Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27][CH2:26]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([F:22])[CH:24]=4)[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2cc(F)ccc2C1
Yield: 24 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 11 (24.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.90 and 3.13 (2t, 2H), 3.59 and 4.20 (2t, 2H), 4.51 and 5.10 (2s, 2H), 6.79-7.27 (m, 5H), 7.59-7.66 (m, 1H), 7.95-8.05 (m, 2H), 8.16-8.18 (m, 1H), 8.63-8.69 (m, 2H); 19F (282 MHz, DMSO-d6) δ −109.7, −115.1, −115.6; MS (ESI) m/z 402 ([M+H]+).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.N1C=CC(CC(C2C=CC([CH2:42][O:43][Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=CC=2)=O)=CC=1>>[CH3:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:42][O:43][Si:44]([CH:45]([CH3:47])[CH3:46])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[CH:14][CH:13]=2)=[N:16]1
Reactant: CC(C)[Si](OCc1ccc(C(=O)Cc2ccncc2)cc1)(C(C)C)C(C)C
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Product: CC(C)[Si](OCc1ccc(-c2nn(C)cc2-c2ccncc2)cc1)(C(C)C)C(C)C

Procedure:
Following the procedure for the preparation of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine but substituting 2-Pyridin-4-yl-1-(4-triisopropylsilanyloxymethyl-phenyl)-ethanone provided the title compound. MS: (M+H m/z=422.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.[Cl:19][C:20]1[CH:21]=[C:22]([I+2:26])[CH:23]=[CH:24][CH:25]=1.[F:27][B-:28]([F:31])([F:30])[F:29].[Na+]>C(Cl)Cl>[F:27][B-:28]([F:31])([F:30])[F:29].[Cl:1][C:2]1[CH:3]=[C:4]([I+:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1cccc([I+2])c1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc([I+]c2cccc(Cl)c2)c1
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
Borontrifluoride diethyl etherate (16.51 g, 116.3 mmol) was added slowly to 3-chlorophenyl boronic acid (17.37 g, 111.0 mmol) in DCM (170 mL) at −5° C., while stirring. After 15 minutes, the title compound of Example 15.1 (37.71 g, 105.8 mmol) in DCM (150 mL) was added slowly. The reaction stirred for 1 h at 0° C. and sodium tetrafluoroborate (225 g in 300 mL water) was added and stirred for 1 h. The organic layer was separated, dried over sodium sulphate, filtered and concentrated and triturated with ether to afford the title product (31.6 g, 68%) as a light brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[O-].[Na+].Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>CO>[CH3:40][N:39]([CH3:41])[C:37](=[O:38])[CH2:36][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[C:16]([C:14]3[S:15][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)=[CH:12][CH:13]=3)=[CH:17][C:18]([C:28]([F:31])([F:29])[F:30])=[N:19]2)[CH:22]=1
Reactant: CN(C)C(=O)CCl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(O)c3)s2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)COc1cccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (120 mg, 0.26 mmol) was dissolved in anhydrous methanol (10.0 mL). To this solution was added a 25 wt % solution of NaOMe in methanol (130 μL, 0.57 mmol) and 2-chloro-N,N-dimethyl-acetamide (156 mg, 128 mmol). The reaction mixture was heated to reflux at 80° C. under nitrogen atmosphere for overnight. It was cooled off and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in hexane) to yield the product (87 mg, 61% yield). 1H-NMR (Acetone-d6): δ 8.21 (m, 1H), 8.03 (m, 1H), 7.96 (m, 1H), 7.76 (m, 1H), 7.65 (m, 1H), 7.52 (m, 1H), 7.25-7.16 (br, 5H), 4.94 (s, 2H), 3.25 (s, 3H), 3.09 (s, 3H), 2.90 (s, 3H), 2.88 (s, 3H). MS (ES): 550 [M+H]+
Reaction SMILES: [CH2:1]1[CH2:7][CH2:6][C:5]2[N:8]=[CH:9][CH:10]=[CH:11][C:4]=2[CH2:3][CH2:2]1.[OH:12]O>C(O)(=O)C>[N+:8]1([O-:12])[CH:9]=[CH:10][CH:11]=[C:4]2[CH2:3][CH2:2][CH2:1][CH2:7][CH2:6][C:5]=12
Reactant: OO
Reactant: c1cnc2c(c1)CCCCC2
Solvent: CC(=O)O
Product: [O-][n+]1cccc2c1CCCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2,3-cycloheptenopyridine (42.94 g, 0.292 mol) in glacial acetic acid (160 mL) at room temperature was added 30% H2O2 (30 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (30 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CHCl3 (200 mL) and treated with solid Na2CO3 (100 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×200 mL). The combined supernatants were filtered and concentrated to provide 60 g of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide as a yellow oil. 1H NMR (CDCl3) δ 1.63-1.73 (m, 4H), 1.82-1.91 (m, 2H), 2.77-2.83 (m, 2H), 3.36-3.42 (m, 2H), 6.94-7.05 (m, 2H), 8.17 (d, 1H, J=6.1 Hz).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([OH:24])=[C:16]([O:25][CH3:26])[C:15]([O:27][CH3:28])=[C:14]([O:29][CH3:30])[C:13]=1[N:12]2C)C1C=CC=CC=1.O1CCOCC1>C(O)C.[Pd]>[OH:24][C:17]1[C:18]2[C:19](=[O:23])[C:20]3[C:11](=[C:10]([O:32][CH3:33])[C:9]([OH:8])=[CH:22][CH:21]=3)[NH:12][C:13]=2[C:14]([O:29][CH3:30])=[C:15]([O:27][CH3:28])[C:16]=1[O:25][CH3:26]
Reactant: COc1c(OC)c(OC)c2c(c1O)c(=O)c1ccc(OCc3ccccc3)c(OC)c1n2C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1c(OC)c(O)c2c(=O)c3ccc(O)c(OC)c3[nH]c2c1OC
Reaction time: 2.5 h

