Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[F:22]
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: NCc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(CNCc2ccccc2F)n1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.20 g, 0.66 mmol), 2-fluorobenzylamine (0.038 mL, 0.33 mmol), and acetic acid (0.19 mL, 3.3 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.350 g, 1.65 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (30 g) with elution proceeding as follows: 30% ethyl acetate/hexane (100 mL), nil; (50 mL), unweighed impurity; (100 mL), nil; (125 mL), unweighed impurity; (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (450 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-benzylamino)-methyl]-3H-quinazolin-4-one as a pale pink solid which had: mp 140° C.; 1H NMR δ 7.89 (dd, J=3, 8 Hz, 1 H), 7.76 (dd, J=4, 9 Hz, 1 H), 7.58 (dd, J=2, 8 Hz, 1 H), 7.53-7.41 (m, 4 H), 7.35-7.30 (m, 2 H), 7.07 (t, J=8 Hz, 1 H), 6.99 (t, J=10 Hz, 1 H), 3.89 (ABq, Δv1-3=21 Hz, J=13 Hz, 2 H), 3.46 (ABq, Δv1-3=31 Hz, J=17 Hz, 2 H); APCI MS m/z=412 (P−1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)#[N:2].S(Cl)([Cl:15])=O>>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N#CCc1ccc(C(=O)Cl)cc1

Procedure:
Ten grams of 4-(cyanomethyl)benzoic acid is refluxed in 70 mls. of thionyl chloride for four hours. The solvents are removed leaving a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.5 g. of 3-amino-2-hydroxy pyridine in cold pyridine there is added slowly, with cooling, 8 g. of 4-cyanomethyl benzoyl chloride. The mixture is allowed to come to room temperature and stirred overnight. The mixture is added to 300 ml. of ice and the solid amide separated by filtration and recrystallized from methanol. A mixture of 3 g. of the above amide in 50 mls. of phosphorus oxychloride is heated under reflux for 5 hours. The solvents are removed in vacuo and the residue is crystallized from ethyl acetate to give 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=Cc1ccc(COc2cc(F)ccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2cc(F)ccn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of the 4-(4-fluoro-pyridine-2-yloxymethyl)-benzaldehyde (1.5 g, 6.49 mmol) described in Manufacturing Example 59-1-2, nitromethane (698 μL, 13 mmol), ammonium acetate (750 mg, 9.74 mmol) and acetic acid (15 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.72 g).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[C:11](=[CH:14]N(C)C)[CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[SH:21][C:20]1[N:22]=[CH:14][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:19]=1
Reactant: CCCN1CCC[C@@H]2CC(=O)C(=CN(C)C)C[C@H]21
Reactant: NC(N)=S
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(S)ncc3C[C@@H]21

Procedure:
One gram of trans-(±)-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline was reacted with 0.33 g. of thiourea in 20 ml. of ethanol by refluxing overnight under a nitrogen atmosphere. The volatile constituents were removed in vacuo to yield trans-(±)-2-mercapto-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline free base. The free base was converted to the dihydrochloride salt by standard procedures to yield 0.17 g. of dihydrochloride salt melting at 267°-277° C. after recrystallization from methanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][CH:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K39) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (115 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].S(Cl)([Cl:12])=O>>[CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([Cl:12])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCCC(C)(C)C(=O)O
Product: CCCC(C)(C)C(=O)Cl
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
2,2-dimethyl valeric acid (49.0 g, 377 mmol) was added dropwise over 1 hour with stirring to freshly distilled thionyl chloride (102 g, 860 mmol) that was cooled in a water bath. After stirring for an additional 1/2 hour in a warm water bath, excess thionyl chloride was removed by distillation and the crude acid was then fractionally distilled to give 49.7 g of product that assayed >95% by gas chromatography, bp 45°/10.5 mm (lit. bp 45°/10 mm).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:42])[CH2:10][N:11]([C:21](=[O:41])[C@H:22]([CH3:40])[NH:23][P:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[OH-].[Na+]>CC(C)=O.O>[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:43])=[O:2])=[O:42])=[O:41])[CH3:40])([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Dibenzylphosphoryl-L-alanyl-N-(2-indanyl)glycyl-L-proline methylester (0.79 g, 1.2 m mole) was dissolved in acetone (5 ml), and sodium hydroxide (0.15 g, 3.8 m mole) in water (4 ml) solution was added thereto while cooling in the ice bath. The mixture was stirred for 1 hour. To this solution water (100 ml) was added, and thereafter this thus formed solution was washed with ethyl ether (50 ml). the ether washed solution was neutralized with 1N hydrochloric acid, and therefrom the desired product was extracted with ethyl acetate. The thus extracted solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily dibenzylphosphoryl-L-alanyl-N-(2-indanyl)glycyl-L-proline (0.77 g, yield: 99.7%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([O-])([O-])=O.[K+].[K+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O>O1CCOCC1>[N+:22]([C:25]1[CH:30]=[C:29]([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1NCCc2c(-c3cccc([N+](=O)[O-])c3)[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Tricyclic bromide 11 (27 mg, 0.10 mmol) in 1,4-dioxane (1.0 mL) was treated with solid K2CO3 (41 mg, 0.30 mmol), m-nitrophenylboronic acid (34 mg, 0.20 mmol), and water (0.25 mL). The solution was degassed and tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 mol %) was added. The solution was heated at 100° C. for 1 h, then cooled to ambient temperature and diluted with water (2 mL). The aqueous layer was adjusted to pH=7-8 with saturated aqueous K2CO3 and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography (3-5% MeOH in CHCl3) to yield 14 as a yellow solid, 26.3 mg (87%). mp 268-270° C. (dec.); 1H NMR (DMSO-d6) δ3.16 (m, 2H), 3.45 (m, 2H), 7.33 (m, 1H), 7.65 (m, 1H), 7.76 (m, 1H), 7.78 (m, 1H), 8.30 (m, 1H), 8.53 (bs, 1H), 8.16 (m, 2H), 11.93 (bs, 1H); HRMS (M+Na) Calcd for C17H13N3O3+Na: 330.0855, Found: 330.0847; Anal. (C17H13N3O3.H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNc1ccc(C(F)(F)F)cn1

