Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([S:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:42])[CH:35]([CH3:41])[CH2:36][C:37]([O:39]C)=[O:38])=[CH:30][CH:29]=3)[CH:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:45][CH2:46][CH3:47])[C:5]=1[OH:48])(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[OH2:3].[C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([S:27][C:28]3[CH:29]=[CH:30][C:31]([C:34](=[O:42])[CH:35]([CH3:41])[CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:33]=3)[CH:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:45][CH2:46][CH3:47])[C:5]=1[OH:48])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(Sc3ccc(C(=O)C(C)CC(=O)OC)cc3)C(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCSc2ccc(C(Sc3ccc(C(=O)C(C)CC(=O)O)cc3)C(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of ester from Step A of this Example (760 mg) in THF (15 ml) and MeOH (1 ml) was added 2N NaOH (2.4 ml) and stirred overnight at room temperature. The reaction mixture was diluted with H2O (50 ml) and acidified with 2N HCl and extracted with CH2Cl2 (2×50 ml). The combined organic layers were washed with brine, dried over Na2SO4 and purified on a column of flash silica gel 230-400 mesh using toluene-dioxane-acetic acid (10:2:0.1) as eluant to give the title compound as a foam (580 mg, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[S:25][C:15]=3[N:16]=2)=[CH:20][CH:21]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: S(=O)(=O)(O)O.C1CO[C:8]([CH3:24])([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:21](=O)[CH3:22])[CH2:17][CH2:18][C:19]#[N:20])=[CH:12][CH:11]=2)[O:7]1.[OH2:27]>C(O)(=O)C>[CH2:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]=2[CH3:22])=[CH:12][CH:11]=1)[C:8]([CH3:24])=[O:7]
Reactant: CC(=O)C(CCC#N)c1ccc(CC2(C)OCCO2)cc1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Cc1ccc(C2=C(C)NC(=O)CC2)cc1
Reaction time: 72 h

Procedure:
Concentrated sulphuric acid (5 ml) was added dropwise to a solution of 4-(4-(2,2-(ethylenedioxy)propyl)phenyl)-5-oxo-hexane nitrile (3.09 g) in glacial acetic acid (21 ml). The orange solution was allowed to stand at room temperature for 3 days then poured into water and allowed to stand for 2 hr. The solution was extracted with chloroform, the organic layer separated, washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to an oil (2.44 g) which was chromatographed on silica. Elution with chloroform gave 3,4-dihydro-5-(4-acetonylphenyl)-6-methyl-2(1H)-pyridone as an oil.
Reaction SMILES: C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.[C:22]([S:26]/[CH:27]=[CH:28]/[C:29](=[O:31])[CH3:30])([CH3:25])([CH3:24])[CH3:23].CSC.C1(C)C=CC=CC=1.[Cl-].[NH4+]>>[C:22]([S:26]/[CH:27]=[CH:28]/[C@H:29]([OH:31])[CH3:30])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)/C=C/SC(C)(C)C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: Cc1ccccc1
Product: C[C@@H](O)/C=C/SC(C)(C)C
Reaction time: 2 h

Procedure:
(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2] oxazaborol (28 mg, 0.1 mmol) and MS4A (Nacalai Tesque Inc., 500 mg) were dried by a vacuum pump, followed by substituting with an argon gas. To this mixture, (E)-4-(tert-butylthio)-3-buten-2-one (158 mg, 1.0 mmol) and dimethylsulfide (0.22 ml, 3.0 mmol) were added, which were then washed into the mixture with dry toluene (5 ml). After ice cooling, a solution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, an aqueous saturated ammonium chloride solution was added, followed by filtering through a cotton plug. The filtrate was washed with ethyl acetate and, after separating an aqueous layer, the ethyl acetate layer was washed with 2NHCl, water, an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the extract containing the titled compound as a main component was obtained by concentrating under a reduced pressure. The NMR chemical shifts of the titled compound are as follows. Further, the HPLC analytical results are shown in Table V.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH2:12](Br)[CH2:13][OH:14].[OH-].[Na+]>>[C:1]1([S:7]([CH2:12][CH2:13][OH:14])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCBr
Reactant: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(CCO)c1ccccc1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
1,000 ml of an aqueous solution containing 509 g (2.16 mol) of sodium benzenesulfonate (dihydrate) was heated to 80°-90° C. and stirred. To this solution were added at the same time 539 g (4.31 mol) of ethylenebromohydrin and 100 ml of an aqueous solution containing 45 g of sodium hydroxide while maintaining the pH of the reaction solution at 7-8. After the addition was completed, the reaction solution was further stirred for 2 hours at 80°-90° C. and then cooled to room temperature. Then, the reaction solution was extracted with ethyl acetate. The ethyl acetate was concentrated and distilled off under reduced pressure to yield 113 g of the desired product having a boiling point of 172 to 174° C./0.4 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:12](=O)[CH2:13][CH3:14]>C(O)C>[CH2:12]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH2:13][CH3:14]
Reactant: Nc1cccc2ncccc12
Reactant: CCC=O
Solvent: CCO
Product: CCCNc1cccc2ncccc12
Reaction time: 0.25 h

