Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=3[CH:11]=2)=[CH:17][CH:16]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: OB(O)c1ccc(C(F)(F)F)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: [K+]
Solvent: CN(C)C=O
Product: O=C1CCOc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 105 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a solution of 7-bromo-4-chromanone (1.0 g, 4.4 mmol) in DMF (15 mL) was added [4-(trifluoromethyl)phenyl]boronic acid (1.25 g, 6.6 mmol), Pd(PPh3)4 (580 mg, 0.5 mmol) and K2CO3 (1.22 g, 8.8 mmol). The mixture was stirred at 105° C. for 4 h under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 830 mg (61%) of the title compound as white solid. [M+H] Calc'd for C16H11F3O2, 293. Found, 293.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].Cl>>[O:18]=[C:19]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(CCc1cccnc1)NCCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O

Procedure:
Batch size: 2.1 g (13.8 mmol) 3-(3-pyridyl)-propionic acid, 1.6 ml (47.4 mmol) oxalyl chloride, 3.8 ml (27.4 mmol) TEA and 4.0 g (12.5 mmol) 4-(2,5-dioxo-3,4-diphenyl-2,5-dihydropyrrol-1-yl)-butylamine•hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11](OC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1n[nH]c2ccc(Br)cc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of methyl 5-bromo-1H-indazole-3-carboxylate (2.21 g, 8.66 mmol) in THF (60 mL) was cooled to −10° C., and added dropwise with a 1 M solution of diisobutylaluminum hydride in toluene (36.0 mL, 36.0 mmol). After completion of the addition, the mixture was stirred at −10° C. for 1 hour, and then stirred overnight at room temperature. The reaction mixture was added dropwise with saturated aqueous sodium sulfate under ice cooling to terminate the reaction, and then filtered through Celite. The filtrate was concentrated, and the resulting solid was suspended in methylene chloride and thereby washed to obtain (5-bromo-1H-indazol-3-yl)methanol (0.712 g, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Yield: 98.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methylbenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.6 g), the title compound (8.9 g) was obtained.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]([CH3:29])[CH2:11][CH2:12][N:13]([C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[OH:9][C:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:29])[CH2:11][CH2:12][N:13]([C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(=O)CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(CCC(C)(O)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
A solution of phenylmagnesium bromide (1.0 M in THF, 1.0 mL) was added dropwise to a solution of (S)-tert-butyl 3-oxobutyl(1-phenylethyl)carbamate (0.0421 g, 0.144 mmol in THF (4 mL) under N2 at rt. After the solution was stirred for 14 h, the reaction was quenched with 10% aq Na2CO3 (0.5 mL) and diluted with CH2Cl2. The organic layer was dried over Na2SO4. After the solvents were evaporated, the crude product was directly used in the next step without further purification.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.F[C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:5]1[C:9]2=[N:10][CH:11]=[C:12]([O:14][C:22]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1

Procedure:
A mixture of EXAMPLE 3G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI.CCCCCC.C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In a 100 ml 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube were charged of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine (1.10 g) in DMF (10 ml), and cesium carbonate (23.0 g), CH3I (0.641 g) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion, the reaction was poured into cold water. Solid precipitate was filtered out and washed with water. Solid material was dried under reduced pressure at 45° C. for 1 hr to give 1.00 g of 2-chloro-5-fluoro-N-methyl-N-(3-nitrophenyl)pyrimidin-4-amine, which was used in the next step without further purification. M+1=282.8. 1H NMR (DMSO-d6, 400 MHz) 3.50 (s, 3H), 7.701-7.741 (t, 1H, J=8), 7.883-7.902 (d, 1H, J=7.6), 8.287-8.300 (d, 1H, J=5.2), 8.325 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH:42][C@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([N:45]4[CH2:46][CH2:47][C@H:43]([OH:42])[CH2:44]4)=[O:29])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CC[C@H](O)C1
Reaction time: 4 h
Yield: 37.4 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.2 mmol), (S)-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:12]=S)[CH:4]=[N:3]1.[CH2:14]([CH2:16][NH2:17])[OH:15]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]2[O:15][CH2:14][CH2:16][N:17]=2)[CH:4]=[N:3]1
Reactant: NCCO
Reactant: Cn1ncc2cccc(N=C=S)c21
Solvent: CCOCC
Product: Cn1ncc2cccc(NC3=NCCO3)c21

Procedure:
The starting material is prepared as follows: 3 g of 1-methyl-7-isothiocyanato-indazole is added to a stirred mixture of 2 ml of ethanolamine and 100 ml of ether, thus forming a white precipitate. After 2 hours the precipitate is filtered off and washed with ether to yield the starting material; M.Pt. 207° - 209°.
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[NH2:21][CH2:22][CH:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1>ClCCl.O>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:21][CH2:22][CH:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
1-Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride (12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of racemic 4-[4-[5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 4 hours to produce 39.1 g of pure racemic 5-chloro-N-[[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([S:6]([NH2:9])(=[O:8])=[O:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([C:4]2[C:3]3[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=3[S:1][CH:5]=2)(=[O:7])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1csc2ccccc12
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1csc2ccccc12
Yield: 46.9 %

