Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(C=CC[C:22]2([C:35]([NH:37][CH2:38][CH2:39][CH3:40])=[O:36])[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=CC=1)([O-])=O.C([N:43]([CH2:46][CH3:47])CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([NH:43][C:46]1[CH:47]=[CH:35][C:22]([CH2:34][CH2:29][CH2:28][CH2:27][C:22]2([C:35]([NH:37][CH2:38][CH2:39][CH3:40])=[O:36])[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:23][CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CCCNC(=O)C1(CC=Cc2ccc([N+](=O)[O-])cc2)c2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)C1(CCCCc2ccc(NC(=O)c3ccccc3)cc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Benzoyl chloride (156 μL, 1.35 mmol) was added dropwise to a solution of Example 207 Part A compound (490 mg, 1.23 mmol) and triethylamine (257 μL, 1.85 mmol) in CH2Cl2 (4 mL) at 0° C. under argon. The reaction was stirred at 0° C. for 30 min, diluted with CH2Cl2 (20 mL) and CHCl3 (20 mL), washed with 1N KOH (2×10 mL) and water (10 mL), then dried over MgSO4. Evaporation gave a yellow solid, which was adsorbed onto silica gel (10 g), then purified by flash chromatography on silica gel (150 g) eluting with 5% EtOAc/CH2Cl2 to give a solid. The product was dried under high vacuum at 50° C. overnight to provide title compound (412 mg, 67%) as a white solid.
Reaction SMILES: [Cl-].[C:2]1([N+:8]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=CC=CC2C(=O)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([CH2:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH3:42])[CH:36]=[C:35]3[CH2:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+].C(OCC)(=[O:59])C>CO.CN(C)C=O>[C:17]1([N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([O:49][C:48](=[O:50])[C:47]2[CH:51]=[CH:52][C:44]([CH2:43][C:35]3[C:34]4[C:38](=[CH:39][CH:40]=[C:32]([NH:31][C:29](=[O:30])[CH2:28][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH:33]=4)[N:37]([CH2:41][CH3:42])[CH:36]=3)=[C:45]([O:53][CH3:54])[CH:46]=2)=[O:59])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)C1C=CC=C[N+]1(c1ccccc1)c1ccccc1
Reactant: CCn1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Reaction time: 0.03 h

Procedure:
A solution of N,N-diphenylcarbamoylpyridinium chloride (311 mg) in methanol (1 ml) was added to a stirred solution of the acid (J) (450 mg) and sodium hydroxide (1 ml of a 1M aqueous solution) in methanol (4 ml) under an atmosphere of nitrogen. After stirring for 1.5 minutes, ethyl acetate and N,N-dimethylformamide (2 ml) were added and the mixture allowed to stir until all dissolved. The ethyl acetate solution was washed with water and saturated brine, dried (MgSO4) and evaporated to give a quantitative yield of 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (E) as a crusty foam; partial NMR: (80 MHz, DMSO-d6): 1.30(t, J=7.1 Hz, 2H, NCH2CH3), 3.84(s, 3H, OCH3), 3.94(s, 2H, ArCH2), 4.05(q, J=7.1 Hz, 2H, NCH2CH3), 7.41(s, 10H, NArH), 9.56(s, 1H, CONH).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[N:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH3:29])=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[K+]>C(O)C.O>[CH2:1]([N:8]1[C:12]2=[C:13]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[N:14]=[C:15]([C:17]([NH2:18])=[O:31])[CH:16]=[C:11]2[C:10]([CH3:29])=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C#N)cc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(N)=O)cc12
Yield: 83.3 %

Procedure:
1-Benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.76 mmol) prepared in Example 686 was diluted with a mixture of ethanol (7 ml) and water (1 ml). Potassium hydroxide (426 mg, 7.6 mmol) was added to the solution, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 260 mg of the titled compound as a white solid. (Yield: 84%)
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].C1(CNC([C:18]2[CH:35]=[CH:34][C:21]3[NH:22][C:23]([C:25]4[C:33]5[C:28](=CC=CC=5)[NH:27][N:26]=4)=[N:24][C:20]=3[CH:19]=2)=O)CCCCC1>>[CH2:3]([O:4][C:28]1[NH:27][N:26]=[C:25]([C:23]2[NH:22][C:21]3[CH:34]=[CH:35][CH:18]=[CH:19][C:20]=3[N:24]=2)[CH:33]=1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NCC1CCCCC1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Product: CCOc1cc(-c2nc3ccccc3[nH]2)n[nH]1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of trifluoroacetic acid (6 mL) and 2-(5-ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (300 mg, Reference Example 11) was stirred at 50° C. for 1.5 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) and then recrystallised from toluene to give 2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole (0.1 g) as a colourless solid, mp 217-219.5° C. [Elemental analysis:—C, 62.26%; H, 5.23%; N, 23.44%. Calculated for C12H12N4O:—C, 63.15%; H, 5.30%; N, 24.55%].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[CH3:17][O:16][C:14]([C:3]1[C:4]2[NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8][C:9]=2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:2]=1[CH3:1])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1c(C)ccc2[nH]c(=O)c(=O)[nH]c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 23 h