Procedure:
5 g of 5-aminoquinoline, 3 ml of propionaldehyde and 4.7 g of para-thiocresol are dissolved in 100 ml of ethanol in a 250 ml round-bottomed flask. The reaction mixture is heated at reflux for 2 hours and then evaporated to dryness. The residue is dissolved in 100 ml of ethanol and cooled in an ice bath and then 6.5 g of sodium borohydride are added portionwise. When addition is complete, the reaction mixture is heated at reflux for 2 hours and then, successively, 30 ml of water are added, the mixture is basified with 20 ml of concentrated sodium hydroxide and stirred for 15 minutes and the organic solvents are evaporated. Extraction is carried out with dichloromethane and the organic phase is washed with water and then dried over sodium sulphate. The organic phase is evaporated to dryness and the residue is purified on a column of silica gel, eluent: ethyl acetate, to obtain 4 g of an oil which crystallizes. 1H NMR (CDCl3): 1.05 (t, J=3H, --CH3), 1.82-1.71 (m, 2H, --CH2 --CH3), 3.15-3.26 (m, 2H, --NH--CH2 --), 4.37 (sl, 1H, --NH--), 6.61 (dd, J=1.0, J=8.6, 1H, H4), 7.26 (dd, J=4.2, J=8.6, 1H, H6), 7.44-7.59 (m, 2H, H3, H2), 8.12 (dd, J=0.95, J=8.6, 1H, H8), 8.84 (dd, J=1.5, J=4.2, H2).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([O:19]/[C:20](/[C:29]([O:31]CC)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.O[Li].O>C1COCC1.O>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1/[CH:21]=[C:20](\[O:19][C@@H:8]1[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([CH2:34][OH:35])[O:7]1)/[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The ester C4 (20 mg, 0.037 mmol) was dissolved in THF (0.4 mL) and added a solution of LiOH H2O (8.86 mg, 0.37 mmol) in water (0.3 mL). The reaction mixture was stirred at room temperature for one hour and then acidified until pH<3 with Dowex 50-X8 resin, filtered and concentrated, and the residue was purified by preparative HPLC using acetonitrile-water as an eluent. After freeze drying, the final product was isolated in 87% yield: 1H NMR (400 MHz, MeOH-d4): δ 8.31 (t, J=7.1 Hz, 1H), 7.24 (dd, J=13.6, 5.8 Hz, 1H), 7.14 (s, 1H), 7.07 (t, J=7.6 Hz, 1H), 7.03-6.96 (m, 1H), 5.17 (d, J=7.4 Hz, 1H), 3.66 (dd, J=12.0, 2.2 Hz, 1H), 3.52 (dd, J=12.0, 5.2 Hz, 1H), 3.41-3.23 (m, 3H), 3.17-3.11 (m, 1H); 13C NMR (101 MHz, MeOH-d4): δ 166.72, 161.83 (d, 1JC,F=249.7 Hz), 144.28, 132.66, 131.71, 125.15, 122.48, 115.93 (d, 1C), 115.78 (d, 1C), 102.66, 78.59, 78.07, 75.64, 71.35, 62.50; ESI-HRMS m/z: calcd for C15H17FO8Na+: 367.0800. found 367.0800.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: C1CCNC1
Reactant: CCc1cc(Br)ccc1CBr
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CN1CCCC1
Reaction time: 15 h
Yield: 67.4 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (2.00 g, 7.19 mmol) in CH2Cl2 (30 mL) was added dropwise pyrrolidine (1.19 mL, 14.4 mmol). The mixture was stirred for 15 hours, and then partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated to yield a yellow oil (1.3 g, 68%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 1.76 (m, 4 H), 2.47 (m, 4 H), 2.69 (q, J=7.5 Hz, 2 H), 3.54 (s, 2 H), 7.19 (m, 1 H), 7.25 (m, 1 H), 7.29 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].O.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[CH:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCO
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(C=O)o1

