Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:8])(C)(C)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43]C(O)=O)[CH:40]=[CH:39][C:37]=2[N:38]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)CCl>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][C@H:10]3[CH2:14][O:15][CH:16]3[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]3)=[O:8])[CH:40]=[CH:39][C:37]=2[N:38]=1
Reactant: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
In methylene chloride (20 ml), EDC(HCl (691 mg, 3.6 mmol) was added at 0° C. to methyl 4-(1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylate (580 mg, 2.4 mmol), 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (678 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol) and triethylamine (1.0 ml, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. Ice water (10 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous citric acid solution and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (1:2, v/v) eluate fractions, the title compound (500 mg, 48%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)[NH2:5].[S-:16][C:17]#[N:18].[NH4+].BrBr.N>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:7][C:6]2[S:16][C:17]([NH2:18])=[N:5][C:4]=2[CH:3]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OCC2CCCO2)c(Br)c1
Agent: BrBr
Agent: N
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.1 %

Procedure:
To a solution of ii (3.0 g, 11.62 mmol) in acetic acid (50 mL) was added ammonium thiocynate (4.18 g, 55.11 mmol) at RT. The resulting mixture was stirred at RT for 15 min followed by the addition of bromine (0.68 mL, 13.22 mmol) in acetic acid (5 mL). The mixture was stirred at RT for 5 h. The pH was adjusted to >7 with ammonia solution followed by extraction with EtOAc (2×200 mL). The combined organics were washed with H2O, brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified over silica (60% EtOAc-Hexanes) to obtain iii (1.0 g, 26%). 1HNMR (DMSO-d6, 400 MHz): δ 7.50 (s, 1H), 7.49 (s, 1H), 7.43 (br s, 2H), 4.18 (m, 1H), 3.96 (m, 2H), 3.80 (m, 1H), 3.69 (m, 1H), 1.96 (m, 2H) and 1.78 (m, 2H). MS: 329.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: Oc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a suspension of 3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (229 mg, 0.68 mmol) and K2CO3 (179 mg, 1.3 mmol) in acetonitrile (3.0 mL) was added methyl bromoacetate (85 μL, 0.90 mmol). The suspension was stirred at ambient temperature for 16 hours at which time HPLC analysis showed conversion to a product with a slightly longer retention time. The reaction suspension was filtered through a plug of Celite that was then washed thoroughly with EtOAc. The filtrate was concentrated to afford a pale yellow oil. This material was further purified by flash column chromatography eluting with a gradient from 0% to 28% EtOAc/hexane to afford methyl 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetate (158 mg, 57% yield) as an oil. MS(ES): 411 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C=O)C.CCOC(C)=O.C(Cl)Cl.CCCCCC>[CH3:1][C:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](=[O:7])[N:5]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:4](=[O:8])[NH:3]1
Reactant: CC(C)(C)OC(=O)CC1(C)NC(=O)NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1(C)NC(=O)N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.7 %