Procedure:
A mixture of 6-benzyloxy-1-hydroxy-10-methyl-2,3,4,5-tetramethoxy-9-acridone (344 mg, 0.76 mmol) in ethanol (80 ml) containing dioxane (20 ml) and 10% palladium on carbon (200 mg) was hydrogenated at 50 psi for 2.5 hours. The mixture was filtered through a pad of Celite and washed well with ethanol and chloroform. The combined filtrate and washings were evaporated in vacuo to dryness. The solid residue was recrystallized from a mixture of ethanol/hexane (2:3) to give 1,6-Dihydroxy-2,3,4,5-tetramethoxy-9-acridone, 222 mg (80.7%), mp 214-5 ° C. 1H-NMR (DMSO-d6): δ3.69, 3.75, 3.78, 3.80, and 4.02 (each 3H, s, 4×OMe, 1×NMe), 6.94 (1H, d, J=9.0 Hz, H-7), 7.84 (1H, d, J =9.0 Hz, H-8), 10.45 (1H, exchangeable, OH-6), 14.18 (lH, exchangeable, OH-1). Analyses: Calculated for C18H19NO7 : C, 59.83; H, 5.30; N, 3.88. Found C, 60.00, H, 5.38; N, 4.00.
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:60][CH:61]([F:78])[CH2:62][NH:63][CH:64]1[CH2:70][CH2:69][C:68]2=[C:71]([NH2:77])[C:72]([O:75][CH3:76])=[CH:73][CH:74]=[C:67]2[CH2:66][CH2:65]1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:77][C:71]2[C:68]3[CH2:69][CH2:70][CH:64]([NH:63][CH2:62][CH:61]([F:78])[F:60])[CH2:65][CH2:66][C:67]=3[CH:74]=[CH:73][C:72]=2[O:75][CH3:76])=[N:22][CH:23]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCC(NCC(F)F)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine LC/MS (ESI): 540.27. 1H NMR (400 MHz, DMSO, d6) δ 8.99 (m, 2H), 8.71 (m, 1H), 8.31 (m, 1H), 7.79 (s, 2H), 7.14 (m, 2H), 7.04 (m, 2H), 6.88 (m, 2H), 6.61 (s, 1H), 6.38 (td, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.38 (m, 2H), 3.04 (m, 1H), 2.84 (m, 1H), 2.71 (m, 1H), 2.29 (m, 2H), 1.34 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:32])[CH2:23][N:24]3[CH2:29][C@H:28]([CH3:30])[O:27][C@H:26]([CH3:31])[CH2:25]3)=[CH:17][CH:16]=2)(O)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.OS(O)(=O)=O.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:32])[CH2:23][N:24]3[CH2:25][C@H:26]([CH3:31])[O:27][C@H:28]([CH3:30])[CH2:29]3)=[CH:17][CH:16]=2)[CH3:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Cc1ccc(C(C)(O)Cc2ccc(C(C)(C)C)cc2)cc1)CN1C[C@@H](C)O[C@@H](C)C1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(Cc1ccc(C(C)Cc2ccc(C(C)(C)C)cc2)cc1)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 83 %