Procedure:
To a solution of 5-formyl-2-furancarboxylic acid (0.5 g) in ethanol (35 ml), sulfuric acid (3.5 ml) was added at 0° C. and the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.5316 g of the desired product.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[S:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1ccsc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccsc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with thiophene-3-carbaldehyde (0.5 g, 4.5 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.077 g, 63%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].Cl.CN(C)CCCN=C=NCC.[F:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][CH2:33][C:34](O)=[O:35])[S:31][C:27]=2[C:26]([F:37])=[CH:25][C:24]=1[F:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][N:7]([C:34](=[O:35])[CH2:33][CH2:32][C:30]1[S:31][C:27]2[C:26]([F:37])=[CH:25][C:24]([F:38])=[C:23]([F:22])[C:28]=2[N:29]=1)[CH3:8])[CH3:3]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To methylene chloride (10 ml) was added sarcosine ethyl ester hydrochloride (307 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC.HCl; 422 mg, 2.2 mmol), 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) and triethylamine (220 mg, 2.2 mmol), and the mixture was stirred at room temperature for 15 hours. The resulting mixture was washed with water, dried and evaporated to yield a residue, which was purified on a silica gel column to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (610 mg, 85%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-tert-butylbenzyl bromide (4 {20}, 4.05 mL, 22.0 mmol, 1 equiv.), piperazine (11.4 g, 132.1 mmol, 6 equiv.), THF (48.1 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{20} (3.75 g, 73%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 7.30 (d, 2H, J=8.5 Hz), 7.22 (d, 2H, J=8.5 Hz), 3.44 (s, 2H), 2.85 (t, 4H, J=5.0 Hz), 2.38 (br s, 4H), 1.54 (br s, 1H), 1.29 (s, 9H). 13C-NMR (125 MHz, CDCl3): δ 149.6, 134.7, 128.7, 124.8, 63.1, 54.3, 45.9, 34.2, 31.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:39]([F:44])([F:43])[CH2:40][CH2:41][CH3:42])[CH2:13][CH2:14][CH2:15][C@H:16]1[C@H:20]([OH:21])[CH2:19][C@H:18]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:17]1[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[F:44][C:39]([F:43])([CH2:40][CH2:41][CH3:42])[C:12](=[O:11])[CH2:13][CH2:14][CH2:15][C@H:16]1[C:20](=[O:21])[CH2:19][C@H:18]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:17]1[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC(F)(F)C(=O)CCC[C@H]1C(=O)C[C@H](OC2CCCCO2)[C@@H]1C/C=C\CCCC(=O)OC
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (0.24 ml) in methylene chloride was cooled to -78° C., followed by addition of DMSO (0.44 ml). After 15 minutes, a solution of the diol (41) (0.358 g) in methylene chloride was added dropwise to the resultant mixture. After 30 minutes, the mixture was warmed to -50° C., followed by stirring for 1.5 hours. Then, the reaction mixture was allowed to warm to -35° C. and triethylamine (0.88 ml) was added thereto. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the diketone (42).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=1)[NH:25][CH2:24][CH2:23][CH2:22]3)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=1)[N:25]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:24][CH2:23][CH2:22]3)=[O:16]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Product: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 92 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 92% of theory; LC (method 1): tR=2.57 min; Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [C:1]([N:4]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][C:19]=2[CH2:28][NH:29][CH3:30])[CH2:14][CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([O:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:13][CH2:14]2)=[C:19]([CH2:28][NH:29][CH3:30])[CH:20]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1
Product: CNCc1cc(CCCOC(C)=O)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1

