Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:35])([F:34])[F:36])[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide was made as for Example 18 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.78 (1H, s), 8.55 (1H, d, J=2.1 Hz), 8.26 (1H, s), 8.22 (1H, s), 8.11 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.76-7.80 (2H, m), 7.49 (1H, s), 2.19 (3H, s). LCMS: m/z [M+H]+ 505.9663.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:24]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=C2SC(N3CCN(S(C)(=O)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 52 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (50 mg, 92 μmol) (from Example 23) chloroform (5 mL), methyl sulfonyl chloride (3 equiv, 32 μL) and TEA (3 equiv, 40 μL). The reaction was stirred at 60° C. under N2. The reaction solution was diluted with DCM (70 mL), washed with aq NH4Cl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 90:10) to provide the title compound as a white solid (30 mg, 52%). 1H NMR (DMSO-d6) δ 7.99 (2H, s), 7.94 (1H, s), 7.62 (1H, s), 7.18 (1H, s), 7.13 (1H, dd, J1=2.0 Hz, J2=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 5.37 (2H, s), 4.06 (2H, m), 3.88 (3H, s), 3.74 (2H, m), 3.31-3.36 (4H, m), 2.85 (3H, s); MS (ESI) 624 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>O.[Pt](=O)=O.CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: OCc1ccc2ncccc2c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: OCc1ccc2c(c1)CCCN2
Reaction time: 2 h
Yield: 68.7 %

Procedure:
6-Hydroxymethylquinoline (1 g, 6.28 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and methanol (200 mL) were placed in a Parr bomb and platinum (IV) oxide monohydrate (0.5 g, 2.04 mmoles) was added. The mixture was hydrogenated at 50 psi at 25° C. for 2 h. The catalyst was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (0.7044 g, 68%): CIMS: m/z 164.35 (MH+); δH (CDCl3) 1.93 (2H, m, 3-CH2) and 2.76 (2H, t, 4-CH2), 3.30 (2H, m, 2-CH2), 4.50 (2H, s, CH2OH), 6.45 (1H, d, Ar—H8), 6.96 ppm (2H, m, Ar—H5 and Ar—H7); δC (CDCl3) CH2: 22.1, 27.0, 42.0, 65.6; CH: 114.2, 126.4, 129.2; C: 121.5, 129.4, 144.5.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4](/[N:6]=[C:7](/[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)\SC)=O.[NH2:16][NH2:17].C1COCC1>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[NH:17][N:16]=[C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:6]=1
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Reactant: NN
Solvent: C1CCOC1
Product: CC(C)=Cc1nc(N2CCCC2)n[nH]1
Yield: 22.2 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 2, using (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (3.69 g, 16.3 mmol, Eq: 1.00) and hydrazine 1M in THF (16.3 ml, 16.3 mmol, Eq: 1.00). Chromatography afforded 5-(2-Methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (695 mg, 22.2%) as white waxy solid. MS: m/z=193.1 (M+H+)
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)C(C)C)(C)C>C1COCC1>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol) in THF (1.88 mL) was added acetyl chloride (26 μL, 0.36 mmol) and N,N-diisopropylethylamine (170 μL, 0.98 mmol). The reaction was stirred at rt for 17 h. The mixture was partitioned between EtOAc (25 mL) and H2O (25 mL). The layers were separated and the organic phase was washed with H2O (20 mL), brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 0 to 10% MeOH in EtOAc. The isolated compound was crystallized from EtOAc/hexanes to afford 64 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.13 (dd, 1 H), 6.59 (s, 1 H), 5.64 (s, 2 H), 4.48 (d, 1 H) 3.89 (s, 1 H), 3.32-3.41 (m, 3 H), 3.19 (s, 1 H), 2.67 (d, 1 H), 1.98-2.07 (m, 3 H), 1.66 (d, 1 H), 1.51 (s, 1 H); ES-MS m/z 466.4 [M+H]+, HPLC RT (min) 2.49.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]3)[N:14]=2)[CH:5]=1)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:65][N:66]([CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)[CH3:67]>C1COCC1>[CH3:65][N:66]([CH3:67])[CH:68]1[CH2:73][CH2:72][N:71]([C:26]([CH:23]2[CH2:24][CH2:25][CH:20]([NH:19][C:15]3[N:14]=[C:13]([N:6]4[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]([C:1]([NH2:2])=[O:3])=[CH:5]4)[CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)=[O:27])[CH2:70][CH2:69]1
Reactant: CN(C)C1CCNCC1
Reactant: NC(=O)c1cn(-c2ccnc(NC3CCC(C(=O)O)CC3)n2)c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C1CCN(C(=O)C2CCC(Nc3nccc(-n4cc(C(N)=O)c5ccccc54)n3)CC2)CC1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a suspension of 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclo-hexanecarboxylic acid (150 mg, 0.395 mmol) in THF was added BOP, followed by Hünig's base (103 μL, 0.593 mmol), the mixture stirred for 10 min, and 4-(N,N-dimethylamino)-piperidine (76 mg, 0.593 mmol) was added and stirred for 6 days at RT. The resulting white solid was filtered off, washed with dry THF (20 mL) and DCM (30 mL), and air-dried overnight. The product was purified by prep-TLC using 5% MeOH/DCM+NH4OH, and dried under vacuum to provide 1-{2-[4-(4-dimethylamino-piperidine-1-carbonyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indole-3-carboxylic acid amide (78 mg, 40.3% yield) as a yellow solid (Compound 295).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2cc(-c3cc(Cl)ccc3C)nc(N)n2)cc1
Yield: 52 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-methoxy-phenylamine provided the title compound (52% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 3.74 (s, 3H, CH3), 6.01 (s, 1H, Ar), 6.28 (s, 2H, NH2), 6.87-6.89 (m, 2H, Ar), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.34-7.39 (m, 2H, Ar), 7.60 (d, 2H, J=8.9 Hz, Ar), 9.01 (s, 1H, NH).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OC)ccc2n1Cc1ccc(Br)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1nc2cc(O)ccc2n1Cc1ccc(Br)cc1
Temperature: 5 °C
Yield: 77.3 %

