Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[NH2:13][C:14]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:15]([NH2:17])=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:15]([C:14]([N:13]=[CH:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([CH3:21])[CH:18]([CH3:20])[CH3:19])(=[O:16])[NH2:17]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: COC(=O)c1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1C=NC(C)(C(N)=O)C(C)C
Reaction time: 3 h

Procedure:
A mixture containing 5.0 g methyl 2-formylbenzoate [C. Brown and M. V. Sargent, J. Chem. Soc. (C), 1818 (1969)] and 4.0 g 2-amino-2,3-dimethylbutyramide and 50 mg p-toluenesulfonic acid in 100 mL toluene is heated under reflux under a Dean-Stark water separator for three hours. The mixture is filtered and concentrated in vacuo. The residue crystallizes on standing and is recrystallized from etherhexane to give analytically pure methyl o-[N-(1-carbamoyl-1,2-dimethylpropyl)formimidoyl]benzoate, mp 79°-80.5° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][C@H:34]([CH3:38])[CH2:33]2)=[CH:28][CH:27]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][C@H:34]2[CH3:38])=[O:48])[C:44]=1[CH3:45]
Reactant: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)C[C@H]1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-3-(R)-methylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a white solid: 1H NMR (CDCl3, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H), 3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS (ES) expect M+H=435.1, found 435.0.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.Cl>ClCCCl>[CH3:10][S:11]([O:6][CH2:5][C:3]([C:2](=[O:1])[CH3:9])([CH3:4])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)C(C)(CO)CO
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)C(C)(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
66 g (0.5 mol) of 3-oxo-2,2-bis-[hydroxymethyl]-butane (for the preparation, see Beilstein H 1, E III 3306, IV 4132 and J. Chem. Soc., London 1932, 2671) were dissolved in 300 ml of 1,2-dichloroethane, 114.5 g (1 mol) of methanesulphonyl chloride were added dropwise and 158 g (2 mol) of pyridine were added dropwise at 0° to 5° C. The reaction mixture was stirred for a further 15 hours at room temperature and the batch was then introduced into 600 ml of ice-water and 100 ml of concentrated hydrochloric acid. A solid precipitated out and this was filtered off. The aqueous phase was extracted with 1 liter of methylene chloride; the solid was dissolved in the methylene chloride phase, the organic phase was dried over sodium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was suspended in 200 ml of ether. 100 g (about 70% of theory) of 2-acetyl-2-methyl-propane-1,3-diol bismethanesulphonate with a melting point of 105° to 108° C. were obtained. ##STR12##
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 95 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5e (189 mg, 80%); %); 1H NMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 8.19 (dd, J=4.9, 1.7 Hz, 1H), 7.7.81 (dd, J=7.7, 1.7 Hz, 2H), 7.52-7.48 (m, 3H), 7.25-7.19 (m, 2H), 6.85-6.81 (m, 4H), 6.55-6.51 (m, 1H), 5.42 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 3.78 (s, 3H), 3.77 ppm (s, 3H); yield 80%
Reaction SMILES: Cl.[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[C:27]([NH2:29])[CH:28]=1>>[CH:2]([N:5]([CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:29][C:27]2[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=2[CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[CH:11][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1)C(C)C
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Yield: 96.5 %

Procedure:
Synthesized from 4-(2-diisopropylaminoethoxy)benzoic acid hydrochloride (240 mg) and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (150 mg) according to an analogous synthetic method to Example 152, the title compound (264 mg) was obtained.
Reaction SMILES: C1(C)C=CC(S([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=O)=O)=CC=1.[CH2:26]([CH:32]([CH2:35]O)[CH2:33][OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.ClCCl>[CH2:26]([CH:32]1[CH2:35][O:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=3)=[CH:22][CH:21]=2)[O:34][CH2:33]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccc(C=O)cc3)cc2)cc1
Reactant: CCCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCC1COC(c2ccc(-c3ccc(O)cc3)cc2)OC1
Reaction time: 1.8 h
Yield: 71.2 %