Procedure:
To a solution of 6-methyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid, methyl ester (1.11 g, 4.74 mmol) in conc. H2SO4 (15 mL) at room temperature was added in one portion with vigorous stirring potassium nitrate (0.529 g, 5.23 mmol). The reaction mixture was stirred for 23 hours and poured over ice. The precipitated product was thoroughly washed with water upon collection to give 1.28 g (97%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:4]1[CH:3]=[C:2]([B:13]([OH:17])[OH:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(B(O)O)cc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (6.9 g) in 1,4-dioxane (150 ml) was added bis(pinacolato)diboron (8.03 g), dichlorobis(triphenylphosphine)palladium(II) (1.69 g) and potassium acetate (8.87 g), and the mixture was stirred at 95° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product (11 g) in acetone (200 ml) and water (200 ml) was added ammonium acetate (5.1 g) and sodium periodate (14.1 g), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resultant solid was triturated with diisopropyl ether to give [3-methyl-4-(methoxycarbonyl)phenyl]boronic acid (2.65 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][C:27]([O:30][C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl.O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:24][C:25]3[S:26][C:27]([O:30][C:31]4[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=4)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][N:29]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCOC(=O)c1cccc(Oc2cnc(N)s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A 1 L two necked round bottom flask maintained under inert atmosphere was charged with 2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (16 g, 47 mmol; preparation 4), ethyl 3-(2-aminothiazol-5-yl)oxybenzoate (13.6 g, 51 mmol; preparation 20), HOBt (7.6 g, 56 mmol) and EDCl (10.8 g, 56 mmol) in Dichloromethane (500 mL). The reaction mixture was stirred at 25° C. and added triethylamine (15.8 mL, 113 mmol). The resulting mixture was continued to stir for 16 hours at 25° C. Completion of reaction was confirmed by TLC. The reaction mixture was diluted with water (400 mL) and DCM (250 mL). The layers were separated. The aqueous layer was again extracted with DCM (2×200 mL). The combined organic layer was washed with 1N HCl (300 mL), brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained residue was purified by column chromatography using 5-40% ethyl acetate in hexanes as solvent system to get a pure product (16 g).
Reaction SMILES: C([O:3][C:4](=[O:47])[C:5]([CH:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][C:21]([Cl:27])=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)=[N:6][OH:7])C.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:46][C:40]1[CH:39]=[C:38]2[C:43]([CH:44]=[CH:45][C:36]([CH2:35][O:34][C:31]3[CH:30]=[CH:29][C:28]([CH:8]([C:5](=[N:6][OH:7])[C:4]([OH:47])=[O:3])[C:9]4[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][C:21]([Cl:27])=[CH:22][CH:23]=6)[N:18]=5)=[CH:13][CH:14]=4)=[CH:33][CH:32]=3)=[N:37]2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a solution in THF/EtOH/H2O (3:2:1, 35 mL) of bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid ethyl ester (0.66 g, 1 mmol), prepared as in step 2, was added aqueous 1N NaOH (5 mL. The mixture was stirred at room temperature for 18 hours, concentrated in vacuo, diluted with water, and neutralized with 6N HCl. The precipitated solid was collected by filtration and slurried in Et2O/hexane (1:1, 50 mL), filtered, and dried in vacuo to provide bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid (435 mg): mp 201°-202° C.; 1H NMR (300 MHz, DMSO-d6)δ4.55 (s, 2H), 5.39 (s, 2H), 5.44 (s, 2H), 7.08 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.31 (d, 2H, J=9 Hz), 7.41 (d, 2H, J=9 Hz), 7.68 (m, 3H), 7.72 (d, 1H, J=9 Hz), 8.80 (m, 4H), 8.49 (t, 2H, J=9 Hz); MS (DCI/NH3) m/e 638 (M+H)+. Anal. Calcd. for C35H25 Cl2N3O5 ×H2O: C, 64.12; H, 4.12; N, 6.41. Found C, 64.44; H, 3.96; N, 6.30.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1>CN(C=O)C.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1
