Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][C:30]1[CH:49]=[CH:48][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([O:46]C)=[O:45])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CN(C)C=O.C(O)C.O1CCCC1.[OH-].[Na+].O.Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:29][C:30]2[CH:49]=[CH:48][C:33]([CH2:34][O:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: Fc1ccc(CCNc2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
To a solution of N-[2-(4-fluorophenyl)ethyl]-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (400 mg, 1.09 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (50 mg, in oil, 1.3 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg, 1.0 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give a yellow oil. The oil was dissolved in a mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (109 mg, yield 17%, 2 steps) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:17]([C:18]([NH2:20])=[O:19])[C:16]([CH3:24])(C)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29](OCC)=[CH2:30].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>COCCOC.FC(F)(F)C(O[Pd]OC(=O)C(F)(F)F)=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:25]([F:26])([F:27])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]=[CH2:30])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)C=C(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)C=CC1C(N)=O
Reactant: C=COCC
Agent: O=C(O[Pd]OC(=O)C(F)(F)F)C(F)(F)F
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: COCCOC
Solvent: O
Product: C=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-2-methyl benzoic acid amide synthesized in Synthetic Example 29, 0.865 g of ethyl vinyl ether and 0.022 g of 1,10-phenanthroline in 10 ml of 1,2-dimethoxyethane, 0.04 g of bis(trifluoroacetoxy) palladium (II) was added and stirred at room temperature for 19 hours. After the completion of the reaction, 30 ml of water was added in the reaction mixture, and extracted with ethyl acetate (40 ml×1), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, then filtered through silica gel, and the solvent was distilled under reduced pressure to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([CH3:32])([CH3:31])[CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:24]1([CH3:31])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22][CH2:23]1)[CH:28]=[CH:27][CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3cccc1c32

Procedure:
Beginning with (indol-3-yl)acetamide and (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2>Cl.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(O[C@H]3CCNC3)n2)[nH]1
Yield: 221.4 %

Procedure:
A solution of (S)-tert-butyl 3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (50 mg, 0.116 mmol) in HCl/EtOAc (10 mL) was stirred at RT for 2 hours. The reaction mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound (42.6 mg). ESI-MS m/z [M+H]+ 332.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].B(O)(O)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccncc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and pyridyl-4-boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4(s, 1H), 8.7(d, 2H), 8.5(s, 1H), 8.22(m, 1H), 8.15(d, 1H), 8.05(d, 1H), 7.9(m, 1H), 7.85(d, 2H), 7.7(t, 1H), 7.5(m, 2H), 7.45(d, 1H), 7.0(d, 1H), 4.3(t, 2H), 3.6(m, 4H), 2.9(t, 2H), 2.55(m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:35][CH2:34][C:33]([F:37])([F:36])[CH2:32]3)[C:26]([C:28]([OH:30])=O)=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.[F:46][C:47]([F:57])([F:56])[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1.N1C=CC=CC=1>CC#N.C(Cl)Cl>[F:46][C:47]([F:56])([F:57])[O:48][C:49]1[CH:50]=[CH:51][C:52]([NH:53][C:28]([C:26]2[C:25]([N:31]3[CH2:35][CH2:34][C:33]([F:36])([F:37])[CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:30])=[CH:54][CH:55]=1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(F)(F)C3)cc21
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCC(F)(F)C3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[3,3-difluoro-pyrrolidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (50 mg, 0.090 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) and DCM (2 mL) is stirred for 30 min. This mixture is added to 4-trifluoromethoxyaniline (0.100 mmol) and pyridine (25 μL, 0.32 mmol) in MeCN (1 mL) and it is stirred for 2 h at 40° C. and overnight at 60° C. The mixture is concentrated and the residue diluted with DMF/water 19/1 (2 mL) and purified via reverse phase HPLC.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH:22]2[CH:26]([NH:27][C:28]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:35][C:36]([NH:38][CH:39]3[CH2:43][NH:42][CH:41]([C:44]([O:46]C)=[O:45])[CH:40]3[C:48](=[O:66])[CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][C:54]([CH2:57][NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:53][CH:52]=3)=[O:37])=[O:29])[CH2:25][NH:24][CH:23]2[C:67]([O:69]C)=[O:68])=[O:21])=[CH:14][CH:13]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:62]([O:61][C:59]([NH:58][CH2:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][CH2:49][C:48]([CH:40]2[CH:39]([NH:38][C:36]([O:35][CH2:34][C:33]#[C:32][CH2:31][O:30][C:28]([NH:27][CH:26]3[CH2:25][NH:24][CH:23]([C:67]([OH:69])=[O:68])[CH:22]3[C:20](=[O:21])[CH2:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])=[CH:13][CH:14]=3)=[O:29])=[O:37])[CH2:43][NH:42][CH:41]2[C:44]([OH:46])=[O:45])=[O:66])=[CH:56][CH:55]=1)=[O:60])([CH3:63])([CH3:64])[CH3:65]
Reactant: COC(=O)C1NCC(NC(=O)OCC#CCOC(=O)NC2CNC(C(=O)OC)C2C(=O)CCc2ccc(CNC(=O)OC(C)(C)C)cc2)C1C(=O)CCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)C2C(NC(=O)OCC#CCOC(=O)NC3CNC(C(=O)O)C3C(=O)CCc3ccc(CNC(=O)OC(C)(C)C)cc3)CNC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
A 5 N aqueous NaOH solution (2 ml) is added dropwise to a suspension of 1,4-bis-{N-[3-(4-tert-butyloxycarbonylaminomethylphenylpropionyl)-2-methoxycarbonylpyrrolidin-4-yl]aminocarbonyloxy}2-butyne (A2, 0.6 g, 0.63 mmol) in ethanol (6 ml), and the mixture is stirred at RT for 1 h. The reaction mixture is adjusted to pH 3 with a 20% aqueous KHSO3 solution and extracted with CH2Cl2 (50 ml). The organic phase is then dried over MgSO4, filtered and concentrated in vacuo. The title compound (0.15 g) is obtained as a colorless solid. TLC, silica gel (glass plates), [Tol/Ac (6:4)], Rf=0.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:34])([CH:31]([F:33])[F:32])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:34])([F:18])[CH:31]([F:33])[F:32])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=477.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1>[Cl:26][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Reaction time: 1 h
Yield: 114.3 %