Procedure:
2-Chloro-5-(trifluoromethyl)pyridine (5.0 g) was heated with ethylenediamine (20 ml) at 120° C. overnight. The excess ethylenediamine was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The aqueous layer was extracted 5 times further with dichloromethane. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried, then concentrated in vacuo to give (2-aminoethyl)[5-(trifluoromethyl)(2-pyridyl)]amine as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:64][C:57]1[CH:56]=[C:55]([C:50]2[CH:51]=[CH:52][CH:53]=[C:54]3[C:49]=2[CH:48]=[CH:47][NH:46]3)[CH:63]=[C:62]2[C:58]=1[CH:59]=[N:60][NH:61]2)=[O:8])[CH3:2]
Reactant: CCOc1ccccc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 8 h

Procedure:
To a solution of 2-(ethyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml), HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol) were added. The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol). The reaction was stirred overnight then it was loaded onto a PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Appropriate fractions were dried under a stream of nitrogen to give title compound, 27 mg.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=O)[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:16]>>[NH2:16][C:8]1[CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6](=[O:11])[CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Product: CC(C)C1CC(=O)C=C(N)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-isopropylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43](Cl)[CH3:44])=[N:26]2)=[CH:22][CH:21]=1>CN(C=O)C.C1COCC1>[F:19][C:20]1[CH:47]=[CH:46][C:23]([CH2:24][N:25]2[C:30](=[O:31])[C:29]3[C:32]([O:41][CH3:42])=[C:33]4[C:38](=[O:39])[N:37]([CH3:40])[CH2:36][CH2:35][N:34]4[C:28]=3[C:27]([CH:43]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][S:1]3(=[O:8])=[O:7])[CH3:44])=[N:26]2)=[CH:22][CH:21]=1
Reactant: O=S1(=O)CCCCN1
Reactant: COc1c2n(c3c(C(C)Cl)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c2n(c3c(C(C)N4CCCCS4(=O)=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.) solution of 1,2-thiazinane 1,1-dioxide (32 mg, 0.24 mmol) in anhydrous DMF (2 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.18 mL, 1M) was added. After stirred at room temperature for 20 minutes, solid 2-(4-fluorobenzyl)-10-methoxy-4-(1-chloroethyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (50 mg. 0.12 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound. ES MS M+1=518
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]([F:12])([F:22])[F:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1OC(F)(F)F
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1OC(F)(F)F
Temperature: 100 °C

