Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([Br:17])[CH:12]=[C:13]([I:16])[CH:14]=2)[C:9]([OH:28])([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:8]1=[O:29].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>ClCCl>[CH3:37][S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([Br:17])[CH:12]=[C:13]([I:16])[CH:14]=2)[C:9]([OH:28])([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:8]1=[O:29])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N(CCCCCO)c2cc(I)cc(Br)c2C1(O)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Br)cc(I)cc21
Yield: 64.5 %

Procedure:
To a solution of 1-(5-hydroxypentyl)-4-bromo-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole (155 mg, 0.279 mmol) and triethylamine (0.06 mL, 0.43 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.025 mL, 0.323 mmol) at 0° C. The mixture was stirred for 5 min at the same temperature and water was added. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 3:2 hexane/ethyl acetate to give the mixture (116 mg) of the title compound and dimesylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 95.8 %

Procedure:
To a solution of ethyl [4-({(2-methoxyethyl)[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (500 mg, 0.97 mmol) in THF (6 mL) and MeOH (6 mL) was added NaOH (2M; 3 mL) and the resultant solution stirred for 2 h at room temperature. The mixture was concentrated in vacuo, acidified with 2M HCl and extracted with CH2Cl2. The organic solution was dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a colourless oil (453 mg).
Reaction SMILES: [Si:1]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:16])[CH2:14][NH2:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)Cl>[OH:16][CH:13]([CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:14][NH:15][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCC(O)COCCC[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(3-(t-Butyldimethylsilyl)propyloxy)-2-hydroxypropylamine (19.0 g, 0.077 mol), triethylamine (7.8 g, 10.8 mL, 0.08 mol), and methylene chloride (57 mL) were mixed in a 250 mL one-neck flask which was placed in an ice bath. To the above mixture, methacryloyl chloride (8.3 g, 7.73 mL, 077 mol) was added dropwise through an additional funnel at 0° C. After the completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature for two days. The reaction suspension was diluted with 100 mL of methylene chloride and washed with deionized water, 0.5 N sodium hydroxide aqueous solution, 5% sodium chloride solution in water twice and saturated sodium chloride aqueous solution in sequence. The organic phase was dried over sodium sulfate. After the removal of sodium sulfate by filtration, the solvent was evaporated by using a rotary evaporator under vacuum. N-[2-Hydroxy-3-(3-(t-butyldimethylsilyl)propyloxy)propyl]-2-methyl acrylamide was obtained as a white solid after purification by silica gel column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:33]4[CH2:35][CH2:34]4)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1nc(C2CC2)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
4′-(4-Bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (2.6 g, 5.24 mmol), cyclopropylboronic acid (900 mg, 10.5 mmol) 1.0 M tricyclohexylphosphine in toluene (524 μL, 524 μmol), potassium phosphate (3.9 g, 18.4 mmol), and palladium acetate (118 mg, 524 μmol) were combined and dissolved in toluene (95.0 mL, 892 mmol). The mixture was stirred at room temperature under nitrogen for 20 minutes. Water (5.1 mL, 183 mmol) and potassium carbonate (2.5 g, 18.4 mmol) were then added and the mixture heated at 100° C. for 3 hours. Water (100 mL) was added and the layers separated. The organics were washed with water (50 mL) and saturated aqueous NaCl (50 mL), dried over Na2SO4, and the solvent evaporated. The product was purified by flash chromatography (0-40% EtOAc in hexanes to yield compound A (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH2:60])[CH3:59])=[N:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([C@@H:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][C:14]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:59])=[N:57][C:53]=2[CH:52]=1
Reactant: COc1cc(C(=O)O)ccc1CN1CCCC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1CN1CCCC1=O
Yield: 59 %

Procedure:
Prepared analogously to Example 1g from 3-methoxy-4-(2-oxopyrrolidin-1-ylmethyl)benzoic acid, TBTU, diisopropylethylamine and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 59%; Rf value: 0.41 (silica gel; dichloromethane/ethanol=9:1); C22H23ClN4O3 (426.9); mass spectrum: (M+H)+=427/429 (chlorine isotope) and (M−H)-=425/427 (chlorine isotope).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH2:3]1.Cl>>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH2:3]1
Reactant: CCOC(=O)c1cccc(OCCN2CC[C@@H](F)C2)c1
Agent: Cl
Product: O=C(O)c1cccc(OCCN2CC[C@@H](F)C2)c1
Reaction time: 2.5 h