Procedure:
To 5-bromo-1-triisopropylsilyl-7-azaindole (2, 1.60 g, 4.53 mmol) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at −78° C., was added tert-butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachloroethane (1.29 g, 5.43 mmol). The reaction was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound (3, 1.60 g). MS (ESI) [M+H+]+=309.3.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:25]=[CH:24][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]3[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=3)=[CH:25][CH:24]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)NC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CC(C)NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 23.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-isopropyl-1-piperidinecarboxamide formate (0.35 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.152 g, 0.214 mmol).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].[CH3:14][N:15]([CH3:21])[NH:16][C:17](=[O:20])[CH2:18][Cl:19].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:21])[NH:16][C:17](=[O:20])[CH:18]([O:6][C:4](=[O:5])[C:3]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][CH:2]=1)[Cl:19]
Reactant: CN(C)NC(=O)CCl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)NC(=O)C(Cl)OC(=O)c1ccccc1Cl
Yield: 99.8 %

Procedure:
This compound was prepared in the manner of Example I, using 12.2 grams (0.064 mole) of 2,6-dichlorobenzoic acid, 4.2 grams (0.064 mole) of potassium hydroxide, 8.7 grams (0.064 mole) of chloroacetic acid 2,2-dimethylhydrazide, and 1.7 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 180 ml of dry toluene. The crude product was recrystallized twice from ethyl acetate using decolorizing carbon to give 18.6 grams of 2,6-dichlorobenzoyloxyacetic acid 2,2-dimethylhydrazide; mp 160°-162°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[NH:39][C:38]1=[O:46])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][CH2:35][CH2:36][N:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[NH:39][C:38]3=[O:46])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=c1[nH]c2ccccc2n1CCCS(=O)(=O)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CCCn3c(=O)[nH]c4ccccc43)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and 1-(3-((2-bromophenyl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one. MS (ESI): mass calcd. for C26H22FN5O3S, 503.14; m/z found, 503.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.45 (s, 2H), 8.12-8.03 (d, J=7.8, 1H), 7.83-7.75 (m, 1H), 7.75-7.66 (m, 1H), 7.45-7.30 (m, 2H), 7.27-7.19 (d, J=11.5, 1H), 7.09-6.88 (m, 6H), 3.79-3.72 (t, J=6.5, 2H), 2.97-2.88 (dd, J=9.7, 6.3, 2H), 1.79-1.68 (m, 2H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[SH:8][C:9]1[NH:14][C:13](=[O:15])[C:12]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH3:27])[CH:20]=2)=[CH:11][N:10]=1>O.[OH-].[K+]>[CH3:27][O:26][CH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH2:16][C:12]1[C:13](=[O:15])[NH:14][C:9]([S:8][CH3:5])=[N:10][CH:11]=1
Reactant: COCc1cccc(OCCc2cnc(S)[nH]c2=O)c1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCc1cccc(OCCc2cnc(SC)[nH]c2=O)c1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Dimethyl sulphate (0.363 g) was added to a stirred solution of 2-mercapto-5-[2-[3-(methoxymethyl)phenoxy]ethyl]-4(3H)-pyrimidinone (0.85 g) in water (20 ml) and potassium hydroxide (0.163 g). After 1 h., the suspension was filtered to give the title compound (0.76 g) m.p. 129°-131°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:10]([Br:12])[Br:11])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C=C(Br)Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
4-Chlorobenzaldehyde (2.81 g) was dissolved in methylene chloride (300 mL), and carbon tetrabromide (13.3 g) and triphenylphosphine (21.0 g) were added to the solution, followed by stirring at room temperature for 90 minutes. After insoluble matter precipitated was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), to thereby give the title compound (5.54 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-])=O)[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[O:17][CH3:18])([O-:3])=[O:2].[PH2]([O-])=O.[Na+]>[Pd].O1CCCC1.O>[NH2:12][C:8]1[C:9]([O:10][CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:17][CH3:18])=[CH:6][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Reaction time: 0.5 h