Procedure:
A solution of 50 g of (VII) in 1 l of glacial acetic acid and 30 ml of concentrated H2SO4 was hydrogenated in the presence of 5 g of 5% strength Pd/C at room temperature and under 5 bar, until the pressure remained constant. The catalyst was filtered off and the filtrate was made alkaline with dilute aqueous NaOH. The crude product was extracted with CH2Cl, and the solution was washed with H2O, dried over Na2SO4 and concentrated. Distillation of the residue gave 40 g of product of boiling point 200°-202° C./0.3 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13]3[C:15]([CH:10]=2)=[CH:16][CH:17]=[CH:18][CH:12]=3)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Nc1ccccc1I
Reactant: C#Cc1ccc(C=C)cc1
Product: C=Cc1ccc(-c2cc3ccccc3[nH]2)cc1
Yield: 72 %

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 72% yield. 1H NMR (300 MHz, CDCl3) δ 8.31 (s, br, 1H), 7.64-7.61 (d, J=8.29, 3H), 7.49-7.46 (d, J=8.29, 2H), 7.40-7.38 (d, J=8.10, 1H), 7.22-7.16 (dt, J=6.97, 1H), 7.14-7.09 (dt, J=7.91, 1H), 6.84 (s, 1H), 6.78-6.69 (dd, J=10.73, 1H), 5.82-5.76 (dd, J=17.70, 1H), 5.30-5.26 (dd, J=10.73, 1H). Anal. Calcd. for C16H13N: C, 87.64; H, 5.98; N, 6.39.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:19])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 94 %

Procedure:
0.56 g (0.00238 mol) of 2-nitro-4-trifluoromethyl-benzoic acid was dissolved in 7 ml of thionyl chloride and boiled under reflux for 2 hrs. The reaction mixture was concentrated and the residue was taken up twice in toluene and evaporated to dryness each time. 0.53 g (94%) of 2-nitro-4-trifluoromethyl-benzoyl chloride was obtained as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31]C=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.CC1ON=C(N)C=1>C1COCC1.CN(C=O)C>[CH3:31][C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:14]2[CH:13]=[CH:12][C:10]3[CH:11]=[C:3]4[C:2](=[O:1])[NH:8][CH2:7][CH2:6][CH2:5][N:4]4[C:9]=3[N:15]=2)=[O:18])[CH:29]=1
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cc1cc(N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 100 mg, 0.41 mmol) in THF (2 mL) and DMF (0.5 mL) is added HATU (171 mg, 0.45 mmol). The mixture is stirred at room temperature for 1 h, after which 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (556 mg, 1.22 mmol) is added. The mixture is stirred at room temperature for 10 min and 5-methyl-3-aminoisoxazole (120 mg, 1.22 mmol) is added. The reaction is stirred at 60° C. for 16 h and is then cooled to room temperature. The mixture is filtered, washing with methanol and the filtrate is concentrated under reduced pressure. The residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/H2O with 0.1% TFA to afford the title compound (11 mg, 8%). LCMS: 326.20 (M+H+). (System V-med polar)
Reaction SMILES: C1CO[C:8]2([NH2:9])[N:3]([C:4]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[O:21][C:20]([CH2:22][OH:23])=[CH:19][C:18]=4[CH:24]=3)=[N:5][CH:6]=[C:7]2[F:12])O1.CC(C[AlH]C[CH:31]([CH3:33])[CH3:32])C>>[F:12][C:7]1[C:8]([NH:9][C:32]2[CH:31]=[CH:33][CH:22]=[C:20]([OH:21])[CH:19]=2)=[N:3][C:4]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([CH2:22][OH:23])=[CH:19][C:18]=3[CH:24]=2)=[N:5][CH:6]=1
Reactant: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Reactant: CC(C)C[AlH]CC(C)C
Product: OCc1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N-2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.06 (d, 1H, J=3.9 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.41-7.35 (m, 2H), 7.26 (d, 1H, J=8.1 Hz), 7.11-7.05 (m, 2H), 6.60 (s, 1H), 6.51 (dd, 1H, J=2.4 and 8.4 Hz), 5.41 (t, 1H, J=6.0 Hz), 4.51 (d, 2H, J=5.7 Hz); LCMS: ret. time: 16.21 min.; purity: 95%; MS (m/e): 367 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]1=[O:15].[CH3:16][C:17]([C:20]1[N:21]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:23][CH:24]=1)([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+].Cl>O.C(O)C.CCOCC.CN(C)C=O>[CH3:13][C:9]1([CH3:14])[CH2:10][C:11](=[O:12])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:22]3[S:23][CH:24]=[C:20]([C:17]([CH3:19])([CH3:18])[CH3:16])[N:21]=3)[CH2:26][CH2:27]2)[C:7](=[O:15])[CH2:8]1
Reactant: CC(C)(C)c1csc(N2CCNCC2)n1
Reactant: CC1(C)CC(=O)N(CCCCBr)C(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)N(CCCCN2CCN(c3nc(C(C)(C)C)cs3)CC2)C(=O)C1