Procedure:
To a suspension of tert-butyl 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetate (100 mg, 0.44 mmol) in DMF (1 mL) was added potassium carbonate (121 mg, 0.88 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (112 mg, 0.48 mmol). The reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted with EtOAc (30 mL), and the solution washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude residue as a colorless oil. The crude residue was dissolved in DCM/hexane, charged to a 12 g silica gel cartridge which was eluted with a 15 min gradient from 0-100% EtOAc/hexane, followed by 10% MeOH/DCM over 10 min to give Compound 31a (102 mg, 75% yield). 1H NMR (400 MHz, CDCl3-d) δ 6.12 (br. s., 1H), 4.14 (q, J=8.5 Hz, 2H), 2.78-2.62 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([C:42]([OH:44])=O)[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:42]([C:37]2([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=3)[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:44])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)C1(c2ccc(F)cc2)CCCC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 1-(4-fluoro-phenyl)-cyclopentanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 1-(4-fluoro-phenyl)-cyclopentanecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 628.3 [M]+.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.Cl.CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O1CCOCC1.O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)=O
Reactant: COC=Cc1ccc(C(=O)OC)cc1
Agent: O=[Cr](=O)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(CC(=O)O)cc1
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a solution of methyl 4-(2-methoxyethenyl)benzoate (E9) (2.41 g, 12.5 mmol) in dioxane (50 ml) 1N water solution of HCl (40 ml) was added and the resultant mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate (3×50 ml), the organic extracts were combined, washed with brine (2×30 ml), and dried (Na2SO4). The solvents were evaporated, the residue was dissolved in acetone (70 ml) and cooled to −50° C. To the cold solution at this temperature slowly (ca. for 5 minutes) 2.67 M Jones reagent (CrO3/H2SO4; 7.5 ml, 20.0 mmol) was added and the obtained mixture was stirred at −40 to −50° C. for 1 hour and at −30° C. for 20 minutes. Isopropyl alcohol (2 ml) was added to the reaction mixture and the cooling bath was removed allowing the reaction to warm up for 10 minutes. The mixture was poured into water (150) and extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with brine (2×50), and dried (Na2SO4). The solvent was evaporated and the residue was dissolved in a small amount of hot dioxane (1-2 ml). Addition of petroleum ether (4-6 ml) caused the formation of a precipitate. The mixture was filtered and the precipitate was washed with dioxane-petroleum ether (1:4). The filtrate was evaporated and the precipitate formation procedure was repeated as described above. Then the filtrate was evaporated and the residue was chromatographed on silicagel (100 g) with petroleum ether-dioxane-acetic acid (2.5:7.5:0.1) to give the title compound (0.681 g, 28%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 3.68 (2H, s); 3.89 (3H, s); 7.33 (2H, d, J=8.2 Hz); 7.97 (2H, d, J=8.2 Hz); 10.82 (1H, br s).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([N:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17].C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl>[CH2:16]([N:18]1[C:19]2[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[CH:23][C:24]=2[S:25][C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:17]
Reactant: CCN1c2ccccc2Sc2ccccc21
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCN1c2ccccc2Sc2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
N-Methylformanilide (5.35 ml, 43.6 mmol) and phosphorus oxychloride (4.06 ml, 43.6 mmol) were added at room temperature to a mixture of 10-ethylphenothiazine (7.62 g, 33.5 mmol) and 1,2-dichlorobenzene (34 ml), and the mixture was stirred at 100° C. for 24 hours. At room temperature, a sodium acetate aqueous solution (45 wt. %, 85 g) was added to the reaction mixture, which was subsequently concentrated under a reduced pressure. Ethyl acetate and water (each 300 ml) were added to the resulting residue in that order and then the reaction product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give the title compound (5.91 g, 23.1 mmol, 69%) as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35](O)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35]([NH:19][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]
Reactant: CCCCCC(N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCCCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-n-hexylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogous to Example 1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:51][OH:52])[CH2:53][OH:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Reaction time: 0.5 h
Yield: 14 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 4k (7.9 g, 10.45 mmol) was dissolved in 50 mL of mixed solution (THF and MeOH, v:v=2:3), followed by addition of sodium borohydride (794 mg, 20.9 mmol). The reaction mixture was stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure after a small amount of acetone was added and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 4m (1.11 g, colourless grease), yield: 14.1%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>FC(F)(F)C(O)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2ccccc2o1)C1CCCCN1
Yield: 99 %

Procedure:
A solution of (RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine, D2 (0.86 g, 2.61 mmol) in trifluoroacetic acid (5 ml) and dichloromethane (20 ml) was warmed at 35° C. for 0.5 h. The reaction mixture was evaporated in vacuo and the residue partitioned between dichloromethane (30 ml) and 1N sodium hydroxide (30 ml). The aqueous layer was extracted with dichloromethane (30 ml) and the combined organic layers dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale yellow gum (0.59 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[N:5][N:6]2[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH:45]1([C:48](Cl)=[O:49])[CH2:47][CH2:46]1.O>O1CCCC1>[Br:1][C:2]1[C:10]([NH:11][C:48]([CH:45]2[CH2:47][CH2:46]2)=[O:49])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[N:5][N:6]2[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br)C1CC1

Procedure:
A total of 513 mg of 4-bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine obtained in Production Example II-21 was dissolved in 19 ml of tetrahydrofuran. Under ice-cooling and stirring, 0.261 ml of triethylamine and 0.089 ml of cyclopropanecarbonyl chloride were added, and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and, separated by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 471 mg of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[N:7]2[C:8]3[C:13]([NH:14][CH2:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCOC(=O)c1cnc2cnc3ccccc3n2c1=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1NC2
Reaction time: 5 h
Yield: 83.4 %

Procedure:
5.0 g of ethyl 1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate [Hermecz et al., J. Chem. Soc. Perkin I, 789 (1977)] were dissolved in 400 ml of ethyl acetate and 1.0 ml of HCl was added thereto followed by 300 mg of 5% Pd-C. The mixture obtained was hydrogenated for 5 hours at room temperature and atmospheric pressure. On completion of the reaction, the solution was made alkaline with NaHCO3 solution addition and filtered over celite. The organic phase was dried over MgSO4 and evaporated to dryness under nitrogen at 35° C. to obtain 4.2 g (83% yield) of ethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate melting at≃170° C.
Reaction SMILES: C(O[CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=O)C.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:5]=[CH:18][C:17]([OH:20])=[O:19]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(OC(C)=O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1cccc(Cl)c1
Temperature: 200 °C