Procedure:
To the material of ethyl 3-({2-[(3R)-3-fluoro-1-pyrrolidinyl]ethyl}oxy)benzoate D48 (220 mg) was added HCl (0.3 ml, 9.87 mmol) at room temperature. The reaction was stirred at 100° for 2.5 hours. The mixture was concentrated in vacuo. To the residue was added 5 ml of ether and stirred 0.5 hours, filtered and the filtrate was evaporated in vacuo to give the expected product D52 in 160 mg. LCMS Retention time=0.90 mins, [M+H]+254 (5 min run)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]
Reactant: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
A mixture of 3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (0.2 g, 0.72 mmol), potassium carbonate (0.1 g, 0.72 mmol) and (1-bromoethyl)benzene (0.19 g, 1 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc in hexane (1:3 v/v) to give pale yellow syrup. This material was further purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2SO4). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.15 g, 52%) as an amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.56 (d, 1H, J=7.6 Hz), 7.4-7.2 (m, 5H), 7.0 (m, 3H), 6.28 (d, 1H, J=7.6 Hz), 5.65 (m, 1H), 5.19 (d×d, 2H, J=14.8 Hz), and 1.64 (d, 3H, J=6.4 Hz), ES-HRMS m/z 402.0492 (M+H C20H18NO2Br, requires 402.0499).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]2[CH:16]=[C:15]([CH:17]=[CH:18][P:19](=[O:26])([O:23]CC)[O:20]CC)[O:14][N:13]=2)=[CH:4][C:3]=1[C:27]([CH3:30])([CH3:29])[CH3:28].C[Si](C)(C)Br.O>ClCCl>[OH:1][C:2]1[C:3]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][C:5]([C:12]2[CH:16]=[C:15]([CH:17]=[CH:18][P:19](=[O:20])([OH:23])[OH:26])[O:14][N:13]=2)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOP(=O)(C=Cc1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2cc(C=CP(=O)(O)O)on2)cc(C(C)(C)C)c1O

Procedure:
4.0 g (0.009 mol) of the product from Example 57 were stirred, under a protective gas and at room temperature, in 300 ml of absolute dichloromethane together with 3.9 ml (0.03 mol) of trimethylbromosilane until the reaction was complete (monitoring by TLC). After adding 0.5 ml of water, the mixture was concentrated; the residue was taken up several times in methanol and concentrated under reduced pressure. The oil was stirred with tert-butyl methyl ether until a crystalline residue remained. Yield: 3.0 g.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19])[CH3:15]>C1COCC1>[CH3:19][C:18]([O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:20])[C:17]([O:16][CH2:14][CH3:15])=[O:22]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of potassium t-butoxide (1M in THF, 531 ml, 0.531 moles, 1 eq) precooled to 0° C. (ice bath) was added phenol (50 g, 0.531 moles, 1 eq) in dry THF (50 ml) dropwise via an addition funnel over 20 minutes maintaining the internal temperature of the reaction below 5 degrees centigrade. Ethyl-2-bromoisobutyrate (70.14 ml, 0.9 eq, 0.478 moles) in dry THF (20 ml) was added dropwise over 10 minutes maintaining the internal reaction temperature below 5° C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was brought to reflux and maintained at this reflux temperature for 8 hours. Following the cooling of the reaction to 0° C. the volatiles were removed in vacuo. The residue was then partitioned between EtOAc and 1N NaOH. The phases were separated and the organic phase was washed with 1N NaOH, H2O, brine and dried over Na2SO4. After filtration the solution was concentrated under reduced pressure to yield 83 g (75%) of clean title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)C>O>[CH:22]1([NH:27][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC3CCCC3)cc2c1=O
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 140 mg (0.44 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 0.17 ml (1.76 mmol) of cyclopentylamine and 3 ml of ethanol is heated at 150° C. in a closed vial in a microwave reactor for 5 minutes. After cooling to room temperature, water is added and the resulting suspension is filtered. Conc. aqueous hydrochloric acid is added to the filtrate until a pH value of 2-3 is reached and the formed suspension is filtered. The residue is crystallized from ether-hexane to yield 52 mg (31%) of the title compound as red crystals, m.p. 146-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=310.4 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-4-methyl-pyrimidine.
Reaction SMILES: C(O)C.C([BH3-])#N.[Na+].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]([CH:31]=[O:32])[CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:19][CH2:18]2)=[C:13]([F:33])[C:12]=1[F:34])[CH3:9].Cl>O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:31][O:32][C:26](=[O:28])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([F:33])[C:12]=1[F:34])[CH3:9]
Reactant: CCOC(=O)CCC(C=O)C1CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
In a reactor under nitrogen atmosphere, 20 mL of ethanol and 0.4 g of sodium cyanoborohydride were added to 5.7 g of ethyl 4-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-5-oxopentanoate obtained in the fourth step, and pH of the mixture was adjusted to about 3 with hydrochloric acid (2M), followed by stirring at room temperature for 15 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of toluene. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was placed in a flask equipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 1 hour while the solvent was distilled off with the Dean-Stark apparatus. The solution was cooled to room temperature, washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to provide 4.2 g of 5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]tetrahydropyran-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([S:36][CH:37](O)[CH3:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:38][CH2:37][S:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCCCCCCCCCCCSC(C)O
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1
Product: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)OCC)cc1
Yield: 66.5 %

