Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][CH:6]=1.[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
2-Chloro-5-acetylthiophene (80.3 g, 0.5 mol) was added in portions to fuming nitric acid (500 mL) cooled to −5° C. with an ice/methanol bath. On completion of addition the reaction was removed from the cold bath and stirred at ambient temperature for 30 minutes before the reaction mixture was poured into ice water (4 L). After stirring for 10 minutes the solid which formed was collected by filtration and washed with water (500 mL). The solid was then dissolved in dichloromethane (500 mL) the water was separated and the organic solution was dried (MgSO4). Removal of the solvent under reduced pressure gave an orange solid. The crude material was re-crystallized from IMS (350 mL) to give the title product as a light brown solid (46.89 g, 45% yield). 1H NMR (CDCl3) δ: 8.07 (1H, s), 2.58 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[N:5]=[C:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[NH:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=Nc1cccc(Cl)c1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(Nc1cccc(Cl)c1)c1ccccc1

Procedure:
m-Chloro-N-(α-methyl benzylidene) aniline (XIX) (24 g) prepared by the procedure described in example XXVIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. m-Chloro-N-(α-methyl benzyl) aniline (XX) was obtained by fractional distillation. XX had a boiling point of 133° C. at 0.15 millimeter.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:29][C:30]([O:32][CH:33](I)[CH3:34])=[O:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:27]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCOC(=O)OC(C)I
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCOC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 93.4 %

Procedure:
In the same manner as in Example 81, 167 mg of the title compound was prepared from 145 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 148 mg of 1-(ethoxycarbonyloxy)ethyl iodide.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>C(O)C>[F:22][C:21]1[C:16]2[N:13]=[C:12]([CH2:11][C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[C:8]([CH3:10])[CH:7]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Cc1cc(CC#N)cc(CC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Product: Cc1cc(CC#N)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 32.9 %

