Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:4][C:5]=2[C:15]2[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1
Reactant: N#CCC(N)=O
Reactant: CSc1ccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 846.9 %

Procedure:
A solution of 26.1 g of 1-(N,N-dimethylamino)-3-(4-fluorophenyl)-2-[4-(methylthio)phenyl]prop-1-en-3-one (Step 1), 200 ml of dry DMF, 7.2 g (8.6 mMol) of the cyanoacetamide and 8 ml methanol was transferred to a dropping funnel. This solution was added dropwise to a slurry of 4.0 g of sodium hydride in 100 ml of DMF in a 3-necked round bottom flask with a magnetic stirrer and cooled with an ice bath. The temperature reached to 25° C. After complete addition of the reactants the mixture was heated to 80° C. for 4 hours, cooled and poured into one liter of 1M NaH2PO4 to give an insoluble yellow solid which was washed with water and air dried to yield 24.5 g of a yellow powder (95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:37])[C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:22]=2)[NH:19][CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41]Br.C(=O)([O-])O.[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:37])[C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:22]=2)[N:19]([CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])[CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: CN[C@H](c1ccc(OC)c(OCc2ccccc2)c1)[C@@H](O)c1ccc(OC)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc([C@H]([C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)N(C)CC(OC)OC)cc1OCc1ccccc1

Procedure:
Mixture: 1.40 g 2.8 mmol) of rel-(1S,2R)-1,2-bis(3'-benzyloxy-4'-methoxyphenyl)-2-methylaminoethanol, 0.43 ml (0.61 g, 3.6 mmol) of bromoacetaldehyde dimethyl acetal, 0.71 g (8.4 mmol) of sodium hydrogen carbonate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nn2)C1=O

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-acetylimidazolidin-2-one (64 mg) and by the reaction and treatment in the same manner as in Example 511, 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one was obtained as a crude product (170 mg). Methanol (1.2 mL) and 1N aqueous sodium hydroxide solution (0.57 mL) were added to the obtained crude product (170 mg) of 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one, and the mixture was stirred at 40° C. for 1 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (48 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]4[CH:17]([N:5]([C:6]=23)[CH:4]=[C:3]1[C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]4.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[N+:21]([C:8]1[C:7]2[C:2](=[O:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4][N:5]3[C:6]=2[C:11]([CH:12]2[CH:17]3[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)C1CCCCC12
Temperature: 0 °C

Procedure:
6 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid was dissolved in 35 ml of concentrated sulfuric acid and stirred while cooling with ice, followed by dropwise addition of a mixture of 4.3 ml of concentrated nitric acid having a specific gravity of 1.42 and 15 ml of the concentrated sulfuric acid. After completion of the addition, the resulting mixture was stirred for 1 hour at room temperature and poured into 200 g of ice to precipitate yellow crystals. Recrystallization from dimethylformamide-water gave 7 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid having a melting point of 251°-253° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-methyl-propyl-amine (2.50 g, 34.2 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a pale brown solid (3.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[C:31]1([C:28]2[CH:29]=[N:30][C:25]([N:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]4[C:6](=[O:8])[C:5]5[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=5)[C:9]4=[O:10])[CH2:24][CH2:23]3)=[N:26][CH:27]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NCCCCN1CCN(c2ncc(-c3ccccc3)cn2)CC1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: c1ccncc1
Product: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1CCCCN1CCN(c2ncc(-c3ccccc3)cn2)CC1

Procedure:
0.005 mol of 4,5-dichlorophthalic anhydride and 0.005 mol of 1-(4-aminobutyl)-4-(5-phenyl-2-pyrimidinyl)-piperazine in 20 ml of absolute pyridine are boiled under reflux, under an atmosphere of N2, for several hours. After cooling, the product which has crystallised out is filtered off and washed with isopropyl ether.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][C:21]([OH:24])=[N:22][CH:23]=2)=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N.CCN(C(C)C)C(C)C>CN(C=O)C.O1CCOCC1>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:23]=[N:22][C:21]([OH:24])=[N:20][CH:19]=2)=[O:17])[CH2:9][C@H:10]([C:11](=[O:12])[NH2:32])[OH:14])=[CH:3][CH:2]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O)c1cnc(O)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(O)nc1
Reaction time: 0.03 h
Yield: 13.8 %

Procedure:
(2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5-carbonyl)amino]pentanoic acid (14.5 mg, 35.6 μmol, 1.0 eq.) and HATU (13.5 mg, 35.6 μmol, 1.0 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. 0.5 M ammonia in dioxane was added, followed by DIPEA (12.4 μL). The resulting mixture was stirred for 1 hour then dried under vacuum. The product was purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C22H22N4O4, 407.16. found 407.4.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH2:12][C:13](=[CH2:18])[CH2:14][C:15](=[CH2:17])[CH:16]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)(=O)=O)=CC=CC=1>>[CH2:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH:33]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[CH3:32]
Reactant: C=C1C=C(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)CC(=C)C1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CCCC1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C(C)C2CCCC2)c1
Yield: 24.9 %

