[O:24])[N:11]([CH3:22])[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1.[N+](=[CH2:31])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:31][O:24][C:23](=[O:25])[C@H:10]([CH:9]([OH:26])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:28][CH:27]=1)[N:11]([CH3:22])[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)O)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine (20.0 g) in ethyl acetate (100 ml) was added diazomethane in diethyl ether (80 ml). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was put on a silica gel column (MERCK 7734:500 g) and eluted with chloroform to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester. (threo isomer: 8.82 g, erythro isomer: 6.63 g)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]2[CH2:28][CH2:27][CH2:26][C:6]2=[N:7][C:8]=1[S:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)[S:14][CH:15]=1)#[N:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]2[CH2:28][CH2:27][CH2:26][C:6]2=[N:7][C:8]=1[S:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[S:14][CH:15]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2nc(CSc3nc4c(c(-c5ccccc5)c3C#N)CCC4)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1c(SCc2csc(-c3ccc(C(=O)O)cc3)n2)nc2c(c1-c1ccccc1)CCC2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
80 mg (0.17 mmol) of the compound from Example 13 were dissolved in 1.7 ml of dioxane, and 0.33 ml of a 1N aqueous sodium hydroxide solution were added. The reaction mixture was stirred at 50° C. for 3 h. 0.36 ml of 1N hydrochloric acid was then added to the mixture, and the resulting precipitate was filtered off, washed with water and dried.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=O)[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.[Zn]>[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=[C:21]([F:23])[F:22])[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: FC(F)(Br)Br
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C=O)cc2C1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C=C(F)F)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a stirred solution of 4.69 mmol triphenylphosphine in 5 ml DMF at 0° C. was added dropwise a solution of 4.69 mmol dibromodifluoromethane in 1 ml DMF and the mixture was stirred at RT for 30 min. 2.35 mmol 5-formyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester was then added at 0° C. and then 4.69 mmol zinc dust was added in small portions. The mixture was stirred at RT for 16 and then concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (31% yield). MS (m/e): 226.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:23])=[N:11][N:12]([CH3:22])[C:13]=1/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1>CO.[Pd]>[CH3:22][N:12]1[C:13](/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])=[C:9]([OH:8])[C:10]([CH3:23])=[N:11]1
Reactant: CO/C=C(/C(=O)OC)c1c(OCc2ccccc2)c(C)nn1C
Agent: [Pd]
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1c(O)c(C)nn1C
Yield: 949 %

Procedure:
To a solution of (E)-methyl 2-(4-benzyloxy-1,3-dimethylpyrazol-5-yl)-3-methoxyacrylate (56 g, 17.7 mmol) in methanol (560 ml) was subjected to hydrogenation in the presence of 5% powdered palladium/carbon (5.3 g). When the reaction completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue, when recrystallized from a solvent system of methanol/ethyl acetate/n-hexane, gave a purified (E)-methyl 2-(1,3-dimethyl-4-hydroxypyrazol-5-yl)-3-methoxyacrylate (38 g, yield 94.8 %). M.p.=172.7°-173.4 ° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:43]=[CH:44][CH:45]=1)[C:24]([NH:26][C:27]1[C:28]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]2)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=1)=[O:25].C(Cl)(Cl)(Cl)[Cl:47]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:43]=[CH:44][CH:45]=1)[C:24]([NH:26][C:27]1[C:28]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][Cl:47])[CH2:36][CH2:35]2)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=1)=[O:25]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CCO)CC1)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCl)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 0.76 g (10 mmol) of triphenylphosphine and 1.97 g (5.00 mmol) of the above amide in carbon tetrachloride (50 mL) is stirred overnight at room temperature. The solvent is concentrated, and the residue is purified by flash silica gel chromatography to provide 1.24 g (30%) of 3-chloro-N-[5′-chloro-4-(2-chloro-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a white solid.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:3]1=2.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:3]=2[CH:16]=1
Reactant: Fc1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C(N1CCNCC1)c1ccccc1CO2
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 15 g of 11-chloro-2-fluoro-6,11-dihydrodibenz[b,e]oxepin, which is prepared according to the procedure of Reference Example 1, in 300 ml of chloroform is added a solution of 25 g of anhydrous piperazine in 50 ml of chloroform at 0° C. After the temperature of the reaction mixture is raised to room temperature over 2 hours, it is added with 10% aqueous sodium hydroxide and extracted with chloroform. After the extract is washed with a saturated saline solution and dried over anhydrous potassium carbonate, the solvent is distilled off under reduced pressure. After the residue is added with 500 ml of toluene, an excess amount of piperazine is distilled off under reduced pressure to give 12 g of the objective compound as an oil. Mass spectrum m/z:298(M+).