Procedure:
from trans-N-acetyl-N-benzyl-4-[4-(3-hydroxypropyl)-methylaminomethylphenyl]cyclohexylamine and acetylchloride. Oil. Rf value: 0.67 (alumina, ethyl acetate/petroleum ether=1:1, v:v).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1
Reactant: CCOC(=O)CC1(C)C=Cc2c(C)cc(C)c(C)c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(C)CCc2c(C)cc(C)c(C)c2O1
Yield: 92.9 %

Procedure:
A solution of ethyl (2,5,7,8-tetramethyl-2H-chromen-2-yl)acetate (20.00 g) in methanol (MeOH) (300 ml) was hydrogenated in the presence of 10% palladium on carbon (50% wet, 4.0 g) in one atmosphere of hydrogen at room temperature for 16 hours. The catalyst was filtered off and MeOH was removed under reduced pressure to give a residue. The residue was purified by chromatography over silica gel (AcOEt-hexane 3:97 as eluent) to give ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate as an oil (18.72 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([Cl:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-Dibenzyloxyphenylacetic acid [IX] (1.4 g) was dissolved in anhydrous benzene (30 ml) and then thereto was added thionyl chloride (5 g) and the mixture was left to stand at room temperature (20° C.) for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude 2,4-dibenzyloxyphenylacetyl chloride [X]. This was used for the subsequent reaction without purification.
Reaction SMILES: [OH-].[K+].Br[CH:4]([CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:5]([OH:7])=[O:6]>C(O)C>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]#[C:4][C:5]([OH:7])=[O:6]
Reactant: Cc1ccccc1C(Br)C(Br)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C#CC(=O)O
Yield: 54.2 %

Procedure:
To a suspension of 35.5 g of KOH in ethanol (250 ml) there were added 51.0 g (158.9 mmol) of 2,3-dibromo-3-tol-2-ylpropionic acid portionwise over a period of 30 min. The mixture was then heated under reflux over a period of 4 h. Following removal of the solvent in vacuo, the residue was taken up in 10% strength hydrochloric acid. The solution was washed with EA and then set to pH>10 with a 6N aq. NaOH solution. The mixture was then extracted with EA and the organic phase was dried over MgSO4. Following filtration and the removal of solvent in vacuo, there were obtained 13.8 g (86.2 mmol, 54%) of tol-2-ylpropiolic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12]C(=O)C)[CH3:11])[N:7]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: CC(=O)N[C@@H](C)c1nc2ccc(F)cc2n1-c1cccnc1
Agent: Cl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A mixture of N—[(S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethyl]acetamide (126 mg) and 6N HCl (2 mL) was heated at 100° C. in a sealed vial for 1 h. After cooling to RT, the crude reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo to afford 10 mg of crude material as an orange oil. The aqueous phase was re-extracted with DCM (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 71 mg of crude material as a colourless oil. The crude materials were combined to afford the title compound as a pale orange oil (81 mg, 75%). 1H NMR (CDCl3, 400 MHz): δ 8.82 (1H, d, J=5.43 Hz), 8.75 (1H, s), 7.83 (1H, d, J=8.06 Hz), 7.73 (1H, dd, J=8.85, 4.75 Hz), 7.61-7.56 (1H, m), 7.06 (1H, t, J=9.26 Hz), 6.77 (1H, d, J=8.49 Hz), 4.14-4.04 (1H, m), 1.50 (3H, d, J=6.65 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:27]1[S:28][C:29]([CH2:33]OC)=[C:30]([CH3:32])[N:31]=1.ClC1C=C(Cl)C=CC=1C(N)=S.ClC(C(C)=O)C(OCC)=O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][C:29]2[S:28][C:27]([C:21]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=3[Cl:19])=[N:31][C:30]=2[CH3:32])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: COCc1sc(-c2ccc(Cl)cc2Cl)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3Cl)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-(2,4-dichloro-phenyl)-5-methoxymethyl-4-methyl-thiazole (prepared from 2,4-dichloro-thiobenzamide and ethyl 2-chloro-acetoacetate in analogy to the procedures described in examples 33 a] and 33 b]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-3-{4-[2-(2,4-dichloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless liquid.