Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])(C(CO)=O)[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[O-][Bi](=O)=O.[Na+]>C(O)(=O)C>[OH:26][C@H:13]1[CH2:14][C@@:15]2([CH3:25])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:24])[C@H:11]2[C@H:12]1[C@:2]1([CH3:1])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: O=[Bi](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
11β-Hydroxy-4-androstene-3,17-dione was synthesised in a single stage, oxidative reaction from hydrocortisone. The starting material was dissolved in acetic acid and allowed to react with sodium bismuthate overnight in the dark. The mixture was then filtered and washed with dichloromethane. The organic phase was separated, washed with water and neutralised with sodium bicarbonate (to pH 8). The organic phase was again separated and then washed, dried and filtered. Finally, the organic solvent was removed under reduced pressure. Pure product was achieved by recrystallising from ethyl acetate/heptane.
Reaction SMILES: [C:1]([O:5]C(=O)NC1(C2C=CC(C3C(=O)C4C=CC5NC(=O)NC=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[NH2:40][C:41]1[C:50]([OH:51])=[C:49]2[C:44]([C:45](=[O:59])[C:46]([I:58])=[C:47]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48]2)=[CH:43][CH:42]=1>>[I:58][C:46]1[C:45](=[O:59])[C:44]2[CH:43]=[CH:42][C:41]3[NH:40][C:1](=[O:5])[O:51][C:50]=3[C:49]=2[O:48][C:47]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Product: O=c1[nH]c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2o1
Yield: 100 %

Procedure:
Following the procedure used to {1-[4-(2,6-dioxo-8-phenyl-1,2,3,6-tetrahydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-amino-8-hydroxy-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a yellow solid (105 mg, 100%). LCMS (Method G): RT=3.27, [M+H]+=406.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:13]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=1)[CH3:14])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(OC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OC(F)(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (971 mg, colorless oil) from 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone (1.00 g, 4.58 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (833 mg, 6.88 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:41]=[O:42].[Cl-].[NH4+]>O1CCCC1.C1CCCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[CH:41]=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1ncn2Cc1ccccc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Compound 35a (3.45 g, 8.96 mmol) obtained in Example 35 was dissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50 mol/L solution (9.0 mL) of lithium diisopropylamide (13.5 mmol, 1.5 equivalents) in cyclohexane at −78° C., and the mixture was stirred for 1 hour. To the reaction solution was added a solution (10 mL) of N,N-dimethylformamide (2.83 g, 38.7 mmol, 4.3 equivalents) in tetrahydrofuran, and the mixture was stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=33:67 to 50:50). To the residue was added ethyl acetate, and the deposited crystals were collected by filtration to obtain the title compound (3.31 g, 89%) as white crystals.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:22][C@H:23]([C:40]([NH:42][C@H:43]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:41])[CH2:24][C:25]1[N:29]=[CH:28][N:27]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:22][C@H:23]([C:40]([NH:42][C@H:43]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:41])[CH2:24][C:25]1[N:29]=[CH:28][N:27]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:26]=1)=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Temperature: -15 °C
Yield: 79.1 %

Procedure:
A mixture of 1.67 g of Boc-Ser(Bzl), 3.75 g of His(Tos)-Lys(Z)-OBzl and 13.2 ml of methylene chloride was cooled to -15° C., and 1.28 g of DCC was added to the mixture under stirring. Two hours later, the mixture was further stirred at room temperature for 2 hours. Insoluble matters were filtered off and washed with ethyl acetate. The filtrate and the washing were combined and washed with aqueous citric acid, saturated saline and sodium bicarbonate aqueous solution, dried over sodium sulfate anhydride. Then, the solvent was distilled off. The resultant oil residue was crystallized by adding ether to obtain 4.2 g of Boc-Ser(Bzl)-His(Tos)-Lys(Z)-OBzl.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[CH3:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1>C(O)CO.O>[Zn:2].[CH3:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1
Reactant: [Zn+2]
Agent: Cc1ccc(N)c(C(=O)O)c1
Agent: [Cl-]
Solvent: O
Solvent: OCCO
Product: [Zn]
Temperature: 130 °C
Reaction time: 2 h

Procedure:
27.3 g (0.2 mol) of zinc chloride was dissolved in 500 ml of ethylene glycol. To the solution was gradually added 60.4 g (0.4 mol) of 5-methyl-anthranilic acid. After the addition, the mixture was stirred for 2 hours at 130° C. and then dispersed in 3 liters of water. The dispersion was subjected to filtration and the precipitate was washed with water until the filtrate water reached neutrality. The precipitate was then dried at 90° C. to obtain about 40 g of white powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([I:1])[CH:3]=1
Reactant: COc1ncc(I)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(I)cc1CBr
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A solution containing 5-iodo-3-methyl-2-methoxy-pyridine (1.00 g, 4.00 mmol) and NBS (0.78 g, 4.40 mmol) in CCl4 (20 mL) is warmed to reflux. AIBN is added in 5 mg portions (0.03 mmol) every hour. After 3 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (150 mL) and washed successively with aqueous Na2S2O3 (100 mL), water (100 mL), brine then dried over anhydrous Na2SO4, filtered and concentrated. The crude product ispurified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 0.72 g (55%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ3.97 (s, 3H), 4.38 (s, 2H), 7.83 (d, J=2.2 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H) ppm; MS (EI): m/z 327 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@@H:18]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[C@@H:19]([OH:21])[CH3:20])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@@H:18]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[C@@H:19]([OH:21])[CH3:20]
Reactant: C[C@H](O)[C@@H](CCc1ccc(F)cc1OCc1ccccc1)n1cnc(C(N)=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccc(F)cc1O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.9 %