Procedure:
2,6-Dichloro-3-nitropyridine (10.0 g, 51.8 mmol) and 2-(trifluoromethoxy)aniline (18.4 g, 104 mmol) were taken up in ethanol (50 mL) and heated to 100° C. for 48 h in a sealed tube. The reaction mixture was cooled in an ice bath, and the resulting precipitate was collected by vacuum filtration to give an intermediate 6-chloro-3-nitro-N-(2-(trifluoromethoxy)phenyl)pyridin-2-amine, which was dissolved in dioxane (65 mL) and H2O (35 mL). Potassium hydroxide (2.90 g, 51.7 mmol) was added and the reaction mixture was heated to 100° C. for 16 h. After cooling, the pH was adjusted to less than 7 with 1 N HCl. The resulting precipitate was collected by vacuum filtration to give the title compound as a bright yellow solid (5.10 g). LCMS m/z=316.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 5.91 (d, J=10.1 Hz, 1H), 7.51 (m, 4H), 8.26 (d, J=10.1 Hz, 1H), 8.50-8.85 (broad s, 1H), 10.78 (broad s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:10]=1[CH2:11][NH:12][C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:10]=1[CH2:11][NH:12][C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][CH:24]=2)[N:14]=1
Reactant: [H][H]
Reactant: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1c(F)cccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1c(O)cccc1F
Reaction time: 6 h
Yield: 48.6 %

Procedure:
A 20 ml portion of THF-methanol (2:1) mixed solution of 290 mg of 4-[(2-benzyloxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide synthesized in the same manner as in Production Example 13 was mixed with 50 mg of 10% palladium-carbon, followed by stirring for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered and then mixed with 100 mg of 10% palladium-carbon, followed by stirring for 6 hours in a hydrogen atmosphere. After filtration of the reaction mixture and subsequent evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (chloroform-methanol). By recrystallizing the resulting crude crystals (THF-methanol), 117 mg of 4-[(2-hydroxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide was obtained as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([N:15]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[N:26]=[CH:25]4)[S:17][C:16]2=[O:43])[CH2:9]1)=O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:27]2[C:28]3[C:24](=[CH:23][C:22](/[CH:21]=[C:18]4/[C:19](=[O:20])[N:15]([CH:10]5[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]5)[C:16](=[O:43])[S:17]/4)=[CH:30][CH:29]=3)[CH:25]=[N:26]2)=[C:33]([C:39]([F:41])([F:42])[F:40])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCNCC1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.2 mmol) in DCM (2 mL) was added Dess-Martin periodinane powder (0.25 mmol). The mixture was stirred at rt for 18 h, then purified by silica gel chromatography (0-30% EtOAc/hexanes). The product was obtained as pale yellow solid, which was treated with TFA/DCM following General Procedure M to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4]=2[CH2:3][CH2:2]1.[I:19]I>C(O)(=O)C.C(Cl)Cl>[I:19][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[C:9]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reactant: II
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(=O)NC[C@@H]1C[C@H]1c1c(I)ccc2c1CCO2
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 0.12 g (0.6 mmol) (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]propanamide and 0.27 g (0.6 mmol) of lead IV tetraacetate in 1 mL acetic acid was added 0.075 g (0.25 mmol) iodine. The solution was allowed to stir for 1.5 h and was diluted with methylene chloride. The resulting solution was washed with water and saturated sodium bicarbonate solution and dried. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-hexane, 3:7 containing 0.2% methanol to give the product (25 mg, 11%, mp 148-149° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22]CC)=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.Cl>O.C(O)C.[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([OH:22])=[O:21])[CH2:17][CH2:18][CH2:19]3)[NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Temperature: 50 °C

Procedure:
A suspension of 1 g of the compound of Example 1 in 15 ml of water, 30 ml of ethanol and 5 ml of 1 M sodium hydroxide solution is heated at 50° C. for 10 hours. The reaction mixture is then cooled and 5 ml of 1M HCl are added. The resulting precipitate is suction-filtered off, washed with water and then dried in vacuo, enabling the expected product to be isolated.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[OH:37][C:38]1[CH:39]=[N:40][C:41]([F:44])=[CH:42][CH:43]=1>>[CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11]([O:37][C:38]3[CH:39]=[N:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(OCC2CCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: Oc1ccc(F)nc1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OCC3CCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cn1

Procedure:
2-Cyclobutylmethoxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (the MRf product from Example 83), (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and 3-hydroxy-6-fluoro-pyridine according to the procedure described in Reference Examples 6 and 7 to afford 2-cyclobutylmethoxy-4-(6-fluoro-3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=530 (M++1); Rt=5.01 min. 1H-NMR 400 MHz (CDCl3): δ 1.80-1.98 (m, 4H), 2.10-2.11(m, 2H), 2.74 (m, 1H), 4.20 (d, J=7 Hz, 2H), 7.00 (m, 1H), 7.13-7.18 (m, 2H), 7.20-7.30 (m, 5H), 7.63-7.68 (m, 1H), 8.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Product: Cc1cc(C)cc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,5-dimethylbenzene-1-sulfonyl chloride.