Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.CO>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A mixture of (1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicylco[3.2.1]oct-3-en-2-one (Description 23; 26 g, 66 mmol), 10% palladium on charcoal (3.5 g, 3.3 mmol), ethyl acetate (50 ml) and methanol (100 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The filter cake was well washed with dichloromethane and the filtrate was concentrated to give the title compound as a solid (26 g, 100%). The isomers were separated on silica gel (iso-hexane:ethyl acetate) and crystallised from acetone:iso-hexane yielding pure ketones as a colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[C:46]([CH:50]=1)[C:47]([OH:49])=[O:48]>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@@H:9]([C:28]([NH:41][C:42]3[CH:43]=[CH:44][C:45]([N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:46]([CH:50]=3)[C:47]([OH:49])=[O:48])=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCCC3)c(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (99.6 mg, 0.770 mmol) and N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) followed by 5-amino-2-(pyrrolidin-1-yl)benzoic acid (38.5 mg, 0.187 mmol, Array). The reaction mixture was stirred for 2 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 8 g, 0.5% to 5% MeOH in CH2Cl2) to give rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-pyrrolidin-1-yl-benzoic acid as white solid (14.6 mg, 15.4%). MS (ES+) m/z Calcd: [(M+H)+]: 655. found: 655.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:20](OCC)=[O:21]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH:20]=[O:21])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCOC=O
Reactant: NCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Product: O=CNCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 94 %

Procedure:
A mixture of 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethylamine (906 mg, 3.32 mmol) prepared in Reference Example 154 and ethyl formate (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}formamide (942 mg, yield 94%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)[CH3:2]>[OH-].[Na+]>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(C(=O)O)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Methyl 4-ethyl-2-methoxybenzoate (example 18c) (2.01 g, 10.3 mmol) was suspended in 1M aq. NaOH (40 mL) and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to rt and washed with hexanes. The aqueous layer was then separated and acidified with 6N HCl to pH 2. A white precipitate was collected washed with water and dried to give 4-ethyl-2-methoxybenzoic acid (1.8 g, 97%) as a white solid. 1H NMR (300 MHz, dMSO): δ 1.16-1.20 (t, 3H), 2.60-2.65 (dd, 2H), 3.80 (s, 3H), 6.82-6.84 (d, 1H), 6.95 (s, 1H), 7.57-7.59 (d, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][O:14][C:15]=2[CH2:16][C:17](O)=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CSC.B.C(CC(C)(C)C)(C)C>C1COCC1.ClCCl>[OH:18][CH2:17][CH2:16][C:15]1[O:14][N:13]=[C:12]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2CC(=O)O)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2CCO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.8 %

Procedure:
To a stirred solution of [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]acetic acid (Step 1) (0.85 g, 2.37 mmol) in THF (25 mL) was added borane dimethylsulfide (0.47 mL of 10.0M solution, 4.74 mmol). After stirring at room temperature for 2 days, the reaction was quenched with aqueous KHSO4 (0.25M) and extracted with ethyl acetate. The combined ethyl acetate phases were washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding a pale yellow solid. The crude product was dissolved in hot dichloromethane and isooctane was added to induce crystallization. Vacuum filtration of the resulting suspension yielded 4-[5-(2-hydroxyethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide (0.276 g, 34%) as a pale yellow solid: mp 186°-190° C. 1H NMR (DMSO d6 /300 MHz) 7.81 (d, 2H, J=8.0 Hz), 7.48-7.28 (m, 9H), 4.95 (t, 1H, J=5.0 Hz), 3.70 (q, 2H, J=5.6 Hz), 2.92 (t, 2H, J=6.2 Hz). FABLRMS m/z 345 (M+H). FABHRMS m/z 345.0923 (M+H, C17H17N2O4S requires 345.0909). Anal. Calc'd for C17H17N2O4S.1.66 wt % H2O: C. 58.30; H, 4.79; N, 8.00. Found: C, 58.37; H, 4.89; N, 7.60.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([CH:14]=1)[CH:12]=O.[C:21]([OH:33])(=[O:32])[CH2:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(OC(=O)C)(=O)C>C(O)C>[C:26]1([C:24]2[O:33][C:21](=[O:32])[C:22](=[CH:12][C:11]3[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=3[S:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[N:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: O=Cc1cc(Cl)ccc1Sc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=C1OC(c2ccccc2)=NC1=Cc1cc(Cl)ccc1Sc1cccs1
Reaction time: 2 h