Procedure:
A solution of boron tribromide (2.2 mL, 1 M in DCM) was added drop-wise to a 100 mL round bottomed flask containing ethyl 3-(1-(4-bromobenzyl)-5-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (493 mg, 1.11 mmol) and DCM (20 mL) at −78° C. The resulting solution was allowed to warm to 5° C. over 3 h and partitioned with sat. NaHCO3 (50 mL). The aqueous layer was extracted with DCM (25 mL×3). The combined organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (370 mg, 77%). MS (ESI): mass calcd. for C21H23BrN2O3, 430.08; m/z found, 431.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.43-7.39 (m, 2H), 7.25 (d, J=2.3, 1H), 6.94 (d, J=8.6, 1H), 6.88-6.84 (m, 2H), 6.77 (dd, J=8.7, 2.3, 1H), 5.32 (s, 2H), 4.07 (q, J=7.1, 2H), 3.05 (s, 2H), 1.35 (s, 6H), 1.16 (t, J=7.1, 3H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]1=[O:17])/[CH:2]=[CH:3]/[CH3:4].B.[OH-:19].[Na+].OO>O1CCCC1.[Cl-].[Na+].O>[CH2:3]([CH:2]1[CH2:1][CH:5]2[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2([OH:19])[O:17]1)[CH3:4]
Reactant: [OH-]
Reactant: C/C=C/CC1CCCC(CC(=O)OCC)C1=O
Agent: B
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCC2CC(CC)OC12O
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a stirred solution of ethyl {3-[(2E)-but-2-en-1-yl]-2-oxocyclohexyl}acetate (565 mg, 2.37 mmol) in tetrahydrofuran (20 ml) at 0° C. was added borane.tetrahydrofuran complex (1 M in tetrahydrofuran, 3.56 ml, 3.56 mmol) and the reaction allowed to stir at 0° C. for 35 min. Sodium hydroxide (4N, 5.6 ml) and hydrogen peroxide (5.6 ml) were added and the reaction allowed to stir at room temperature for 1 h. Diluted with brine, then extracted three times with dichloromethane. The combined organics were washed twice with brine, dried over sodium sulfate, concentrated in vacuo and purified by column chromatography (50% EtOAc/hexanes). The desired title compound (345 mg) was obtained as a colourless oil as a complex mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[CH:16]=[CH:17][S:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CN(C)C=O.Cl.[CH3:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[CH3:27][N:28]([CH3:41])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:11]2[CH2:12][CH2:13][C:14]3[S:18][CH:17]=[CH:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=2)=[O:37])=[CH:39][CH:40]=1
Reactant: FC(F)(F)Oc1ccc(C2NCCc3sccc32)cc1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(C(=O)N2CCc3sccc3C2c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Similarly as described in example 22 using a solution of 4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([N:26]([CH3:27])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with 4-(benzyloxy)-N-methylaniline (1.45 g, 6.8 mmol) and DIPEA (0.59 g, 4.53 mmol) using method A to give 4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 716 mg (40%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.46-7.30 (m, 5H), 7.01-6.94 (m, 4H), 5.08 (s, 2H), 3.13 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][OH:43]>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH:42]=[O:43])=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reactant: CO
Agent: [Fe]
Solvent: O=CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(NC=O)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (2.02 g) in 90% aqueous formic acid (56 mL) was added iron powder (3.9 g). The mixture was stirred at room temperature overnight. Methanol was added and the reaction mixture filtered through diatomaceous earth to remove the excess iron. Ethyl acetate was added and the resultant solution washed with water (twice), brine, then dried (MgSO4) and evaporated. The crude material was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98.2) as the eluent, followed by trituration with hexane:diethyl ether (80:20), to provide the title compound (1.12 g) as an off-white solid; TLC: Rf =0.39, dichloromethane:acetone (70:30); NMR: 0.67-1.03 (m,6), 2.03-2.33 (m,1), 4.00-4.80 (m,3), 5.17 (s,2), 7.20-7.60 (m,7), 7.57-7.77 (m,2), 8.22 (s,1), 8.43 (s,1), 8.83- 9.07 (m,2), 10.30-10.57 (m,1); MS: m/z=574(M+1).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:12]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCOC(=O)C#N
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nnnn1Cc1ccccc1
Yield: 93.9 %

