Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40].S(=O)(=O)(O)O.[CH3:47]O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([O:41][CH3:47])=[O:40]
Reactant: CO
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Yield: 75.2 %

Procedure:
(±)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (54 g) is dissolved in methanol (540 g), then concentrated sulphuric acid (7.85 ml) is added. The mixture is stirred under reflux for 26 h, then cooled and concentrated in vacuo to ca. one third of the original volume. Water (150 ml) and dichloromethane (150 ml) are added, then the phases are separated. The organic phase is extracted with saturated sodium hydrogencarbonate solution (two times 140 ml), dried over sodium sulphate and concentrated to give a foamy residue. This is dissolved twice in succession in ethanol (150 ml each) and concentrated, and subsequently dried for 18 h in vacuo using entraining nitrogen. A total of 41.6 g of methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate are thus obtained as an amorphous solid, corresponding to 75.2% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(OC1CCC1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of 6.0 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 50 ml DMF were added 3.3 g piperazine-1-carboxylic acid cyclobutyl ester, 9.1 ml N-ethylmorpholine and 5.9 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 11.1 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C@H:19]([CH3:36])[C@:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])([OH:27])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:15]([NH:18][C@H:19]([CH3:36])[C@:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])([OH:27])[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[O:17])=[C:12]([CH3:14])[N:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@H](N)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F

Procedure:
Following a similar procedure to that described in example 1 but using 2-(4-cyanophenyl)-4-methylthiazole-5-carboxylic acid (reference example 24) and (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-imidazol-1 -yl)-2-butanol (75 mg, 0.28 mmol, obtained following the general procedure described in J. Org. Chem., 1995, 60, 3000-3012) in DMF (5 mL) the title compound was obtained as a white solid: mp 126°-128° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.05 (dt, Jt =2, Jd =8.4, 2H, arom), 7.50 (dt, Jt =2, Jd =8.4, 2H, arom), 7.47 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.24 (s, 1H, imidazole), 6.84.6 (m, 2H, arom), 6.52 (br d, J=9.5, 1H, NH, 6.51 (s, 1H, imidazole), 6.32 (s, 1H, imidazole), 4.85 (br quint, J=7, 1H, CHMe), 4.68 (d, J=14.5, 1H, ImCH(H)), 4.29 (d, J=14.5, 1H, ImCH(H)), 2.80 (s, 3H, Me-thiazole), 1.06 (d, J=6.8, 3H, MeCH); MS 227 (acyl group, C12H7N2OS), 223 (Im--CH2COHAr, C11H9F2N2O); [α]D =-20.4° (c 1, CHCl3). Analysis calculated for C25H21F2N5O2S: C 60.84; H 4.29; N 14.19; S 6.50 Found: C 60.85; H 4.31; N 13.75; S 6.18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[NH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:24])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c(O)c1Cc1cccc(Cl)c1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(NC(=O)OC(C)(C)C)c(Cc2cccc(Cl)c2Cl)c1O
Yield: 30 %

Procedure:
To a solution of tert-butyl(4-(2,3-dichlorobenzyl)-5-hydroxy-1H-pyrazol-3-yl)carbamate (160 mg, 0.447 mmol), triphenylphosphine (128 mg, 0.491 mol) and methanol (16 mg, 0.491 mol) in anhydrous THF (25 mL), a solution of DIAD (99 mg, 0.491 mmol) in anhydrous THF (2 mL) was added dropwise at 0° C. with stirring. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The resulting residue was purified by silica gel chromatography eluted with PE:EA=2:1 to provide the titled compound (50 mg, 30%), as a white solid; LC/MS: MS (ES+) m/e 372 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.56 (s, 9H), 3.05 (s, 3H), 3.52 (s, 2H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (s, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: COc1cccc(N=C=O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cccc(OC)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of m-methoxyphenyl isocyanate and 40 ml of dimethylformamide, as yellow crystals having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCn1c2c(c3ccc(NCC(=O)O)cc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 785.3 %

Procedure:
The ester 39 (0.1 g, 0.02 mmol) was dissolved in MeOH-THF (10+10 mL) and aq NaOH (4 N, 5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed on a rotary evaporator and the residue washed with 1 N HCl (30 mL) and extracted with CHCl3 (2×50 mL). The extract was dried over Na2SO4 and concentrated to afford pure 42 (0.075 g, 80%) which was obtained as a brown solid: mp 190-192° C. IR (KBr) 3350, 2973, 1692, 1645, 1619, 1578, 1520, 1364, 1164, 666 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 8.30 (d, J=8.7 Hz, 1H), 7.59 (m, 1H), 7.45 (m, 2H), 7.39 (m, 1H), 7.21 (dd, J=2.4, J=8.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.07 (m, 1H), 4.40 (m, 2H), 3.90 (s, 2H), 3.09 (m, 2H), 1.86 (m, 2H), 1.33 (s, 9H); ESIMS (m/z, relative intensity) 500 (MNa+, 100); HRESIMS calcd for C26H27N3O6Na 500.1798 (MNa+). found 500.1806 (MNa+); HPLC purity: 95.5% (MeOH—H2O, 75:25).
Reaction SMILES: [F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(#N)C>[F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: Oc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Yield: 54.1 %