Procedure:
8.4 g (0.1 mole) of sodium bicarbonate is added, with stirring, to the mixture of 25.5 g (0.1 mole) of 5-chloro-2-(2-thienylthio)-benzaldehyde and 17.9 g (0.1 mole) of hippuric acid in 34.7 g (0.34 mole) of acetic anhydride, and the reaction mixture is stirred at 90°-95° for two hours. It is thereupon cooled to 25°; to the thick crystal mass is added 300 ml of 50% ethanol, the solid substance is filtered off with suction and is washed with 150 ml of 50% ethanol. Drying in a vacuum chamber leaves 2-phenyl-4-[5-chloro-2-(2-thienylthio)-benzylidene]-2-oxazolin-5-one in the form of yellow crystals, m.p. 125°-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]#[N:10])[CH:7]=1.C[NH:18]C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:18])=[NH:10])[CH:7]=1
Reactant: CNC
Reactant: N#CNc1cc(Cl)ccc1N1CCOCC1
Solvent: CCO
Product: N=C(N)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 272, N-(5-chloro-2-morpholinophenyl)cyanamide (2.3 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) were heated under reflux for 4 hours to give 1,1-dimethyl-2-(5-chloro-2-morpholinophenylguanidine (m.p. 135°-138° C.) which was recrystallised from hexane and then was converted into its monofumarate salt (m.p. 223°-225° C.) which was recrystallised from methanol.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].O>O1CCCC1>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2cnc(CCC(=O)OC)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2cnc(CCC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
1.44 ml (1.45 mmol, 5 eq) of lithium hydroxide are added to a solution of 111 mg (0.29 mmol, 1 eq) of methyl 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}propanoate in 3 mL of tetrahydrofuran. The reaction mixture is stirred for four hours at room temperature. The reaction is stopped by adding 10 ml of water, washed with ether and then acidified with 1N hydrochloric acid solution, and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then crystallized from ether. 66.7 mg of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}propanoic acid are obtained in the form of white crystals. Yield=48%.
Reaction SMILES: O(CC([N:11]1[CH:15]=[CH:14][CH:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.CO>[Pd]>[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:12]1
Reactant: COC(=O)c1cccc(C2C=CN(C(=O)COc3ccccc3)C2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(C2CCNC2)c1
Reaction time: 5 h

Procedure:
To a solution of methyl 3-[1-(phenoxyacetyl)-2,3-dihydro-1H-pyrrol-3-yl]benzoate (0.5 g, 0.001 mol) in methanol (15 mL, 0.37 mol) was added 10% Pd/C (80 mg), and the resulting suspension was stirred under 1 atm of H2 (balloon) for 5 h. The mixture was filtered and the filtrate was concentrated to afford the desired product.
Reaction SMILES: [CH:1]([CH:14]1[C:19](=[O:20])[CH:18]2[CH2:21][CH2:22][N:15]1[CH2:16][CH2:17]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[C:27]([OH:36])(=[O:35])[C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29]>C(O)C>[C:27]([OH:36])(=[O:35])[C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29].[CH:1]([C@H:14]1[C:19](=[O:20])[CH:18]2[CH2:17][CH2:16][N:15]1[CH2:22][CH2:21]2)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Racemic 2-benzhydryl-3-quinuclidinone (52.45 g, 180 mmol) was dissolved in denatured ethanol (525 ml) with acetic acid (10.4 ml, 180 mmol) and L-tartaric acid (27 g, 180 mmol) was added. The mixture was heated to reflux for 12 hours and then allowed to cool to room temperature and held for one hour. The solids were collected and dried under vacuum at 40° C. for 12 hours. The yield of the desired salt was 69.9 g, 88% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:54]>O1CCOCC1.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:30].[ClH:54].[ClH:30].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Temperature: 80 °C
Yield: 148 %

Procedure:
To a suspension of (6-bromo-4-((6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)amino)quinolin-3-yl)(cyclopropyl)methanone (91 mg, 0.20 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (87 mg, 0.30 mmol) and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol) in dioxane (6 mL) was added Cs2CO3 (1.0 M in H2O, 0.6 mL, 0.6 mmol). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with a satd. aq. NaHCO3 (20 mL) and extracted with CHCl3/isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with a mixture of CHCl3/isopropanol (3:1). The desired fractions were concentrated and dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol). The resulting solution was concentrated to give the desired product (95.6 mg, 74%) as an off-white solid. NMR (500 MHz, MeOD) δ 9.38 (s, 1H), 8.33-8.23 (m, 2H), 8.19 (d, J=2.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.77 (dd, J=9.2, 2.6 Hz, 1H), 7.45 (s, 2H), 7.06 (d, J=9.2 Hz, 1H), 3.88 (t, J=6.1 Hz, 2H), 3.45 (t, J=6.1 Hz, 2H), 2.98 (s, 6H), 2.88-2.79 (m, 1H), 1.24-1.18 (m, 4H). ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=10.24 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[CH:24]=1)[CH3:15]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCc1cccc(C)c1-c1cccc(CO)c1
Product: CCc1cccc(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 230 from methyl 3-(4-hydroxyphenyl)propanoate and (2′-ethyl-6′-methylbiphenyl-3-yl)methanol. colorless crystals (yield 57%). MS (APCI−): 373 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[CH3:38][O:39][C:40](=[O:58])C1C=CC=CC=1C1NC2C=C(F)C(F)=CC=2N=1.BrCC1CCCCC1>>[CH3:38][O:39][C:40](=[O:58])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2[nH]1
Agent: BrCC1CCCCC1
Product: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzoic acid methyl ester and bromomethyl-cyclohexane (2550-36-9). Off-white powder (15%). MS (Turbo Spray): m/z=384.8 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[Cl:20].O>C1COCC1>[Cl:20][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)CCCCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)CCCCCl)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 696 μl (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chloro-benzoate in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50° C. and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([OH:21])S[CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>O.CO.[Ru](Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([OH:21])[O:2][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1C(O)SCN1c1ccc(Cl)c(Br)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)OCN1c1ccc(Cl)c(Br)c1
Reaction time: 1 h
Yield: 15.2 %