Procedure:
A solution of 1,3-biscyanomethyl-5-methylbenzene (2.89 g, 17 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (3.66 g, 17 mmol) in absolute ethanol was heated at 170° C. for 15 hours under a nitrogen stream in an autoclave. After the reaction, evaporation of the solvent left a residue, which was purified on a silica gel column and recrystallized from ethyl acetate-hexane to obtain 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylacetonitrile (1.86 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([N:22]([CH2:29][CH3:30])[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:15]([CH3:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C=O)C.O>[CH3:72][C:71]1[CH:70]=[C:69]([CH3:73])[NH:68][C:67](=[O:74])[C:66]=1[CH2:65][NH:64][C:17]([C:16]1[CH:20]=[C:12]([CH:10]2[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:13]=[C:14]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]=1[CH3:21])=[O:19]
Reactant: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 5-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoic acid (54 mg, 0.13 mmol) in DMF (2 ml) and the reaction was cooled using an ice bath followed by the addition of DIPEA (45 μl, 0.26 mmol) and HATU (59 mg, 0.15 mmol)). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 24 mg, 0.14 mmol) was added and the reaction was warmed room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water and the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4), filtered and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 2.5% MeOH in DCM and evaporated to afford tert-butyl 3-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)azetidine-1-carboxylate as a colourless oil (29 mg). LC-MS 90%, m/z=553.3. This material was dissolved in 4M HCl in dioxane solution (3 ml) and stirred at room temperature for 90 min after which the solvent was evaporated to dryness and the compound purified by preparative HPLC to afford the title compound as a white solid (11 mg, 8% over 2 steps). LC-MS 97%, 2.17 min (7 minute LC-MS method), m/z=453.2, 1H NMR (500 MHz, MeOD) δ 7.26 (s, 1H), 7.18 (s, 1H), 6.14 (s, 1H), 4.48 (s, 2H), 4.39 (s, 2H), 4.22 (s, 3H), 3.93 (d, J=10.5 Hz, 2H), 3.40-3.33 (m, 2H), 3.29-2.90 (m, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 1.68 (d, J=26.3 Hz, 4H), 0.87 (s, 3H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.O>ClCCl>[CH3:9][S:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCCCCO
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
This example illustrates a synthesis of 1-(6,7-Oxidoheptyl)-3,7-dimethylxanthine (inventive compound no. 1586). To a solution of 6-hepten-1-ol (6.00 g, 52.6 mmol) in dichloromethane (120 mL) at 0° C. was added methanesulfonyl chloride (6.07 g, 4.0 mL, 53.0 mmol), followed by triethylamine (7.79 g, 77.0 mmol). After stirring for 10 minutes at 0° C., the reaction was allowed to warm to 25° C. and then stirred for 2 hours. The reaction was poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The organic portions were combined, dried over magnesium sulfate, and evaporated to give the 7-methanesulfonyl-1-heptene as a yellow oil (9.30 g, 93%), which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH2:13]([S:20][C:21]1[NH:22][C:23]([CH3:28])([CH3:27])[C:24](=[S:26])[N:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([S:20][C:21]1[N:25]=[C:24]([S:26][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]([CH3:12])[CH3:2])[C:23]([CH3:28])([CH3:27])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC1(C)NC(SCc2ccccc2)=NC1=S
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSC1=NC(SCc2ccccc2)=NC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 0.65 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 0.7 g of 2-benzylthio-5,5-dimethylimidazolin-4-thione in 20 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for one hour, and concentrated in vacuo. The residue was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization from diethyl ether-n-hexane gave 2-benzylthio-4-(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole in the form of a needle-like crystal. The yield of this compound was 0.75 g with a yield ratio of 72.2%, and the melting point was 91°-92° C.
Reaction SMILES: [CH3:1][C:2]1([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.C[N+]1([O-])CCOCC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][C:2]1([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[O:3][CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][O:7]1
Reactant: CC1(C)COC(C)(C2CCC(O)CC2)OC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC1(C)COC(C)(C2CCC(=O)CC2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
TPAP (161 mg, 0.05 eq.) was added to a solution of 4-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-cyclohexanol (2.22 g, 1 eq.) and NMO (2.28 g, 2 eq.) in MeCN (65 mL). The reaction mixture was stirred at room temperature overnight. Saturated aqueous solution of Na2S2O3 was added to the mixture and the resulting mixture was stirred vigorously for 15 minutes. The separated aqueous phase was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered through Celite and concentrated. The crude product was purified by silica gel column chromatography (25% to 50% EtOAc/hexanes) to give 4-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-cyclohexanone (1.87 g, 85%).
Reaction SMILES: Br[CH:2]=[C:3]([CH3:5])[CH3:4].[Mg].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:14].[Cl-].[NH4+]>O1CCCC1>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)([OH:14])[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CBr
Reactant: COc1ccccc1C(=O)c1ccccn1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(C=C(C)C)c1ccccn1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
43.84 g of 1-bromo-2-methylprop-1-ene in 150 ml of tetrahydrofuran were added dropwise to 9.8 g of magnesium in 50 ml of tetrahydrofuran while heating at reflux. After 1 hour the mixture was allowed to cool to room temperature, whereupon 47.7 g of 2-methoxyphenyl 2-pyridyl ketone in 200 ml of tetrahydrofuran were added slowly. After stirring for 2 hours at room temperature 200 ml of saturated ammonium chloride were added and the mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:6) followed by ethyl acetate/petroleum ethyl (1:4) for the elution to yield 36.6 g of 1-(2-methoxyphenyl)-3-methyl-1-(2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])=[O:8])=[CH:22][CH:23]=1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 6.5 g (0.03 mole) of 2,6-dichloro-benzoylisocyanate in 20 ml of toluene was added to 5.4 g (0.03 mole) of 4-trifluoromethoxy-aniline dissolved in 80 ml of toluene at 60° C. The batch was stirred for two hours at 80° C, a part of the solvent was distilled off in vacuo and the product which had precipitated was filtered off. After drying, 10 g (84.5% of theory) of analytically pure N-(4-trifluoromethoxyphenyl)-N'-(2,6-dichlorobenzoyl)-urea of melting point 202° C were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].Cl.[CH2:25]([CH:32]1[C:37]2[N:38]=[C:39]([C:42]([F:45])([F:44])[F:43])[N:40]=[CH:41][C:36]=2[CH2:35][CH2:34][NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl.CN1CCOCC1>C(#N)C>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:33]1[CH2:34][CH2:35][C:36]2[CH:41]=[N:40][C:39]([C:42]([F:45])([F:43])[F:44])=[N:38][C:37]=2[CH:32]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1ncc2c(n1)C(Cc1ccccc1)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cnc(C(F)(F)F)nc2C1Cc1ccccc1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 115.4 %

Procedure:
A mixture of 133 mg (0.40 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid and 162 mg (0.50 mmol) of 8-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, hydrochloride in 1.5 mL of acetonitrile at 0° C. was treated sequentially with 81 mg (0.42 mmol) of EDC and 0.047 mL (0.42 mmol) of N-methyl morpholine. After 10 min, the mixture was warmed to ambient temperature and stirred for 3 h, then partitioned between 10 mL of ethyl acetate and 4 mL of water. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried and concentrated to give 281 mg of the title compound as a mixture of diastereomers. Purification by flash chromatography (silica gel, 10 to 35% ethyl acetate/hexane) followed by HPLC on a Chiralpak AD column (9% ethanol/hexane) gave 51 mg of the faster eluting isomer and 47 mg of the slower eluting isomer.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br>O1CCCC1.CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrCc1cccc(Br)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Reaction time: 0.25 h

Procedure:
Sodium hydride (60%, 1.6 g) was suspended into 20 ml of dry tetrahydrofuran/15 ml of dry N,N-dimethyl formamide, and 7.6 ml of diethyl malonate was added dropwise under ice-cooling. The mixture was stirred for 15 minutes. A solution of 5 g of 3-bromobenzyl bromide/10 ml of dry tetrahydrofuran was then added, and stirred for 1 hour under ice-cooling. To the reaction solution was added ice-cold water, and extracted with ether, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=10:1) to provide 5.41 g of the objective compound as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:34][CH3:35])=[CH:20][C:21]([CH:23](OC(=O)C)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CO>C1COCC1.[Pd]>[CH2:23]([C:21]1[CH:20]=[C:19]([O:34][CH3:35])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[N:11][C:12]=2[CH:22]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Yield: 91.3 %