Procedure:
3-Benzo[B]thiophenesulfonamide (6.4 mmol) was reacted with 4-chlorophenylisocyanate (6.4 mmol) as described in Method A to obtain 1.1 g of the title product as a solid. 1H NMR (CD3SOCD3): δ10.94 (bs, 1 H), 8.99 (s, 1 H), 8.75 (s, 1 H), 8.27 (d, J =8 Hz, 1 H), 8.16 (d, J =8 Hz, 1 H), 7.60 (dd, J =8, 8 Hz, 1 H), 7.53 (dd, J =8, 8 Hz, 1 H), 7.38 (d, J =9 Hz, 2 H), 7.31 (d, J =9 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:21][C:20](=[O:22])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([NH:17][CH2:18][CH3:19])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[Cl:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:21][C:20](=[O:22])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([N:17]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1

Procedure:
Prepared by the method described for Example 59 from 9-chloro-3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (0.9 g, 0.003 moles), glacial acetic acid (5 ml), and sodium borohydride (0.6 g, 0.016 moles). Recrystallization from isopropyl ether gave the product (0.45 g), mp 78°-80° C.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH:40]([CH3:42])[CH3:41])[N:33]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:53]>C(O)C>[Na+:53].[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:23]=1[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH:40]([CH3:42])[CH3:41])[N:33]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (70 mg) is dissolved in ethanol (2 ml), and thereto is added 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (62 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (729 mg). MS (m/z): 729 [M−Na]−
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][OH:20])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.[O-:27]S([O-])=O.[Na+].[Na+]>C(#N)C.O.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([C@H:18]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:19]([OH:27])=[O:20])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethanol (1.95 g, 5.00 mmol) in acetonitrile (25 mL) and water (1 mL) was added H51O6 (1.37 g, 6.00 mmol) and CrO3 (1.00 g, 10.0 mmol). The mixture was stirred at room temperature for 1 h and was diluted with EtOAc (50 mL) and a saturated solution of Na2SO3 (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The crude material was taken on without further purification. 1H-NMR: 400 MHz, (CDCl3) δ: 7.42-7.61 (m, 4H), 7.20 (s, 1H), 5.11 (s, 1H), 2.47 (s, 3H), 0.93 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>C(O)(C)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:11]=[C:12]1[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]1=[O:18]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1ccccc1Br
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2ccccc2Br)C(=O)O1
Yield: 87.9 %

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in isopropanol (240 ml) was heated to reflux for 1 hour. After cooling, the deposit was filtrated to obtain 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). A suspension of the obtained 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution. The deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). 4-Chloro-8-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline was obtained according to Example 3(2) using the obtained 8-bromoquinolin-4(1H)-one instead of compound (3a). Compound (130) was obtained as a pale yellow solid (yield based on 6 steps: 3.4%) according to Example 3(3) using 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[S:55])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (137 mg) and (+)-10-camphorsulfonic acid (151 mg) in ethanol (3.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.73 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (86.5 mg, 45%) as white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>CCCCCCC.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 2 h

Procedure:
To a vigorously stirred solution of 2-tert-butylphenol (10 g, 66.6 mmol) in heptane (67 ml) was added at a fast drip a solution of 70% nitric acid (4.25 ml, 66.6 mmol) diluted with water (4.25 ml). The resulting dark red/brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration washed with hexane (300 mL), water (200 mL) and once again with hexane (200 mL) to give a cocoa colored powder that was dried to constant mass (4.65 g, 35.6%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[OH:10][NH:11]C(N)=O>CO>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[C:5]([NH2:6])[O:10][N:11]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NC(=O)NO
Solvent: CO
Product: Nc1cc(C(F)(F)F)no1
Yield: 11 %

Procedure:
Trifluoroacetoacetonitrile (5.12 g, 0.030 mole), hydroxyurea (2.51 g, 0.033 mole) and methanol were heated under reflux for 150 hours to give the title compound (0.50 g, 11.0%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:17]([O:19][P:20]([CH2:25]Cl)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Cl-].[Na+].O>[CH2:17]([O:19][P:20]([CH2:25][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:2][CH2:3]1)([O:21][CH2:22][CH3:23])=[O:24])[CH3:18]
Reactant: O=C(O)c1ccc(CN2CCNCC2)cc1
Reactant: CCOP(=O)(CCl)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CN1CCN(Cc2ccc(C(=O)O)cc2)CC1)OCC
Temperature: 25 °C

Procedure:
To a solution of 4-Piperazin-1-ylmethyl-benzoic acid (4c) and chloromethyl-phosphonic acid diethyl ester (4d) in ethanol was added potassium carbonate. The resulting reaction mixture was refluxed, then cooled to room temperature, diluted with brine, acidified to pH˜4, and extracted with EtOAc until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated on rotary evaporator. The desired product was purified by silica gel flash chromatography.