Procedure:
Sodium periodate (14.2 g) was dissolved in water (175 ml) and ruthenium trichloride (0.7 g) added to give a black solution. The solution was stirred during the addition of 3-(3-bromo-4-chlorophenyl)-5-hydroxythiazolidin-4-one (7.85 g) in methanol (35 ml) over 5 min, the reaction vessel was cooled in an ice bath to control the resulting exotherm. The mixture was stirred for 1 hour before quenching with sodium metabisulfite. The mixture was extracted with ethyl acetate and the combined organic extracts washed with aqueous sodium metabisulfite solution and water, then dried (MgSO4). Evaporation of the solvent under reduced pressure gave a gum which was triturated with dichloromethane to give the title compound as a grey solid (1.13 g), m.p. 139-140° C.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:8]=1[OH:21])=CC>C(OCC)(=O)C.C(O)(=O)C>[OH:21][C:8]1[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][CH:11]=[CH:12][C:7]=1[CH:4]=[O:1]
Reactant: CC=Cc1cccc(Oc2ccccc2C)c1O
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1Oc1cccc(C=O)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(1-propenyl)-6-(o-tolyloxy)phenol (13.7 g) in a mixture of ethyl acetate (300 ml) and acetic acid (50 ml) at 0°-3° C. with stirring for an hour. The reaction mixture was washed with water, aqueous sodium bicarbonate and saline successively, dried over magnesium sulfate and when evaporated. The oily residue (12.9 g) was dissolved in diethyl ether, and the solution was washed with water, dried over magnesium sulfate and evaporated. The oily residue (11.7 g) was pulverized and recrystallized from methanol to give 2-hydroxy-3-(o-tolyloxy)benzaldehyde (4.8 g). mp 56°-58° C.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[Na].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([O-:13])=O.[C:18]1([NH:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:28][C:27]1[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](=[O:13])[C:10]=1[C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: N#Cc1ccccc1Nc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(N)c2ccccc2n(-c2ccccc2)c1=O
Yield: 51.7 %

Procedure:
Into a sodium ethoxide/ethanol solution which had been prepared from 2.07 g (90 mmol) of metallic sodium and 75 ml of anhydrous ethanol, 14.4 g (90 mmol) of ethyl malonate were added dropwise at room temperature. After the resultant mixture was stirred for 30 minutes as was, 5.82 g (30 mmol) of 2-phenylaminobenzonitrile were added and the mixture so obtained was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of ethyl acetate. The resulting solution was washed with water and was then dried. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and was then recrystallized from chloroform/hexane, whereby 4.78 g of ethyl 4-amino-2-oxo-1-phenyl-1,2-dihydro-quinoline-3-carboxylate (Compound No. 1) were obtained (yield: 51.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:56]>C(OCC)C>[ClH:56].[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=3)(=[O:42])=[O:43])[CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCNCC1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperazine-1-carboxylate (190 mg, 0.257 mmol) was deprotected in methanol/HCl in diethyl ether (5/3 ml) to afford 120 mg (69.0% yield) of the titled compound. MS: m/z=637.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Li]CCCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]([OH:32])[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 1-bromo-4-(trifluoromethoxy)benzene (1.88 g, 7.80 mmol) in THF (16 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 4.1 mL, 7.8 mmol), and the solution was stirred at −78° C. for 30 minutes. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 7.03 mmol) in THF (2 mL) was added dropwise, and the mixture was stirred at −78° C. for 45 minutes then allowed to warm to room temperature over 1 h. Work-up and purification gave 4-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (1.75 g, 66%).