Procedure:
A solution of 2.82 g of 4'-(p-toluenesulphonyloxy)biphenyl-4-carboxaldehyde and 1.54 g of 2-hexyl-1,3-propane-diol in 50 ml of toluene was treated with 3 drops of 10% (vol.) sulphuric acid. The mixture was heated to boiling for 1.5 hours, with about 50 ml of damp toluene being distilled off and 30 ml of fresh toluene being simultaneously added dropwise. Then, 10 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 10 ml of lN sodium hydrogen carbonate solution and three times with 20 ml of water each time, dried over sodium sulphate and concentrated. The resulting crude 5-hexyl-2-[4'-(p-toluenesulphonyloxy)-4-biphenylyl]m-dioxane (4.26 g) was dissolved in 160 ml ethanol. The solution was treated with a solution of 2.64 g of potassium hydroxide in 27 ml of water and heated to boiling for 1.8 hours while stirring. After cooling the reaction mixture was neutralized (to pH 6) with 1.9 ml of glacial acetic acid and concentrated to about 20 ml. The suspension obtained was diluted with 80 ml of dichloromethane and the organic phase was washed twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue (2.80 g) on g of silica gel with toluene/acetone (vol. 19:1) gave 1.94 g of 5-hexyl-2-(4'-hydroxy-4-biphenylyl)-m-dioxane.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(NC(C)C)(C)C>[CH2:16]([N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Product: Cc1ccc2c(c1)c1c(n2Cc2ccccc2)CCN(C)C1
Yield: 13.8 %

Procedure:
Preparation of the title compound was carried out according to General Method 5. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (Example 1) (100 mg, 0.5 mmol) and benzyl chloride (0.11 ml, 0.9 mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h. The contents were basified with 1N NaOH and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel chromatography (230-400 mesh) using methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 5-benzyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole as a trifluoroacetate salt.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(F)c(F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.29 g. of (10 mmoles) 3,4-difluoro-aniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 168.5°-170°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)(=[O:9])=[O:8].[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29]>>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH:29][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])=[CH:11][C:12]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccn2)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)c2ccccn2)cc1-c1ccccc1

Procedure:
The resultant product from Example 14B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:36]([NH:35][CH2:32][CH2:33][CH3:34])=[O:37])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN=C=O
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)NCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.7 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.36 g, 0.0008 mol) in hexane (15 mL) was added propylisocyanate (0.094 mL, 0.085 g, 0.001 mol), and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then treated with additional propylisocyanate (0.094 mL, 0.085 g, 0.001 mol) and stirred at ambient temperature overnight and then at reflux for 72 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed using 2:8 hexane-ethyl acetate. The resulting oil was triturated with hexane to give the title compound (0.8 g, 0.00015 mol) as a white solid, mp 78°-80°. 1H NMR (CDCl3) 7.6-7.2(m,10H), 4.4(t,1H,J=7Hz), 3.4-2.9(m,8H), 1.9-1.1(m,19H), 1.0-0.75(m,6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][CH:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[CH:19][CH:20]=1
Reactant: CC(C)CCOc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Reaction time: 14 h
Yield: 98 %

Procedure:
t-Butylbromoacetate (1.12 g, 0.85 mL, 5.76 mmol) was added drop wise over 5 min to a stirred suspension of {4-[(3-methylbutyl)oxy]phenyl}amine (intermediate 5, 0.85 g, 4.8 mmol) and potassium carbonate (0.66 g, 4.8 mmol) in dimethylformamide (23.4 mL) at room temperature under a nitrogen atmosphere. After stirring for 14 h the volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The phases were separated and the aqueous phase washed with dichloromethane (2×50 mL). The organic phases were combined, dried (magnesium sulfate) then the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound (inseparable 10:1 mixture of mono- to di-substitution) as a colourless oil (1.38 g). Mono-product: LC/MS: 3.77 min; z/e 294, calcd (M+1) 294. 1H NMR (400 MHz; CDCl3): 0.90 (6H), 1.45 (9H), 1.65 (2H), 1.85 (1H), 3.75 (2H), 3.90 (2H), 6.55 (2H), 6.80 (2H).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Product: NC1(c2ccccc2)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[Mg]Br.[O:16]1[C@:20]([CH3:37])([CH2:21][CH2:22][CH2:23][C@H:24]([CH3:36])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:17]1[CH:18]=[O:19].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:18]([OH:19])[C@H:17]1[O:16][C@:20]1([CH3:37])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:36])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34]
Reactant: COc1c(C)c(C)c(OC)c([Mg]Br)c1C
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@H]1C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)[C@H]2O[C@]2(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
1 mmol of 2,5-dimethoxy-3,4,6-trimethylphenylmagnesium bromide in 2 ml of tetrahydrofuran was added dropwise at 0° C. while stirring to a solution of 300 mg (0.97 mmol) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanal in 10 ml of tetrahydrofuran. After completion of the dropwise addition, the mixture was stirred at room temperature for a further 3 hours. 20 ml of water weree then added and the mixture was extracted three times with 20 ml of ether each time. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. The thus-obtained crude produce (502 mg) was chromatographed on silica gel with toluene/ethyl acetate (2:1 parts by volume) and there were obtained 448 mg(94%) of (1RS,2R,3R,7R, 11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol, [α]D20 =-0.66° (c=1.51% in chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[N:16]([CH3:20])[N:17]=[N:18][CH:19]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:16]([CH3:20])[N:17]=[N:18][CH:19]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cnnn1C
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnnn1C
Yield: 45.4 %