Procedure:
A mixture of 1-[(2S,3R)-5-(2-benzyloxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (0.16 g) and 10% Pd—C (32 mg) in EtOAc (2 ml) and EtOH (2 ml) was stirred under hydrogen atmosphere at room temperature for 3 hr. Pd—C was removed by filtration and the filtrate was evaporated to give an off-white powder of 1-[(2S,3R)-5-(2-hydroxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (62) (131 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1.[CH3:11][SH:12].O1CCCC1.[Na]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][F:10])[CH:5]=[C:6]([S:12][CH3:11])[N:7]=1
Reactant: CS
Reactant: Nc1nc(F)cc(CF)n1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1cc(CF)nc(N)n1
Reaction time: 1 h

Procedure:
A mixture of 1.0 part of 2-amino-4-fluoro-6-fluoromethylpyrimidine, 3.0 parts of methanethiol and 50 parts of dry tetrahydrofuran was stirred at 5° C. whilst a solution of 0.16 parts of sodium in 20 parts of dry methanol was added dropwise. The temperature was kept below 10° C. with ice-bath cooling. When the addition was complete, stirring was continued for 1 hour. The resulting solution was evaporated and the residue was diluted with water and extracted three times with 50 parts of ether. The ethereal solutions were combined and dried (MgSO4). The solvent was evaporated and the crude product was purified by recrystallisation from carbon tetrachloride to give 2-amino-4-fluoromethyl-6-methylthiopyrimidine m.p. 95°-97° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:53])[CH2:10][C:11]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:53])[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(F)(F)F)ccc4CC(N)=O)n3)cc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(F)(F)F)ccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.5 %

Procedure:
TFA (0.1 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A62) (0.170 g, 0.261 mmol) in DCM (4 mL) and the resulting mixture stirred for 24 hours at room temperature. The volatiles were evaporated under reduced pressure then the residue adsorbed onto silica gel and purified by column chromatography (SiO2, 1-50% MeOH in DCM). The volatiles were removed in vacuo and the residue dissolved in dry MeOH (5 mL). Formaldehyde (37 wt. % in H2O; 0.030 mL, 0.36 mmol) was added and the resulting mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.077 g, 0.362 mmol) was added under nitrogen and the resulting mixture stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure then the residue dissolved in EtOAc and washed with 10% NaHCO3 (20 mL). The organics were dried (MgSO4) and the volatiles removed under reduced pressure. The residue was adsorbed onto silica gel, then purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 50-100% MeOH in EtOAc then 10% NH3 in EtOH). Further purification by semi preparative HPLC was required to give the title compound 17 as a pale cream solid (0.011 g, 26%); 1H NMR (400 MHz, d4-MeOH) δ 8.55 (s, 1H), 7.67-7.60 (m, 2H), 7.50-7.40 (m, 3H), 7.28-7.19 (m, 2H), 3.74 (s, 2H), 3.54-3.40 (m, 2H), 3.31-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.80 (m, 4H), 2.08 (d, J=13.8 Hz, 2H), 1.97-1.92 (m, 2H). LCMS-B: rt 4.52 min; m/z 566 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:32]>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]=3[CH2:19][NH:20][CH3:21])[CH2:16][CH2:15]2)[CH3:18])=[O:28])=[CH:25][C:24]=1[CH3:32]
Reactant: Cc1cc(C(=O)Cl)ccc1Cl
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)c(C)c2)CC1