Procedure:
A suspension of 26 g of palladium on charcoal (10%) is refluxed in 1.3 l of tetrahydrofuran and 26 ml of water containing 1 mole (258 g) of 2,4-dinitro-1,3,5-trimethoxybenzene. A solution of 247 g of sodium hypophosphite in 260 ml of water is added to this suspension over 3 hours. Refluxing is continued for an additional 30 minutes. After cooling, the catalyst is removed by filtration and the aqueous phase by phase separation. The organic phase is concentrated under vacuum and is then poured onto ice. The expected product precipitates. It melts at 111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22]COC)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C(OCC)(=O)C>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[C:14]([OH:22])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: COCOc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(O)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-methoxymethoxy-5-trifluoromethyl-phenyl)-urea (100 mg, 0.25 mmol) from above was dissolved in a 1:1 solution of 3N HCl/ethyl acetate (20 mL) and stirred vigorously at room temperature for 16 h. Additional ethyl acetate was then added (50 mL) and the mixture was washed with water (2×50 mL), brine (50 mL), dried over Na2SO4, and concentrated. The resulting residue was purified using silica gel flash chromatography eluting with a 3:1 hexane/ethyl acetate solution. Similar fractions were pooled and concentrated to the title compound (72 mg, 72%) as an off-white solid. 1H NMR (CD3OD) δ 7.97 (d, J=2 Hz, 1 H), 7.64 (dd, J=2 Hz, J=8 Hz, 1 H), 7.50 (d, J=8 Hz, 1 H), 7.22(s, 1 H), 7.21 (s, 1 H), 6.75 (s, 1 H); Electrospray MS (MH+) m/z 399.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:26])[CH3:25])[C@H:19]1[CH3:27].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:26])[CH3:25])[C@H:19]1[CH3:27]
Reactant: CCOC(=O)CCCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)O)c(=O)c1Br)C2(C)C
Yield: 45 %

Procedure:
Ethyl 4-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoate (454 mg, 0.981 mmol) in 1,4-dioxane (4.5 mL) was stirred with 1 M aqueous sodium hydroxide (2.06 mL, 2.06 mmol) at room temperature for 6.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (182 mg, 64% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[Cl:12][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carboxylic acid methyl ester (300 mg, 1.45 mmol) in dimethylsulfoxide (2 ml) is added morpholine (0.126 g, 1.0 eq) followed by diisopropylethylamine (0.285 ml, 1.1 eq). The mixture is stirred at room temperature for 15 h before being diluted with water and extracted with ethyl acetate (2×20 ml). The combined organic layers are washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate:hexane (1:1) to provide methyl 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylate as a white solid (0.30 g). Mp: 135-138° C., 1H NMR (300 MHz, DMSO-d6) δ 7.34 (s, 1H), 3.86 (s, 3H), 3.67 (brs, 8H). MS: 257 (M+1).
Reaction SMILES: S(Cl)(Cl)=[O:2].[O:5]=[C:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][N:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:2][C:10]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:5]
Reactant: O=C(O)C1CCN(c2ccccc2)C1=O
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: O=C(O)C1(O)CCN(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (5.8 g) is added dropwise at 0° C. to a solution of 2-oxo-1-phenylpyrrolidine-3-carboxylic acid (5 g) in 5 ml of ethanol, and the mixture is stirred at 80° C. for 4 h.