Procedure:
A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (11.0 g, 34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4 mmol) and ytterbium trifluoromethanesulfonate (2.2 g, 10 mol %) in 20 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 16 h. The reaction mixture was cooled, water was added, and the reaction mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium bicarbonate and brine and dried over MgSO4 The dried organic layer was evaporated to give 8.07 g (89%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2hydroxypropyl)amino]phenol product as a yellow oil. HRMS calcd. for C18H17F7NO3: 428.1097 [M+H]+, found: 428.1104. 1H NMR (CDCl3) δ3.58 (dd, 1H), 3.88 (dd, 1H), 4.39 (m, 1H), 4.68 (s, 2H), 5.91 (tt, 1H), 6.25-6.37 (m, 3H), 7.07-7.14 (m, 4H), 7.35 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A reaction flask was charged with 4-hydroxypiperidine-1-carboxylic acid t-butyl ester (10.05 g, 49.9 mmol) in dry DMF (50 mL) under Argon. NaH (60% in oil, 2.0 g, 50.0 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (6.752 g, 50.0 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (6.809 g, 53%). 1H NMR (CDCl3) d 3.66-3.58 (m, 2H), 3.31-3.24 (m, 1H), 3.12 (d, 2H), 2.90-2.83 (m, 2H), 1.68-1.60 (m, 2), 1.38-1.30 (m, 2H), 1.28 (s, 9H), 0.91-0.82 (m, 1H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) d 154.8, 79.3, 74.4, 72.6, 41.4, 31.2, 28.4, 10.9, 3.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[ClH:30]>C(Cl)Cl>[ClH:30].[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH2:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (0.2 g) was taken in 4 mL of DCM and cooled to 0° C. and HCl (1 mL, 4N in dioxane) was added and reaction was stirred at room temperature for 2 hours. All volatiles were evaporated and residue was triturated with DCM/hexanes (0.17 g). LCMS (m/z): 302.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:54]1[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=1.[NH:65]1[CH2:70][CH2:69][CH:68]([NH:71][C:72](=[O:92])[CH2:73][CH2:74][CH2:75][N:76]2[CH2:81][CH2:80][N:79]([C:82]3[CH:87]=[CH:86][C:85]([C:88]([F:91])([F:90])[F:89])=[CH:84][CH:83]=3)[CH2:78][CH2:77]2)[CH2:67][CH2:66]1>C1(C)C=CC=CC=1.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]>[F:91][C:88]([F:89])([F:90])[C:85]1[CH:86]=[CH:87][C:82]([N:79]2[CH2:80][CH2:81][N:76]([CH2:75][CH2:74][CH2:73][C:72]([NH:71][CH:68]3[CH2:69][CH2:70][N:65]([C:54]4[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=4)[CH2:66][CH2:67]3)=[O:92])[CH2:77][CH2:78]2)=[CH:83][CH:84]=1
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)NC1CCN(c2ccc(SC(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (13 mg; 0.01 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg; 0.04 mmol), sodium tert-butoxide (120 mg; 1.20 mmol), 1-bromo-4-trifluoromethylsulfanyl-benzene (160 mg; 0.62 mmol) and N-piperidin-4-yl-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyramide (300 mg; 0.75 mmol, prepared in accordance with Example 75) are suspended in dry toluene (10 mL) and the mixture is irradiated in a mono-mode microwave oven for 90 minutes at 120° C. The mixture is then cooled down to room temperature, is diluted with ethyl acetate (50 mL), is filtered and the filtrate is concentrated under reduced pressure. The crude residue is then purified by column chromatography on silica gel (dichloromethane:isopropyl alcohol 9:1) to afford the desired product (155 mg; 0.27 mmol). The structure was confirmed using Protocol I-B. Calculated mass=575; observed mass=575; HPLC retention time=5.26 min.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]1(=[O:14])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[C:1]([N:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])(=[O:5])[C:2]([N:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])=[O:3]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CCCCCN1C(=O)C(=O)N1CCCCCC1=O
Temperature: 40 °C

Procedure:
Oxalyl dichloride (63.4 g, 0.5 mol) is added dropwise in the course of 30 minutes to a solution of ε-caprolactam (107.6 g, 0.95 mol) in toluene (300 ml). The internal temperature increases in the course of this from 20 to 60° C. The mixture is then refluxed for 2 hours. After removal of the solvent in vacuo, the resulting oil is taken up in methanol, the colorless precipitate precipitating out in the cold is isolated and dried. Yield 113.8 g (86%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([NH2:36])=[N:31][CH:32]=[N:33]2)=[CH:28][CH:27]=1)=[O:4].C1COCC1.CO>O>[NH2:36][C:30]1[C:29]2[C:34](=[CH:35][C:26]([CH2:25][N:6]3[C:7](=[O:24])[CH2:8][N:9]([S:11]([C:14]4[S:18][C:17]5[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=5[CH:15]=4)(=[O:12])=[O:13])[CH2:10][CH:5]3[C:3]([OH:4])=[O:2])=[CH:27][CH:28]=2)[N:33]=[CH:32][N:31]=1
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ncnc2cc(CN3C(=O)CN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3C(=O)O)ccc12
Reaction time: 16 h
Yield: 75.2 %