Procedure:
5-Isopropyl-6-(3,5-dimethlylbenzoyl)-2,4-pyrimidinedione and (2-cyclopentyl)ethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound (95 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[SH:34][C:35]1[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][S:34][C:35]3[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=3)[C:12]=2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1S
Product: CCCCCC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 4, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 128°-129° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10]C)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(OC)=O)=[CH:18][CH:17]=1>CO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:8]([C:7]2[CH:12]=[CH:13][N:14]=[C:5]([CH3:4])[CH:6]=2)=[O:10])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccnc(C)c1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)Cc2ccc(F)cc2)ccn1
Temperature: 95 °C
Reaction time: 17.5 h

Procedure:
To a freshly prepared solution of NaOMe (3.0 M in MeOH) was added a solution of methyl 2-methyl-isonicotinate (6.81 g, 45.1 mmol) in MeOH (10 mL). This was followed by the dropwise addition of a solution of methyl 4-fluorophenylacetate (8.34 g, 49.6 mmol) in MeOH (10 mL). The MeOH was distilled off while heating the reaction mixture at 95° C. After 17.5 h, the solid residue was cooled. Concentrated HCl (15 mL) was added, and the mixture was heated at reflux. After 4 h, the mixture was cooled then diluted with H2O. The aqueous mixture was washed with Et2O, adjusted to pH 5 with 1N NaOH, then adjusted to pH 8 with saturated NaHCO3. The alkaline aqueous was extracted with EtOAc. The EtOAc extracts were washed with saturated NaCl, then dried over Na2SO4. Evaporation of solvent in vacuo afforded a red oil which was purified by column chromatography, eluting with a gradient of 0-3% MeOH/CHCl3. The title compound was isolated as a red oil (1.5 g, 15%).
Reaction SMILES: [CH:1]1([C:4]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=2[C:6](OC)=[O:7])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH:1]1([C:4]2[C:5]([CH2:6][OH:7])=[CH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C1CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(C(F)(F)F)nc1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
To a solution of methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate (1 g, 4.08 mmol) in THF (6 mL) at 0° C. under argon was added 1.0 M lithium aluminum hydride in THF solution (6 mL, 6.0 mmol). The reaction mixture was stirred at 0° C. for 15 min. EtOAc (20 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 min. A 10% aqueous potassium sodium tartrate solution (20 mL) was added to the reaction mixture and stirring was continued for another 30 min. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to obtain 890 mg of the title compound as a pale yellow oil. HPLC/MS: retention time=3.055 min, [M+H]+=218.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[C:16]([O:17][CH2:18][CH3:19])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: Clc1cn2ccccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)nc2ccccn12
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 45.1 mL) was added to a solution of 2-chloroimidazo[1,2-a]pyridine (10 g) in THF (120 mL) at −78° C. After stirring for 30 min, ethyl chlorocarbonate (7.82 g) in THF (10 mL) was added to the mixture at the same temperature and stirred for 1 h and then 10 h at room temperature. The mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (13.20 g) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24].C(OCC)C>C1COCC1.O>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 25 °C