Procedure:
A solution of 150 mg (0.317 mmol) acetic acid[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methyl ester in 8 ml THF:MeOH=1:2 is hydrogenated in the presence of 50 mg Pd/C (Engelhard 4505). Then the catalyst is filtered off and the filtrate is concentrated in vacuo to afford 120 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])[CH3:16]>>[C:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13])(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccc1N
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1C(C)=O

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-acetylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:24]>C(Cl)(Cl)Cl>[Br:24][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2α, 3α-Epoxy-5α-pregnan-20-one (356 mg.) was dissolved in chloroform (20 ml.) and hydrobromic acid (48%, 7 ml.) was added. The mixture was stirred at room temperature for 30 minutes and then poured into chloroform (100 ml.). The organic solution was washed with dilute sodium bicarbonate solution and with water, then dried over sodium sulphate and evaporated to give a crystalline residue which was recrystallised from ethyl acetate containing some ether to give title compound (144 mg.) as colourless needles m.p. 171°-175°, [α]D + 117°.
Reaction SMILES: C([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[C:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14])C1C=CC=CC=1.CO.[OH-].[Na+].Cl>O>[CH2:15]([C:13](=[CH2:14])[C:12]([NH:11][CH2:10][C:9]([OH:23])=[O:8])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)O

Procedure:
2.10 (6.8 mmoles) of N-(2-benzyl propenoyl-glycine benzyl ester, M.P. =60° C, are stirred at 10° C. for 2 hours with a mixture of 30 ml of methanol and 0.27 g of NaOH (6.8 mmoles), dissolved in 5 ml of water. The pH is brought to 1 by the addition of 2N HCl and the material is extracted with ethyl acetate. The solvent is washed with 2×20 ml of water, dried and evaporated under a vacuum. 1.36 g of crystals are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:17]=O.CO.[C:21]([O:25][CH3:26])(=[O:24])[NH:22][NH2:23]>C(O)(=O)C>[CH3:26][O:25][C:21](=[O:24])[NH:22][N:23]=[CH:17][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1]
Reactant: COC(=O)NN
Reactant: Cc1[nH]c(-c2cccc(C(F)(F)F)c2)nc1C=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)NN=Cc1nc(-c2cccc(C(F)(F)F)c2)[nH]c1C
Yield: 90.1 %

Procedure:
A mixture of 5-methyl-2-(α,α,α-trifluoro-m-tolyl)imidazole-4-carboxaldehyde (20.0 g, 0.0787 mole), methanol (500 ml), methyl carbazate (7.8 g) and glacial acetic acid (0.5 ml) is refluxed overnight. The solution is then concentrated to afford 23.14 g of title product. A sample is recrystallized from methanol-acetone, m.p. 251°-251.5° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:22][CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Product: O=CC=Cc1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18](I)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(OC([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[ClH:49].O1CCOCC1>COCCOC.O.C(Cl)Cl.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]>[ClH:49].[ClH:49].[ClH:49].[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:31]5[CH2:32][CH2:33][NH:28][CH2:29][CH:30]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Ic1cc2c(Nc3ccc4ncsc4c3)ncnc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of benzothiazol-6-yl-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (4.05 g, 10.3 mmol) in 1,2-dimethoxyethane (125 mL) and water (25 mL) were added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.50 g, 11.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II), complex with dichloromethane (1:1) (420 mg, 0.51 mmol) and potassium carbonate (2.85 g, 20.6 mmol). The flask was evacuated and refilled with N2 (3×). The mixture was heated at 80° C. overnight. The reaction mixture was diluted with EtOAc (200 mL) and water (50 mL) and filtered through a pad of celite. The organic phase was separated, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (100 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded a brown solid. To a suspension of this crude material in methylene chloride (30 mL) was added 4M HCl/1,4-dioxane (30 mL), and the resulting mixture was stirred at rt overnight. The mixture was diluted with CH2Cl2 (30 mL), and the light-yellow solid was collected by filtration and dried in vacuo to give the title compound. LC-MS (ES, Pos.): 349 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=2.51 (m, 2H), 3.34 (m, 2H), 3.81 (m, 2H), 6.52 (s, 1H), 7.09 (s, 1H), 7.73 (dd, J=8.7 Hz, 2.0 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 9.46 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1.00 g (5.15 mmol) of 4-(4-methoxyphenyl)butyric acid in 100 mL of dichloromethane at 0° C. was added 15.5 mL (15.5 mmol) of boron tribromide and the reaction was then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then poured into 200 mL of saturated sodium bicarbonate solution and the organic layer was separated. The aqueous layer was acidified with concentrated HCl solution and then extracted with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide 0.696 g of impure 4-(4-hydroxyphenyl)butyric acid.