Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[Br:19][C:16]1[CH:15]=[N:14][C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)cnc3n2)cc1
Temperature: 110 °C
Yield: 28.5 %

Procedure:
748 mg (corresponding to 3.5 mmol) of 2-bromo-4′-hydroxyacetophenone and 605 mg (corresponding to 3.5 mmol) of 2-amino-5-bromopyrimidine were dissolved in 30 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 15 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure. The resulting crude product was recrystallized from N,N-dimethylformamide, to obtain 289 mg (corresponding to 0.997 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyrimidine (FIG. 6, Step 2).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].S(Cl)([Cl:11])=O.O>C(Cl)Cl>[Cl:11][C:2]([CH3:1])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CC(C)(C)Cl
Temperature: -30 °C
Yield: 85 %

Procedure:
15 ml of 2,4,4-trimethyl-pentene-1 are dissolved in 150 ml of CH2Cl2, cooled to -30° C. and mixed dropwise with a mixture of 10.3 ml of thionyl chloride and 5.4 ml of H2O. The mixture is then heated to 0° C. and washed after 2.5 hours with cold 1% aqueous K2CO3 solution, then with ice-cold water. The product is dried over MgSO4 and distilled off. Yield 85%; nD20 =1.4308; Bpt.10 mm 38° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([O:26]S(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:40])([F:39])[CH:36](O)[CH3:37]>>[C:1]([O:5][C:6]([C:8]1[C:9]([O:26][CH:36]([CH3:37])[C:35]([F:40])([F:39])[F:34])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Reactant: CC(O)C(F)(F)F
Product: CC(Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 92 step A from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and 1,1,1-trifluoro-propan-2-ol (0.052 ml, 0.58 mmol). Sticky pale yellow liquid (70 mg, 50%). LC-MS (ESI): 486 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16](OC)=[O:17])=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][OH:17])=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(CC(C)C)nc2ccc(Br)cc2c1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CO
Temperature: -75 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of methyl 6-bromo-2-isobutyl-4-phenylquinoline-3-carboxylate (3.0 g, 7.5 mmol) in toluene (100 ml) was added 0.95 M solution (20 ml) of diisobutylaluminum hydride in toluene at −75° C. under a nitrogen atmosphere. After stirring the mixture at −75° C. for 1 hr., a solution of sodium sulfate (2.7 g) in water (15 ml) was added. The temperature of the mixture was raised to room temperature and the mixture was further stirred for 1 hr. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane, and recrystallized from n-hexane-toluene to give (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methanol (1.6 g, yield 57%) as pale-yellow crystals.
Reaction SMILES: C(OC([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][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:17][CH:18]=2)[C:13]1=[O:39])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][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][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:17][CH:18]=2)[C:13]1=[O:39]
Reactant: COC(=O)CCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 19 (0.060 g, 0.112 mmol) was treated with trifluoroacetic acid (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.8:1.2, to yield the product 24 (0.028 g, 60%) as a brown solid: mp 272-274° C. IR (KBr) 2952, 1735, 1690, 1656, 1572, 1532, 1510, 1160, 765, 455 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.28 (s, 1H), 7.92 (m, 1H), 7.31 (m, 3H), 7.20 (s, 2H), 4.30 (t, J=4.8 Hz, 2H), 3.71 (s, 3H), 2.83 (m, 2H), 2.68 (m, 4H), 2.00 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 191.8, 174.9, 172.6, 164.4, 155.6, 139.2, 138.2, 135.9, 134.8, 131.9, 129.3, 127.1, 125.0, 124.9, 124.0, 123.8, 122.9, 118.5, 114.8, 109.5, 57.6, 57.4, 57.2, 43.6, 36.3, 32.2, 30.3, 29.7; ESIMS m/z (relative intensity) 434 (MH+, 100); HRESIMS calcd for C24H23N3O5 434.1852 (MH+). found 434.1835 (MH+); HPLC purity: 98.0% (1% TFA in MeOH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH2:16]([NH:18][C:19](=[O:36])[NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:19]([NH:18][CH2:16][CH3:17])=[O:36])=[CH:26][CH:25]=2)[CH:7]=1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
(S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (Intermediate 1B) (992 mg, 4.0 mmol), 4-(3-ethylureido)phenyl boronic acid pinacol ester (1.05 g, 3.6 mmol), cesium carbonate (3.9 g, 12.0 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (163 mg, 0.2 mmol) in dioxane/water (1:3, 2.4 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, the residue suspended in water (150 mL) and the pH adjusted from 10 to 7 with HCl (2M aq solution). EtOAc (150 mL) was added and aqueous layer removed. The organic layer was washed with brine (70 mL) and then concentrated in vacuo to leave a brown solid which was purified by flash chromatography (0-5% MeOH in DCM over 30 min) to yield an orange solid, 630 mg, 42%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][C:13]([F:24])([F:23])[C:14]([O:17][CH:18]([O:20][CH2:21][CH3:22])[CH3:19])([CH3:16])[CH3:15])(=O)C>CCOCC>[CH2:21]([O:20][CH:18]([O:17][C:14]([CH3:16])([CH3:15])[C:13]([F:23])([F:24])[CH2:12][CH2:11][OH:10])[CH3:19])[CH3:22]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CCO