Procedure:
N-Benzoyl-L-tyrosine ethyl ester (4.0 g, 12.76 mmol) and dodecanylthioethanol [Patent Application WO 99/15129] (3.15 g, 12.76 mmol) were reacted as described in Example 2 for the preparation of 1-[2-{2-[bis(4-chlorophenyl)ethyl]methylamino}ethoxy]-4-bromo-benzene and gave the title material (4.6 g, 66%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:16]([C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:20][C:19]=3[CH3:33])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][C:19]1[N:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[S:22][C:18]=1[CH:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:7]=[CH:8]2)[CH3:17]
Reactant: CCOC(=O)Cn1ccc2cc(OC(C)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2c(ccn2CC(=O)O)c1

Procedure:
In analogy to the procedure described in example 2 c], [rac]-(5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain [rac]-(5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as yellow solid.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]3[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:27]=4)=[CH:24][N:25]=[C:19]3[CH:18]=2)[N:12]=1)(=O)=O.CO.Cl>CCO>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]3[C:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:40])[F:39])=[O:34])[CH:29]=[CH:30][CH:31]=4)=[CH:24][N:25]=[C:19]3[CH:18]=2)[N:12]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1-c1ccnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nccc(-c5ncc[nH]5)n4)ccn23)c1
Temperature: 60 °C
Yield: 18.2 %

Procedure:
2-[2-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-pyrimidin-4-yl]-imidazole-1-sulfonic acid dimethylamide (140 mg, 0.23 mmol) dissolved in EtOH (5 ml) and MeOH(1 ml) treated with 2M HCl (1 ml) heated at 60° C. for 2 hours. Reaction mixture concentrated under reduced pressure and was purified by preparative HPLC to give product (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[C:33]([C:40]([F:43])([F:42])[F:41])[N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[C:33]([C:40]([F:42])([F:43])[F:41])[N:32]=[C:31]([O:30][CH3:29])[CH:36]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(B(O)O)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) were added (2-methoxy-6-(trifluoromethyl)pyridin-4-yl)boronic acid (53 mg, 0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) and 159 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 72 mg (82% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:18])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(Cl)cc3n2CC(O)c2ccncc2)C1
Reaction time: 12 h

Procedure:
To a stirred solution of 7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 2.265 mmol) in anhydrous DMF was added sodium hydride (271 mg, 3 eq.) portionwise followed by 4-(oxiran-2-yl)pyridine (548 mg, 4.5 mmol) at RT. The reaction mixture was stirred for 12 h. The reaction mixture was quenched with ice water and extracted with EtOAc, the organic layer washed with water, dried on anhydrous sodium sulfate, concentrated under vacuum to obtain crude product that was triturated with diethyl ether to obtain 2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol as solid. 1H NMR (CDCl3, freebase) δ (ppm): 8.53 (d, 2H), 7.2 (m, 3H), 7.14 (d, 1H), 7.05 (d, 1H), 4.82 (t, 1H), 4.03 (d, 2H), 3.4 (q, 2H), 2.85 (m, 1H), 2.76 (m, 1H), 2.64 (m, 2H), 2.37 (s, 3H). Separation by chiral HPLC provided enantiomers 53a and 53b.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([O:26][C:27](=[O:37])[CH:28]=[CH:29][C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[C:22]([O:26][C:27](=[O:37])[CH2:28][C@@H:29]([C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of (R)-(+)—N-benzyl-α-methylbenzylamine (4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3 mL, 2.5 M, 28.2 mmol) over 5 min. The mixture was stirred for 30 min at 0° C. and cooled to −78 ° C. A solution of 10-2 (2.0 g, 9.4 mmol) in 20 mL THF was gradually added. After stirring for 40 min at −78° C., it was treated with NH4Cl (sat.) at −78° C., warmed to room temperature and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After solvent evaporation, the residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:2) to afford the desired product 10-3 as an oil.