Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:4])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CN
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 20.7 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 34, but starting from 2.0 g of tert-butyl (2R,4R) 3-(2-aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate and 1.6 g of 4-chloro-3-trifluoromethylphenyl isocyanate. The crude product obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in 20 cm3 of hexane, 0.7 g of tert-butyl (2R,4R)-3-{2-[3-(4-chloro-3-tri-fluoromethylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of an amorphous powder, ([α]D20 =+58.2°±1.3° (C=0.49%; CH3OH), [proton NMR (250 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 130° C., characteristic chemical shifts at 130° C.: 1.53 (s, 9H, --C(CH3)3); 3.29 and 3.47 (2dd, J=12.5 and 6.5, 2H, S--CH2 --); 3.73 (broad, 1H, of N--COCH2 --N); 4.10 (dd, J=17.5 and 4, 1H, the other H of N--COCH2 --N); 5.0 (broad, 1H, N--CH--COO); 6.33 (broad, 1H, --NHCO--); 6.4 (s, 1H, S--CH--N); 7.2 to 7.8 (m, 7H, aromatic); 7.97 (bs, 1H, in position 2 on CO--NH--Ph); 8.98 (broad, 1H, --CO--NH--Ph), [infrared spectrum (KBr), characteristic bands in cm-1 : 3375, 2980, 2930, 2875, 1740, 1640, 1595, 1550, 1485, 1455, 1370, 1325, 1175, 1150, 895, 730, 695].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([NH:19][CH3:20])[N:3]=1.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([NH:19][CH3:20])[N:3]=1
Reactant: CN
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1Cl
Product: CNc1nc(NC)c2ncn(Cc3ccccc3Cl)c2n1

Procedure:
In a manner analogous to that described in Example 2 it is possible, by reacting 2-chloro-9-(2-chlorobenzyl)-6-(N-methylamino)-9H-purine (Example 18) with N-methylamine, to obtain the 2,6-bis(N-methylamino)-9-(2-chlorobenzyl)-9H-purine, which has a melting range of from 151° to 152°, the reaction mixture being heated at 120° for 20 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]5[CH2:28][CH3:29])=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:37])[CH2:24][C@@H:23]5[CH2:28][CH3:29])=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:3]=1
Reactant: C=O
Reactant: CC[C@H]1CNCCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC[C@H]1CN(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2-ethyl-4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2-ethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one and formaldehyde following procedure used as in example 195.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]([C:16]#[N:17])[C:7]2=O)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2c(=O)c(C#N)c[nH]c2cc1OC
Product: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC

Procedure:
A mixture of 7.95 g (32.6 mmol) of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 mL of phosphorous oxychloride was refluxed for 3 h 40 min. The phosphorous oxychloride was removed in vacuo and the residue was slurried with ice water. Solid NaHCO3 was added (pH8) and the product was collected by filtration, washed well with water and dried in vacuo (40° C.). The yield was 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 262.8, 264.8.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.O=S(Cl)Cl.[F:20][C:21]([F:31])([F:30])[S:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(Cl)Cl>[N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([S:22][C:21]([F:31])([F:20])[F:30])=[CH:24][CH:25]=2)=[O:12])[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) and SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-((trifluoromethyl)thio)aniline (106 mg, 0.55 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in EtOAc (10 mL), filtered through a 10 μm Isolute® fritted cartridge and the filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound. LC-MS (Condition 4) tR=1.19 min, m/z=375.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.67-7.78 (m, 3H) 7.93-8.02 (m, 2H) 8.04-8.10 (m, 2H) 8.38 (t, J=1.83 Hz, 1H) 9.21-9.29 (m, 3H) 10.63 (s, 1H).
Reaction SMILES: [CH2:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].O[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.C(N(CC)CC)C>[N:33]1([O:28][C:27](=[O:29])[C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH2:7][CH2:6][CH:5]([S:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH2:9]5)=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:31][CH:30]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1
Reactant: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)On5nnc6ccccc65)cc4)CC3)cc2)CC1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To a solution of 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid (0.98 g), 1-hydroxybenzotriazole (0.39 g) in dichloromethane (20 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.85 g), and the mixture was stirred for 15 minutes. To the solution was added triethylamine (0.31 ml), and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into a mixture of 0.1N-hydrochloric acid (25 ml) and dichloromethane (60 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the resulting precipitates were washed with water and IPE (50 ml), collected by filtration and dried under reduced pressure to give 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl)piperazin-4-yl]benzoic acid benzotriazol-1-yl ester (1.04 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]([CH2:16][CH2:17][CH3:18])([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)[CH3:7].[N-:19]=[N+]=[N-].[Na+].[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[CH2:6]([C:8]([NH2:19])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7]
Reactant: CCCCC(CC)(CCC)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCC(N)(CC)CCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a condenser, were introduced 70 ml of chloroform, 18 ml of concentrated sulphuric acid (d = 1.83) and 11 g (0.06 mol) of 2-ethyl-2-n-propyl-hexanoic acid prepared as described above. The mixture was heated to 50° C. and while stirring 7.5 g of sodium azide in powder form were added. The operation of addition lasted 90 minutes after which the reaction mixture was heated to 50° C. for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide previously cooled to 0° C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided 1-ethyl-1-n-propyl-n-pentylamine in free base form.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:13]([O:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Oc1ccc(O)c2ccccc12
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
112 g of naphthohydroquinone and 560 ml of n-decanol were placed in a 1 l three-necked flask and 56 ml of concentrated sulfuric acid was dropwisely added thereto for 30 minutes under nitrogen gas stream while stirring. Thereafter, the mixture was further stirred for 30 minutes and, then, heated at 50° C. for 1 hour and 30 minutes. After cooling, ethyl acetate-water was added to the reaction mixture and the precipitated crystals were filtered off. An aqueous sodium hydroxide solution was added to the filtrate so as to water layer reach pH of 5 to 6. Then, the ethyl acetate layer was washed with water and dried with MgSO4 overnight. The dried ethyl acetate solution was evaporated under reduced pressure to remove ethyl acetate and n-decanol. The residue was dissolved in 1 l of ethyl acetate and treated with 26 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane and, further, recrystallized from benzene to obtain 73 g of white crystals having a melting point of 89° to 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>ClCCl>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Benzyl Alcohol 3 (1.02 g, 3.59 mmole) was dissolved in dichloromethane (70 mL) and cooled to −78° C. in an dry ice/acetone bath. Boron tribromide (1.0 M in dichloromethane), (3.95 mL, 3.95 mmole) was added drop wise over 15 minutes. After 30 minutes, the light orange solution was allowed to come to room temperature and reacted for an additional four hours. The solution was concentrated and added to saturated sodium bicarbonate, and extracted with ethyl acetate. Organic layers were combined and washed with water and brine, dried over magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 2.91 g (81%) of benzyl bromide17 as a white solid: Mp=158–160° C.; 1H NMR (DMSO-6) δ 7.88(d, 2 H, J=8.8 Hz), 7.23 (s, 1 H), 7.11 (d, 2 H, J=2.5 Hz), 7.09 (d, 2 H, J=8.9 Hz), 6.99 (d, 1 H, J=2.5 Hz), 4.96 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: BrCC1CC1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(CC4CC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclopropylmethylbromide were reacted in dimethylformamide as described in Example 7 to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[CH:5]2.[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[CH:5]2
Reactant: COC(=O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1
Yield: 66.7 %