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2.25 g (0.059 mol) of lithium aluminum hydride in 50 mL of ether at 0° C. was added dropwise, 11.30 g (0.040 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-acetate in 130 mL of ether. The mixture was heated at reflux (35° C.) for 3 hr and then was recooled to 0° C. The mixture was quenched by adding dropwise 4.5 mL of water followed by 3.6 mL of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. Evaporation of solvent and column chromatography of the residue on 0.06-0.20 mm silica gel afforded 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol. NMR (CDCl3) δ5.00 (quartet, 1, J=7 Hz), 3.86 (broad, 2), 3.51 (quartet, 2, J=7 Hz), 2.25 (multiplet, 2), 1.35 (triplet, 6, J=1 Hz), 1.30 (doublet, 3, J=7 Hz), and 1.18 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:56]([NH:58][CH3:59])=[O:57]>CN(C=O)C>[CH3:61][C:60]([CH3:63])([CH3:62])[C@H:55]([NH:54][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:56](=[O:57])[NH:58][CH3:59]
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.7 %

Procedure:
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 0.1 g, 35 mmol) was suspended in DMF (3 mL). HBTU (266.14 mg, 0.7 mmol), DIEA (0.31 mL, 1.75 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 52.82 mg, 0.42 mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 10.39%) as white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20].O>C(Cl)Cl>[C:17]([NH:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)N[C@H]1C=C[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
34.7 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride and 2 g of 4-N,N-dimethylaminopyridine were dissolved in 600 ml of methylene chloride. The solution was cooled to 0° C. Then 52 g of triethylamine were added dropwise (5 min). The mixture was stirred for a further 30 min. A solution of 35.2 g of butyryl chloride in 60 ml of methylene chloride was metered into the mixture at 0° C. over the course of 1 h. The mixture was stirred for a further 1.5 h at between 0 and 20° C., and then 600 ml of water were added. After phase separation, the aqueous phase was extracted with 600 ml of methylene chloride. The combined organic phases were washed 3 times with 500 ml of 10% strength KaOU each time, and then completely evaporated. The dried solid was dissolved in 120 ml of methanol. The solution was mixed with 5 g of K2CO3 and stirred for a further 2 h at room temperature. The inorganic salts were filtered off and washed with 20 ml of methanol. The filtrate was neutralized with 2N HCl. The suspension was filtered and the filter cake was washed with 20 ml of methanol. The filtrate was completely evaporated. The solid residue was dried and crystallized in 150 ml of toluene. 28.5 g of title compound were obtained. The yield was 67%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N1CCN(C2CCC(=O)CC2)CC1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl>[N:11]1([C@@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O[C@H]1CC[C@@H](N2CCN(Cc3ccccc3)CC2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Solvent: ClCCl
Product: O[C@H]1CC[C@@H](N2CCNCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
cis-4-(4-Benzylpiperizin-1-yl)cyclohexanol (prepared according to the process described in Example 5 using 4-(4-benzylpiperizin-1-yl)cyclohexanone in Stage a) (11.6 g, 30.3 mmol) is placed in 80 ml of dichloromethane at 0° C. α-Chloroethyl chloroformate (9.9 ml, 90.9 mmol) is run in dropwise and the mixture is stirred for 0.5 h at 0° C.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N-(N-tert-Butoxycarbonylpipecolyl)-4-amino-5-benzyloxy-2-oxo-tetrahydrofuran (654 mg) was dissolved in 15 ml of 25% trifluoroacetic acid in dichloromethane and stirred at room temperature. The mixture was concentrated to give a gummy residue. The residue was dissolved in dichloromethane and washed with 10% sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 422 mg of the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)cn2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)cn2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoate (480 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (25 mL), and trifluoroacetic acid (12.5 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to yield 56.1 mg (13%) of 3-(3-((2-((5-(3,4-dimethylphenyl)pyrazin-2-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoic acid as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.34 (s, 1H), 11.06 (s, 1H), 9.39 (d, J=1.2 Hz, 1H), 9.03 (d, J=1.2 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.92˜7.84 (m, 3H), 7.78 (d, J=7.2 Hz, 1H), 7.55˜7.46 (m, 3H), 7.29 (d, J=8.1 Hz, 1H), 3.83 (s, 1H), 3.28 (m, 4H), 2.73˜2.72 (m, 2H), 2.32 (s, 3H), 2.28˜2.27 (m, 4H), 1.61˜4.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([CH3:27])[NH:7][C:8](=[O:26])[CH2:9][N:10]([C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1)[CH:11]1[CH2:13][CH2:12]1)C.[Li+].[OH-]>C1COCC1>[NH2:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]([N:10]([CH:11]2[CH2:12][CH2:13]2)[CH2:9][C:8]([NH:7][C@H:6]([CH3:27])[CH2:5][C:4]([OH:28])=[O:3])=[O:26])=[O:25])[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)C[C@@H](C)NC(=O)CN(C(=O)CCCc1ccnc(N)c1)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](CC(=O)O)NC(=O)CN(C(=O)CCCc1ccnc(N)c1)C1CC1