Procedure:
from trans-4-[4-(3-hydroxypropyl)methylaminomethyl-phenyl]-N-methylcyclohexylamine and 4-chloro-3-methylbenzoylchloride. Melting point: 98°-100° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:52])[NH:10][CH:11]([CH3:51])[CH2:12][C:13]([NH:15][CH:16]([C:29](=[O:50])[N:30]([CH2:42][CH:43](OCC)OCC)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[O:40][CH3:41])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C(C)(C)C)=[CH:20][CH:19]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([NH:8][C:9]([N:10]1[CH:11]([CH3:51])[CH2:12][C:13](=[O:14])[N:15]2[CH:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:29](=[O:50])[N:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=3[O:40][CH3:41])[CH2:42][CH:43]12)=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc(OC)c1OC)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Solvent: O=CO
Product: COc1cccc(CN2CC3N(C(=O)NCc4ccccc4)C(C)CC(=O)N3C(Cc3ccc(O)cc3)C2=O)c1OC
Yield: 46.6 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-N-{2-(4-tert-butoxy-phenyl)-1-[(2,2,-diethoxy-ethyl)-(2,3-dimethoxy-benzyl)-carbamoyl]-ethyl}-butyramide (3.56 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 8-(2,3-Dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.32 g, 3 step yield: 40%). 1H NMR (CDCl3, 300 MHz) δ 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.82 (s, 3H), 3.66 (s, 3H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.45 (m, 3H) MS ESI 573 (M+H), 595 (M+Na).
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(-c2cc(NCC(=O)OC(C)(C)C)ccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2cc(NC)ccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
415 mg (1.08 mmol, 1 eq) of ethyl 3-{4-[4-(tert-butoxycarbonylmethylamino)pyrid-2-yl]phenyl}propanoate are dissolved in 10 mL of dichloromethane. 3 mL of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 mL of saturated sodium hydrogen carbonate solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. 270 mg of ethyl 3-[4-(4-methylaminopyrid-2-yl)phenyl]propanoate are obtained. Yield=88%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].[O:19]=[S:20]1(=[O:34])[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:34]=[S:20]1(=[O:19])[CH2:21][CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=4[CH3:18])=[CH:14][CH:13]=3)=[O:17])=[CH:29][CH:28]=2)[CH2:24][CH2:25]1
Reactant: Cc1ccc(C#N)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-cyano-2′-methyl-biphenyl-4-carboxylic acid (100 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (101 mg), EDAC (81 mg), HOBT (57 mg) and N-methylmorpholine (0.09 ml) in dry DMF (2 ml) was stirred at 20 C for 18 h. Water (8 ml) was then added and the resulting solid collected by filtration and dried (160 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2].Cl.[OH-].[NH4+:22]>>[C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH2:22])=[O:14])=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Agent: Cl
Agent: [OH-]
Product: NC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Reaction time: 16 h

Procedure:
Methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate (1 g) from Example 2 is dissolved in 5 mL of 28% ammonium hydroxide solution. The reaction mixture is stirred at ambient conditions for 16 hours. In an ice-water bath, the solution is carefully acidified using concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [F:1][C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.FCCO>>[F:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: N#Cc1ccc(Cl)nc1
Agent: OCCF
Product: CC(N)c1ccc(OCCF)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2-fluoroethanol.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]=[C:14]([CH3:17])[S:15][CH:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]=[C:14]([CH3:17])[S:15][CH:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3csc(C)n3)cc12
Agent: BrB(Br)Br
Product: Cc1nc(-c2cc3c(O)cccc3o2)cs1
Yield: 78.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 4-(4-methoxybenzo(b)furan-2-yl)-2-methylthiazole (2.7 g) obtained in Starting Material Synthesis Example 67 and boron tribromide (7.5 g), 4-(4-hydroxybenzo(b)furan-2-yl)-2-methylthiazole (2.0 g) was obtained as yellow crystals. By the reactions in the same manner as in Starting Material Synthesis Example 2 using this compound, (S)-glycidyl nosylate (2.9 g) and potassium carbonate (3.1 g), (S)-4-(4-glycidyloxybenzo(b)furan-2-yl)-2-methylthiazole (2.1 g) was obtained as a brown oil. By the reactions in the same manner as in Example 1 using the brown oil and 4-(naphthalen-2-yl)piperidine (1.5 g), the title compound (0.3 g) was obtained as white crystals, melting point 148–150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:3]=1[NH2:4].C(OC(=O)C)(=O)C.[CH3:17][C@H:18]1[CH2:23][NH:22][CH2:21][C@@H:20]([CH3:24])[NH:19]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C>C(O)(=O)C.O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C@H:18]1[NH:19][C@@H:20]([CH3:24])[CH2:21][N:22]([C:6]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH:5]=2)[NH2:4])[CH2:23]1
Reactant: Nc1cc(I)ccc1Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1

Procedure:
2-Chloro-5-iodoaniline (630 mg, 2.49 mmol) was heated at reflux in acetic acid (7 ml) and acetic anhydride (7 ml) for 18 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase separated and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a mixture of the mono- and di-acylated acetamide (N-(2-chloro-5-iodophenyl)acetamide and N-acetyl-N-(2-chloro-5-iodophenyl)acetamide). To this product (820 mg) in 1,4-dioxane (12 ml) was added cis-2,6-dimethyl piperazine (416 mg, 3.64 mmol), sodium tert-butoxide (700 mg, 7.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.049 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (39 mg, 0.098 mmol) and the reaction heated at reflux for 18 hours under argon. The reaction mixture was cooled, diluted with ethyl acetate (30 ml) and stirred with a mixture of celite and charcoal. The solution was filtered through celite washing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, 50% saturated brine solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with 5N HCl (20 ml) and heated at reflux for 24 hours under argon. The reaction was cooled, and the solution washed with ethyl acetate (×3), poured onto ice, basified with 0.880 ammonia and extracted with dichloromethane (×4). The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of 2% to 10% methanol in dichloromethane) to afford the title compound (D34). MS (ES+) m/e 240/242 [M+H]+.