Procedure:
A mixture of freshly prepared benzyl azide (1.3 g) and ethyl cyanoformate (1.0 g) in xylene (10 ml) was heated at reflux for 48 hours. The mixture was evaporated under reduced pressure and below 40° C. to give a residue of ethyl 1-benzyl-1H-tetrazole-5-carboxylate (2.13 g).
Reaction SMILES: C([Li])CCC.[Br-].[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:42][C:43]([F:53])([F:52])[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O>CCCCCC.O1CCCC1>[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43]([F:52])([F:42])[F:53])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2cccc(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)C(=CCCc1cccc(Oc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of butyllithium in n-hexane (8.5 ml of 1.6 molar) was added, dropwise, at room temperature and under a nitrogen atmosphere over 10 minutes to [3-(3-phenoxyphenyl)propyl]-triphenylphophonium bromide (7.67 g; 13.75 mmol) in absolute tetrahydrofuran (40 ml). After stirring for 2 hours, α,α,α-trifluoroacetophenone (2.18 g; 12.5 mmol) dissolved in absolute tetrahydrofuran (10 ml) was added dropwise. After stirring for 3 hours at room temperature, the mixture was added to ice-water, extracted with ether and the extract dried over sodium sulphate and evaporated. After chromotography on silica gel using hexane-toluene, there was obtained 4-(3-phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.31 g=71.9% of theory).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[F-:23]>CN1CCCC1=O.C(Cl)Cl>[F:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: [F-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(F)nc3ccccc23)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine 0.150 g (0.5 mmol) and NH4F 0.5 g in 1-methyl-2-pyrrolidinone 3 mL was stirred at 120° C. for 16 h. The reaction mixture was diluted with CH2Cl2 10 mL and directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the crude titled compound product in 10% yield, which was further purified with preparative HPLC. 1H NMR (CD3OD, 400 MHz): δ 7.48-7.43 (m, 1H), 7.25-7.19 (m, 3H), 7.02 (d, 2H, J=9.0 Hz), 6.82-6.73 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H). 19F NMR (CD3OD):−77 (s). m/e: 284.1 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:27]([F:30])([F:29])[F:28])=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:27]([F:30])([F:28])[F:29])=[N:10]2)=[CH:5][CH:4]=1)=[O:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reaction time: 18 h
Yield: 79.9 %

Procedure:
A mixture of N-(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea (250 mg) and mCPBA (326 mg) in CH2Cl2 (10 ml) was stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueous layer was separated and extracted. The combined organic layer was washed with sat. NaHCO3 (twice), dried and evaporated to give 207 mg (79.9%) of crude product. The crude product was column chromatographed by preparative TLC to give 207 mg (80%) of N-(2-{4-[1-[4-(methylsulfinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea as an amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[S:9])=[CH:6][CH:5]=1)[CH3:2].Cl[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:9][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]([OH:16])[N:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(N)=S)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: CCOc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-ethoxythiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:21]1[C:29]([CH:30]2[CH2:32][CH2:31]2)=[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]2[N:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([C:29]2[C:21]([C:9]3[CH:10]=[C:11]([C:15]([OH:18])([CH3:16])[CH3:17])[CH:12]=[N:13][CH:14]=3)=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[CH2:32][CH2:31]1
Reactant: Clc1nn2ccccc2c1C1CC1
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(-c2nn3ccccc3c2C2CC2)c1
Temperature: 100 °C

Procedure:
To a solution of the title compound from Example 1 Step D (0.114 g, 0.434 mmol) and the title compound from Example 1 Step B (0.084 g, 0.434 mmol) in tetrahydrofuran (4.34 mL) were added palladium acetate (0.010 g, 0.043 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.036 g, 0.087 mmol), and potassium phosphate tribasic (0.277 g, 1.30 mmol). The resulting mixture was heated at 100° C. for 18 hours, then filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-25% ethyl acetate in hexanes) provided the title compound: LCMS m/z 293.86 [M+H]+; 1H NMR (500 MHz, CDCl3) 9.16 (s, 1H), 8.76 (s, 1 H), 8.45 (dd, J=2.0, 2.0 Hz, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.11 (d, J=6.9 Hz, 1 H), 6.75 (dd, J=6.7, 6.7 Hz, 1 H), 2.45 (br s, 1 H), 2.01-1.98 (m, 1 H), 1.68 (s, 6 H), 1.01 (d, J=8.0 Hz, 2 H), 0.50 (d, J=5.0 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:12]([N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH:7]=[CH:6][C:5]2[CH:19]=[CH:20][C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:3][C:4]=2[CH2:11]1)(=[O:14])[CH3:13]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2nc(-c3ccccc3)ccc2C=Cc2ccccc21
Yield: 102.1 %

Procedure:
Compound 55D (6.0 mg, 100%) was prepared from 55C (5.0 mg, 0.018 mmol) and phenylboronic acid (2.2 mg, 0.018 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.729 min; LCMS Found: (M+H)+=327.