Reaction time: 8 h

Procedure:
Ester 9-3 (44 mg, 0.1 1 mmol) was dissolved in 1.1 mL THF, then 1 N LiOH (0.28 mL, 0.28 mmol) was added. After stirring overnight the reaction mixture was loaded directly onto a flash chromatography column (silica, eluting with 7:20:1:1 EtOAc/EtOH/H2O/NH4OH) providing 9-4 as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
To a mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in the above (1)) 500 mg and triethylamine 0.58 ml in dimethylformamide 3 ml is added 3-chloro-4-methoxybenzylamine 359 mg in dimethylformamide 3 ml at room temperature over a period of 15 minutes, and the mixture is stirred for 4 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-chloro-2-methylthiopyrimidine as a slightly brown powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a mixture of 6-bromo-3-(4-fluorophenyl)-imidazo[1,2-a]pyridine (intermediate E) (100 mg, 344 μmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (119 mg, 412 μl) in 1,2-dimethoxyethane (2 ml), was added 1M Na2CO3 (859 μl, 859 μmol), and the reaction mixture was purged with argon for 10 min in an ultrasonic bath. Afterwards tetrakis(triphenylphosphine)palladium(0) (39.7 mg, 34.4 μmol) was added, and the stirred reaction mixture was heated under reflux conditions for 17 h. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (190 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH, 0-20%) and trituration (diethyl ether) to yield the title compound as an off-white solid (40 mg, 31%), MS (ISP) m/z=373.4 [(M+H)+], mp 172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](OS(OCC)=O)[CH3:25].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:24][CH3:25])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: CCOS(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of about 50 % sodium hydride, and stirring was performed for 30 minutes. To the mixture was further added 3.5 g of diethylsulfite and the whole was reacted for 2 hours at room temperature. After the reaction was finished, the solvent was distilled off from the mixture under reduced pressure. To the residue thus obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.7 g of 1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 210°-211°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])#[N:2].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([N:10]=[C:16]=[O:17])=[O:9])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cnc(C(F)F)c(C(N)=O)c1
Solvent: ClCCl
Product: N#Cc1cnc(C(F)F)c(C(=O)N=C=O)c1
Yield: 88.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 5-cyano-2-(difluoromethyl)nicotinamide (1.0 g), oxalyl chloride (3.2 g, 25.3 mmol) and DCM (20 mL) to afford 1.0 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2.CN(C)[CH:16]=[O:17].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:16][OH:17])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2
Reactant: CN(C)C=O
Reactant: Cc1cn2c(n1)sc1ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2sc3ccccc3n2c1CO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 100 ml of n-butanol were heated 30.0 g of 2-aminobenzothiazole and 25.0 g of propargyl bromide at 100° C. for 6 hours. After cooling, the precipitated crystals were taken out by filtration and recrystallized from water to give 40.0 g of the intermediate. Next, the intermediate was added to 250 ml of sodium ethoxideethanol solution (Na, 3.3 g). The mixture was heated under reflux for one hour. After completion of the reaction, the solvent was removed and water was added to the residue. The precipitated crystals were taken out by filtration to give 22.4 g of 2-methylimidazo[2,1-b]benzothiazole. The benzothiazole was added to a mixture of 300 ml of dry dimethylformamide and 30.0 ml of phosphorus oxychloride followed by heating at 60° C. for 6 hours. After completion of the reaction, the reaction mixture was poured onto 1 liter of chilled water and then was neutralized with ammonium hydroxide. Then, the precipitated crystals were taken out by filtration. The thus obtained formyl compound, 20.5 g, was suspended in 300 ml of methanol and 1.5 g of sodium borohydride was added to the suspension followed by stirring at room temperature for 2 hours. After methanol was removed, the residue was treated with 200 ml of water and filtered to give 20.0 g of the title compound.