Procedure:
(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (773 g, 1 mole) is dissolved in THF (1500 ml) with an addition of water (40 ml) under reflux. After gradual cooling down to ambient temperature, diethylether (300 ml) is added drop-wise to the mixture over 6 hours. The precipitated crystals are sucked off and washed with THF. Yield: 232 g (30%). Optical purity: 93% ee (CE).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]Br)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Mg].[Cl-].[NH4+]>C(OCC)C>[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCc1ccc(CCBr)cc1
Reactant: N#CC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCc1ccc(CC[C@H]2CC[C@H](C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6 g of 4-cyanocyclohexanone in 50 ml of diethyl ether is added dropwise, while stirring, at room temperature and during the course of 1.5 hours, to a Grignard solution prepared from 13 g of 1-(4-n-pentylphenyl)-2-bromoethane and 1.3 g of magnesium turnings in 200 ml of diethyl ether. The reaction mixture is then heated under reflux to the boil for 2 hours, and, after it has cooled, 150 ml of 10% aqueous ammonium chloride solution is added to it, while stirring. The ether phase is separated off, dried over sodium sulfate and evaporated. The residual 1-(4-n-pentylphenyl)-2-(4-cyano-1-hydroxycyclohex-1-yl)-ethane is dissolved in 40 ml of acetone and this solution is heated to the boil for 1 hour with 0.5 g of p-toluenesulfonic acid. The solvent is then distilled off and the residue is taken up in 100 ml of ethanol. After the addition of 20 mg of copper (II) sulfate, 23 g of hydrazine hydrate and 40 ml of 30% aqueous hydrogen peroxide solution are added successively to the mixture at 0°. The reaction mixture is stirred for 1 hour at room temperature and poured into 500 ml of water, and the 1-(4-n-pentylphenyl)-2-(trans-4-cyanocyclohexyl)-ethane thus obtained is extracted with diethyl ether; the extracts are dried with sodium sulfate and evaporated, and the residue is recrystallized from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1.O>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A solution of 2-amino-5-fluorobenzoic acid (15 g, 96.6 mmol) in dry DMF (35 mL) and dioxane (35 mL) was cooled to 0° C. Bromoacetylbromide (8.43 mL, 96.6 mmol) was added dropwise at 0° C. over a 40 min period, and the reaction mixture was left overnight at room temperature. The reaction mixture was cooled to 0° C., and diluted slowly with water (300 mL). The precipitate which formed was collected washed with 5% HBr (50 mL) and water, and dried, to afford 25.43 g (95.1%) of the title compound as a white solid, mp 191.2°-191.8° C.; 1H NMR (acetone-d6) δ 11.60 (s, 1H), 8.71 (dd, J=5.2, J=9.2, 1H), 7.80 (dd, J=3.2, J=9.6, 1H), 7.48-7.43 (m, 1H), 4.18 (s, 2H); 13C NMR (acetone-d6) δ 168.80, 165.71, 158.37 (d, J=241.9), 138.56, 122.78 (d, J=7.8), 122.70, 122.06 (d, J=21.9), 117.98 (d, J=24.0), 30.45; MS (EI, m/z) 277 (M+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(C)C)cc3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-propionic acid as light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26]>>[NH2:22][C:17]1[N:18]=[C:19]([NH:21][C:30]2[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=2)[CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[O:23][CH3:24])[CH:16]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Yield: 22 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-formyl-phenylboronic acid provided the title compound (22% yield). 1H NMR (acetone-d6) δ3.85 (s, CH3), 5.51 (bs, 2H, NH2), 6.27 (d, 1H, J=1.1 Hz, Ar), 6.38 (d, 1H, J=1.1 Hz, Ar), 7.14 (d, 1H, J=8.8 Hz, Ar), 7.32 (d, 1H, J=2.7 Hz, Ar), 7.38 (dd, 1H, J=8.8 Hz, J=2.7 Hz, Ar), 7.78 (d, 2H, J=8.7 Hz, Ar), 7.96 (d, 2H, J=8.7 Hz, Ar), 8.59 (s, 1H, NH), 9.84 (s, 1H, CH).
Reaction SMILES: [F:1][CH:2]([F:13])[N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1.[F:14][C:15]([F:33])([F:32])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1>>[F:14][C:15]([F:32])([F:33])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH:31][S:8]([C:6]2[C:5]([CH3:12])=[N:4][N:3]([CH:2]([F:13])[F:1])[CH:7]=2)(=[O:10])=[O:9])[CH3:30])=[CH:25][CH:24]=1
Reactant: C[C@@H](N)c1ccc(-c2ccccc2OC(F)(F)F)cc1
Reactant: Cc1nn(C(F)F)cc1S(=O)(=O)Cl
Product: Cc1nn(C(F)F)cc1S(=O)(=O)N[C@H](C)c1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Palladium acetate (34 mg, 0.150 mmol) was added to a mixture of 2-(trifluoromethoxy)phenylboronic acid (773 mg, 3.75 mmol) and (R)-(+)-1-(4-bromophenyl)ethylamine (300 mg, 1.50 mmol) in water (12 ml). This mixture was heated in a microwave oven at 150° C. for 10 min, then diluted with methanol (200 ml) and purified on a SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine (345 mg, 1.23 mmol, 81.9%) as a gum. The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 1-difluoromethyl-3-methylpyrazole-4-sulfonyl chloride and (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.42-7.16 (m, 8H), 6.97 (s, 1H), 4.88 (d, 1H), 4.52 (m, 1H), 2.30 (s, 3H), 1.56 (d, 3H) ppm; MS (ESI) m/z: 476 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])[CH:21]=2)[C:16]=1[Br:42])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:42][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:43])=[O:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
1 N Sodium hydroxide (220 μL, 0.22 mmol) was added under nitrogen to a solution of 2-(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (107 mg, 0.17 mmol), prepared in the previous step, in 40 mL of methanol plus 10 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. By TLC starting material remained. Additional quantities of 1 N NaOH were added until the reaction was complete by TLC. The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the methanol. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (61 mg, 58%) as a white solid, mp 125-130° C.