Procedure:
Racemic compound 73.5 (3.28 g, 12 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 30% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 73.6 (1.5 g, 5.45 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 276.1 (M+H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:6][C:7]1[S:8][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1cccs1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(Br)s1
Yield: 75 %

Procedure:
Chlorosulfonic acid was added dropwise over 20 min. to a cold solution (−78° C.) of 2-bromothiophene (16.3 g, 100 mmol) in methylene chloride (50 ml) was added. After addition of chlorosulfonic acid was complete, the cold bath was removed. The reaction mixture was allowed to attain room temperature slowly (2 h), was added dropwise onto the crushed ice (1000 g) and was extracted with methylene chloride (4×100 ml). The combined organic layers was dried over MgSO4, filtered and the solvent was removed under reduced pressure to give a crude product. This was purified by column chromatography using hexane as eluent to give 5-bromothiophene-2-sulfonyl chloride (22 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[N:18][CH:19]=[N:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3cncnc3)cc2sc1=O
Yield: 35.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added pyrimidine-5-yl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 solid (65 mg, 0.08 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling, the reaction mixture was diluted with water (80 mL), acidified using 1 N HCl to pH 3-4 and extracted with EtOAc. The two phases were filtered through a pad of Celite® to form two clear layers. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (10 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-2-oxo-7-pyrimidin-5-yl-2H-thiochromene-3-carboxylic acid methyl ester (79 mg). MS ESI(−) m/e: 313.09 (M−1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4].[CH2:19]([N:23]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:20][CH2:21][CH3:22].O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([C:13]=1[C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:36][CH:35]=1)[CH:11]=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(C(=O)OCC)ccn2c1
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1cc2cc(C(=O)OCC)ccn2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Yield: 37.4 %

Procedure:
A mixture of 0.35 g (38 mmoles) of 2-n-butyl 7-carbethoxy indolizine and 14.2 g (38 mmoles) of 4-(3-di-n-butylamino-propoxy) benzoyl chloride is heated at 95°-100° C. for 4.5 h. The crude product obtained is dissolved in ethyl acetate and water and is neutralized by sodium hydrogen carbonate. The organic layer is separated and dried over magnesium sulfate. It is filtered and the solvent evaporated. The residue is then purified on a column of silica with ethyl acetate as eluant in order to obtain 7.6 g of the desired compound in the form of the free base (yield: 97%). The oxalic acid salt is then formed in ethyl acetate and recovered by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[BH4-].[Na+].[CH:33](OCC)(OCC)OCC>C(O)C.ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][CH3:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CNc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1042) (50 mg, 0.10 mmol) in triethyl orthoformate (6.5 mL) was stirred at 150° C. for 17 h. Concentration afforded a yellow solid. To a solution of the yellow solid in ethanol (3 mL) was added sodium borohydride (7.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 14 h. A resulting white precipitate was resolved in dichloromethane and the solution was washed with 1 N aqueous NaOH (2 mL). The organic layer was separated, dried over K2CO3, filtered and evaporated. Column chromatography (SiO2, 20% MeOH/CHCl3) gave 4-[N-{5-bromo-2-(methylamino)benzoyl)glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1427) (40 mg, 80%) The purity was determined by RPLC/MS (100%); ESI/MS m/e 505 (C23H28BrClF6N4O2).