Procedure:
A three-neck flask was charged with 24.26 g of m-chlorobenzylidene diacetate and 6.15 g of sodium acetate, and the mixture was refluxed in a 200° C. oil bath for 9 hours. The mixture was cooled, and 100 g of ethyl acetate was added. Furthermore, saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was sufficiently stirred, to produce m-chlorocinnamic acid which was extracted into a water phase. The water phase was separated, and hydrochloric acid was added till the pH became 2, to precipitate m-chlorocinnamic acid which was secured by filtration. It was washed by water sufficiently and dried in vacuum at 60° C. for 8 hours, being weighed. The purity of the obtained product was analyzed by high performance liquid chromatography. The m-chlorocinnamic acid yield and m-chlorobenzylidene diacetate conversion were obtained from the following formulae:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccoc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccoc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (587 mg) and crude 3-bromoacetylfuran (2.00 g, ca. 4.5 mmol, based on purity ca. 40% by 1H n.m.r; contaminated with 3-dibromoacetylfuran and diethyl ether) in triethylamine (0.95 ml) and ethanol (25 ml) was stirred at room temperature. After 45 min with solvent was removed and the residue triturated with ethyl acetate. The resulting solid was collected and retriturated with water. This gave a buff solid which was crystallised from ethyl acetate to give the title pyrimidinone (335 mg), m.p. 195°-197° C. (dec), λmax (EtOH) 333 nm (ε 2,530).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C1C=CC=CC=1>ClCCl.C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: Cn1ccc(=O)c(O)c1C(O)c1ccccn1

Procedure:
3-Benzyloxy-2-(hydrox-pyridin-2-yl-methyl-1-methyl-1H-pyridin-4-one: From 2.5 g of 3-benzyloxy-1-methyl-2-[pyridin-2-yl-(tetrahydropyran-2-yloxy)-methyl]-1H-pyridin-4-one there is obtained analogously to Example 7b: 3-benzyloxy-2-(hydroxy-pyridin-2-yl-methyl)-1-methyl-1H-pyridin-4-one. Yellow resin. Rf value: 0.52 (silica gel 60, dichloromethane/ethanol 4/1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]#[N:37])=[CH:4][CH:3]=1.[OH-:38].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[C:36]([NH2:37])=[O:38])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C#N)C1)c1cccnc1CO2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3)C(C(N)=O)C1)c1cccnc1CO2
Temperature: 80 °C

Procedure:
To a solution of 1-(4-chloro-phenyl)-4-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-piperazine-2-carbonitrile (0.12 g, 0.23 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added 1.0 N NaOH (0.5 mL, 0.5 mmol) and the resulting mixture was heated to reflux at 80° C. for 18 h. Additional 2.0 N NaOH (0.5 mL, 0.5 mmol) was added to the reaction mixture and refluxed further for 18 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate and concentrated. The crude product was purified on a short plug of silica gel using gradient elution from ethyl acetate/methanol (2–10%) to give the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1ccc(COCCOc2ccc(C3CCCCC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1ccc(C2CCCCC2)cc1
Yield: 103 %

Procedure:
1-[2-(Benzyloxy)ethoxy]-4-cyclohexylbenzene (3.2 g) was dissolved in ethanol (100 mL). The resulting solution was added with 20% palladium hydroxide (300 mg) and then stirred in a hydrogen atmosphere at room temperature for 25 hours. The catalyst was filtered off, and washed with ethyl acetate. The filtrate was evaporated, and the residue was azeotroped with toluene (×2) to give the title compound as a colorless solid (2.34 g).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.O=[C:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>Cl>[CH2:22]([C:16]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:23]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCc1cccc2c(CCO)c[nH]c12
Agent: Cl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 27.5 °C
Reaction time: 7 h
Yield: 76.9 %

Procedure:
To a solution of 7-ethyltryptophol (12.0 g) in 1-butanolic hydrogen chloride (5% w/v, 100.0 ml), methyl 3-oxopentanoate (9.1 g) was added in one lot, at 25° C. The reaction mixture was stirred at 25-30° C. for 7 hours. The reaction mixture was extracted with hexane (100.0 ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the titled compound (14.7 g, 79%), m.p. 128-130° C.; purity: 96.2%.