Reactant: CN(c1nnc(-c2ccc(F)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(c1nnc(-c2ccc(-n3cccn3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Cs2CO3 (128 mg, 0.392 mmol) was added to a stirred solution of 5-(2-chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.131 mmol) and 1H-pyrazole (13 mg, 0.196 mmol) in DMF (1.3 mL). The reaction mixture was stirred at room temperature for 4 days then warmed to 60° C. and stirred for an additional 18 hours. The reaction mixture was diluted with DCM (10 mL), filtered through celite, and the DCM was removed in vacuo to afford the crude product as a pale brown liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified), collecting at 324 nm. The product containing fractions were combined and loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (10 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a clear glass-like solid (37 mg, 66% yield). LC-MS: Rt 0.97 min; MS m/z 431.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=2.53 Hz, 1H), 8.14 (dd, J=5.56, 3.03 Hz, 2H), 7.97-8.02 (m, 1H), 7.83 (d, J=1.52 Hz, 1H), 6.64-6.60 (m, 1H), 4.37 (tt, J=12.25, 3.16 Hz, 1H), 3.02 (s, 3H), 1.63 (dd, J=12.13, 3.03 Hz, 2H), 1.45 (t, J=12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S)2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:10]SC)[C:5]([F:17])=[CH:4][N:3]=1.O[O:19][S:20]([O-:22])=O.[K+].[CH3:24]O>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:10][S:20]([CH3:24])(=[O:22])=[O:19])[C:5]([F:17])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: [K+]
Solvent: O
Product: CC(C)(C)[C@@H](CS(C)(=O)=O)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of (S)-2-chloro-N-(3,3-dimethyl-1-(methylthio)butan-2-yl)-5-fluoropyrimidin-4-amine, 78a, (0.15 g, 0.54 mmol) in methanol (10 mL) was added Oxone (0.50 g, 0.81 mmol). The solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo to give a white residue which was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford 150 mg of the desired product as a white solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 310.31 (M+H) RT=2.60 minutes.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:35][N:36]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:29](=[O:31])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CNC1CCOCC1
Product: CC(C(=O)N(C)C1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and N-methyltetrahydro-2H-pyran-4-amine (Peakdale and Cat. No. 2006971). LCMS (M+H)+: m/z=571.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCl>[ClH:13].[C:15]1([NH:14][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH3:12])=[NH:11])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(C)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A mixture of m-ethylphenyl-N-methylcyanamide (520 mg, 3.25 mmol) and 1-aminonaphthalene hydrochloride (508 mg, 3.25 mmol) was placed in a pre-heated oil bath at 160° C. for 3 hours and then allowed to cool to room temperature. The resulting solid was taken into dichloromethane and washed with 10% NaOH solution. The organic layer was concentrated and the resulting residue was dissolved in abs. EtOH (2 ml) and treated with dil. HCl. It was concentrated and the solid was twice recrystallized from abs. EtOH-Et2O to give N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-methyl-guanidine hydrochloride (403 mg, 37%) as off-white needles. mp 223°-25° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[N:15]=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[CH:14][N:15]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[N:17]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: OCCCNc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
1.37 g (54.3 mmol) sodium hydride was given to a solution of 7.19 g (51.7 mmol) 4-nitrophenol in 97 ml DMF. Stirring was continued for 30 min. at room temperature. 9.70 g (51.7 mmol) 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol was added and the mixture heated to 140° C. for 15 h. The reaction mixture was evaporated, taken up with water and extracted with dichloromethane. The organic phase was extracted with sodium carbonate solution, dried (sodium sulphate) and evaporated. The obtained yellow oil (11 g) was dissolved in 10 ml dichloromethane and purified by chromatography over silica (ethyl acetate) to give 8.66 g (58%) 3-[4-(4-Nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:22]>>[Br:22][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: BrC(Br)Br
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
[3-amino-5-(trifluoromethyl)phenyl]methanol (900 mg, 4.71 mmol) (Step A, Example 24) was suspended in CHBr3 (9 mL), and t-butyl nitrite (600 μL, 5.04 mmol) was added dropwise by syringe. The reaction was heated slowly to 80° C. and was maintained at this temperature for 10 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 20% EtOAc/hexanes (2 columns) to afford [3-bromo-5-(trifluoromethyl)phenyl]methanol. Rf=0.31 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.76 (d, J=5.5 Hz, 2H), 1.86 (t, J=5.7 Hz, 1H).