Procedure:
A solution of methyl 4-(5,6-dichloro-1H-indol-2-yl)benzoate (0.86 g, 2.7 mmol) and KOH (0.36 g, 6.4 mmol) in a mixture of EtOH (15 ml) and water (15 ml) was refluxed for 3 h. After concentration of the ethanol, the solution was acidified and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo to afford 0.58 g (1.8 mmol, yield 70%) of the acid used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][CH2:18][C:19]3[N:20]([CH3:33])[C:21]4[C:26]([C:27]=3[C:28]([O:30]C)=O)=[C:25]([Cl:32])[CH:24]=[CH:23][CH:22]=4)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Al](C)(C)C>ClCCl.Cl>[Cl:32][C:25]1[C:26]2[C:27]3[C:28](=[O:30])[N:17]([C:14]4[CH:15]=[C:16]5[C:11]([CH:10]=[CH:9][N:8]5[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[CH:12][CH:13]=4)[CH2:18][C:19]=3[N:20]([CH3:33])[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1c(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n(C)c2cccc(Cl)c12
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cn1c2c(c3c(Cl)cccc31)C(=O)N(c1ccc3ccn(CC(=O)OC(C)(C)C)c3c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Methyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-indol-6-ylamino)methyl)-4-chloro-1-methyl-1H-indole-3-carboxylate (2.416 mmol, 1 equiv.) was dissolved in dichloromethane (36 ml), and (CH3)3Al (2 M solution in toluene, 4.83 mmol) was added at 0° C., under nitrogen. After 10 min, the reaction mixture was heated to 25° C. and then stirred for 2 h. The reaction mixture was diluted with dichloromethane and hydrolysed with 2 M HCl. The phases were separated, and the organic phase was washed with water and sat. NaCl solution (in each case 10 ml). Drying over Na2SO4 was then carried out, followed by concentration under reduced pressure. The product was crystallized from ethyl acetate. Yield: 89%
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+].[C:29](=O)([O-])O.[Na+]>CO>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:29])=[O:11]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reaction time: 30 h
Yield: 90 %

Procedure:
To 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 ml of methanol and then 10 ml of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution. The organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:28][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[CH:22][N:23]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
200 mg (0.66 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 104 mg (0.72 mmol) of 4-chloropyrimidine-2-amine are suspended in 9 ml of water and 4.5 ml of ethanol. 0.33 ml (1.31 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 2 h. The mixture is made alkaline using concentrated aqueous sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The organic phase is separated off and concentrated. The crude product is purified by preparative HPLC. This gives the title compound as crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[C:17]([F:23])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[C:29]2[N:36]([CH3:37])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([CH2:21][O:22][C:27]2[CH:28]=[C:29]3[N:36]([CH3:37])[CH2:35][CH2:34][N:30]3[C:31](=[O:33])[N:32]=2)[CH:18]=[C:17]([F:23])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: N#Cc1ccc(Oc2c(F)cc(CO)cc2F)cc1C(F)(F)F
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C#N)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 4-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile (280 mg, 0.850 mmol) in DMF (5 mL), sodium hydride (61.2 mg, 2.55 mmol) and 7-chloro-1-methyl-2,3-dih-ydroimidazo[1,2-c]pyrimidin-5(1H)-one (158 mg, 0.850 mmol).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>ClCCl.CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (79 mmol) and Boc-L-tyrosine (66 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 12:1 dichloromethane/DMF reaction solvent, 60 hour reaction time) and the product purified by chromatography on silica gel eluted with 10, 20, 30, 50 and 70% ethyl acetate in hexanes. Yield 20.6 g, 102%; HPLC (60/40) 3.21 minutes (96%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-α-amino-cyclopropanepropanamide (CAN 156077-93-9) as starting materials and isolated (18 mg, 53%) as white solid; MS (ESI, m/z): 338.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OCCOC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 54 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.118 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.111 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 7.79 (s, 1H), 7.54 (m, 4H), 7.37 (m, 5H), 7.25 (d, 1H), 6.42 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.76 (m, 2H), 3.34 (s, 3H), 3.25 (q, 2H), 1.46 (s, 6H), 1.04 (t, 3H); LC-MS (ESI) m/z 583 (M−OEt)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1F

Procedure:
Prepared according to procedure A using 2-fluoroaniline (17 mL, 180 mmol), pyridine (29 mL, 360 mmol) and diethyl methylmalonate (46 mL, 270 mmol). The crude was purified by column chromatography on silica (using a gradient of hexane:EtOAc, 1:0 to 4:1 as eluent) to give ethyl 3-(2-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=239.9 (M+1).