Procedure:
Water (1 mL) is added to a solution containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (20 mg, 0.03 mmol), EXAMPLE 799, in a 1:1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (15 mg, 0.35 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 12 mg (63%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Brc1cn2ccnc2c(NCc2ccncc2)n1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2cn3ccnc3c(NCc3ccncc3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4 (1.0 equiv.), 3-aminophenyl boronic acid (1.1 equiv.), Pd (PPh3)4 (0.10 equiv.), and K3PO4 (2.20 equiv.) in 4:1 1,4-dioxane:water is heated to 90° C. for 24 hr. The mixture is cooled to RT and partitioned between EtOAc and sat. NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield [6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-pyridin-4-ylmethyl-amine 5.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:18]([O:17][C:15]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CC(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(C(=O)O)C1

Procedure:
To a solution of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester 3,5-dimethyl ester (6.8 g, 22.5 mmol) in MeOH/water (4:1, 120 mL), K2CO3 (9.4 g, 68 mmol) is added. The reaction is stirred at reflux overnight. The MeOH is evaporated and the residue is extracted with dicholoromethane and 1N aq. HCl. The organic phase is dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 274 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>ClCCl>[Cl:17][C:18]1[N:23]=[C:22]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCCC1
Yield: 71.2 %

Procedure:
Cyclohexylamine (5.72 ml) and N,N-diisopropylethylamine (12.4 ml) were dissolved into 125 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (9.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 80 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (9.1 g) in a yield of 71.2%. ESI-MS (m/z, %) 258 (M−H)+; 1H NMR (400 MHz, CDCl3): δ9.04 (s, 1H), 8.35 (s, 1H), 4.34 (m, 1H), 2.03 (m, 2H), 1.79 (m, 2H), 1.53-1.25 (m, 6H).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]P(OCC)(OCC)=O)=[CH:9][CH:8]=1)C.[CH2:23]([O:25][CH2:26][C:27]1([CH3:40])[CH2:33][CH2:32][CH2:31][S:30][C:29]2[CH:34]=[C:35]([CH:38]=O)[CH:36]=[CH:37][C:28]1=2)[CH3:24]>CN(C=O)C>[CH2:23]([O:25][CH2:26][C:27]1([CH3:40])[CH2:33][CH2:32][CH2:31][S:30][C:29]2[CH:34]=[C:35](/[CH:38]=[CH:13]/[C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:5])=[O:22])=[CH:12][CH:11]=3)[CH:36]=[CH:37][C:28]1=2)[CH3:24]
Reactant: CCOCC1(C)CCCSc2cc(C=O)ccc21
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
85 mg of NaH (ca. 1.4 eq., 50% in mineral oil) was added to a solution of 534 mg (1.4 eq.) of 4-(diethoxyphosphorylmethyl)-benzoic acid ethyl ester in 1.9 ml of abs. DMF at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 1.5 h. After cooling to 0° C., 336 mg (1.27 mmol) of 5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde, dissolved in 1 ml of DMF, was added and allowed to react for 2 h at room temperature. The mixture was then poured onto crushed ice, extracted twice with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/ethylacetate 95/5) afforded 409 mg of pure, colorless title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:35][CH:34]([NH2:36])[CH2:33]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[F:37][C:38]([F:53])([F:52])[C:39]1[CH:40]=[C:41]([CH:49]=[CH:50][CH:51]=1)[C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43]>>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:33][CH:34]([NH:36][C:46]([CH2:45][NH:44][C:42](=[O:43])[C:41]4[CH:49]=[CH:50][CH:51]=[C:39]([C:38]([F:53])([F:37])[F:52])[CH:40]=4)=[O:47])[CH2:35]3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(C2CCC(N3CC(N)C3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid from an EDCI coupling of 1-[4-(4-amino-phenyl)-cyclohexyl]-azetidin-3-ylamine TFA salt (as prepared in the previous step) and (3-trifluoromethyl-benzoylamino)-acetic acid using the procedure described in Step F of Example 1.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.NC(N)=O.[C:21](=O)([O-:23])[O-:22].[Ca+2]>CN(C)C=O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:21]([OH:23])=[O:22])=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Agent: NC(N)=O
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 32 h
Yield: 92 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (2.9 g; 10 mmol), N,N-dimethylformamide (13 g), urea (6 g) and calcium carbonate (1.2 g; 12 mmol) is heated at 95° C. under stirring for 32 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.7 g; 9.2 mmol; yield 92%), m.p. 56°-57° C.