Procedure:
4 g 1-(4-Bromobutyl)-4,4-dimethyl-2,6-piperidin-dione, 3.15 g 1-(4-(1,1-dimethylethyl)-2-thiazolyl)-piperazine, 2.7 g K2CO3, 70 ml dimethylformamide and 20 ml water are stirred at room temperature for about 35 hours. The mixture is diluted with water, extracted twice with ether, the combined extracts are washed with water, dried (Na2SO4) and evaporated. The residue is recrystallized from hexane/ethyl acetate, whereby the title compound is obtained, m.p. 93°-94°. M.p. of the hydrochloride is 199°-201° (ethanol/ether).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.[Mg]>CO>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2C)cc1
Agent: [Mg]
Solvent: CO
Product: C[C@@H]1Cc2ccccc2CN1
Reaction time: 96 h

Procedure:
To a solution of 31.15 g (103.15 mmol) of the monotosyl compound obtained in Step B in 500 mL of anhydrous methanol there are added, in portions, 3.92 g (161 mmol) of magnesium turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction mixture is then filtered and the solid is washed several times with methanol. The filtrate is then concentrated to dryness. After purification by chromatography over silica gel (dichloromethane/EtOH/NH4OH gradient), the title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.OS([O-])(=O)=O.[Na+].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18]C>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCO
Reactant: COc1cccs1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOc1cccs1
Yield: 65 %

Procedure:
15 cm3 of 2-methoxythiophene were dissolved in 40 cm3 of n-hexanol and 30 cm3 of toluene, 1 g of NaHSO4 was added, and the mixture was refluxed for several hours. After distilling off 6 cm3 of an azeotrope of methanol and toluene, the residue was washed with sodium carbonate solution, dried and fractionated. 18 g of 2-hexyloxythiophene of b.p. 66° C./0.26 mbar were distilled off, 96% pure. Yield 65% of theory.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.C([Li])(CC)C.[CH2:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:15][CH3:16].C(I)C>C1COCC1>[CH3:16][CH2:15][CH:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:3][CH3:4]
Reactant: CN(C)CCN(C)C
Reactant: CCCc1ccccc1C(=O)N(CC)CC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(CC)c1ccccc1C(=O)N(CC)CC
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a solution of 9.3 ml (0.058 mol) of tetramethyl-ethylenediamine in 340 ml of THF at -78° C was added 52 ml of a 1.1M solution (0.057 mol) of s-butyl lithium in THF. The solution was then treated with a solution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75 ml of THF at -78° C. and the solution stirred for fifteen minutes and then treated with a solution of 8.3 ml of (0.104 mol) of ethyl iodide in THF. The solution was stirred for an hour and a half at -78° C. and then quenched by the addition of saturated ammonium chloride added dropwise at -78° C. The mixture was then allowed to warm to ambient temperature, diluted with diethyl ether, washed first with dilute hydrochloric acid, then with water, then with saturated sodium bicarbonate, then with brine dried and taken to dryness to give 12.91 g of crude product which was chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 3.23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][OH:14])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[CH3:31][N:32]=[C:33]=[S:34].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13][O:14][C:33](=[S:34])[NH:32][CH3:31])[C:6]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reactant: CN=C=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=S)OCC(COc1noc2ccc(Cl)cc12)NC(=O)OC(C)(C)C

Procedure:
To a solution of 0.8 g of 5-chloro-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 8 ml of N,N-dimethylformamide are added 1.6 ml of triethylamine and 0.51 g of methyl isothiocyanate at room temperature, and they are subjected to reaction at 110° C. for four hours. After cooling, water and ethyl acetate are added to the reaction mixture, they are shaken and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a silica gel column chromatography [eluant:toluene:ethyl acetate=5:1], to obtain 0.4 g of brown, solid 5-chloro-3-(2-tert-butoxy carbonylamino-3-methylthiocarbamoyloxypropoxy)-1,2-benzoisoxazole.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Br:10].OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:19]([O-:21])=[O:20])[C:6]([F:9])=[CH:5][C:4]=1[Br:10]
Reactant: COC(=O)Oc1ccc(F)cc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
(2-Bromo-4-fluoro-phenyl) methyl carbonate (8.25 g, 33.13 mmol) was added portionwise to conc. H2SO4 (45 mL) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and KNO3 (3.7 g, 36.44 mmol) was added portionwise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice-water and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by silica gel column chromatography using 15% EtOAc/hexane gradient to yield 2-bromo-4-fluoro-5-nitrophenyl methyl carbonate (8.93 g, 92%) 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=6.7 Hz, 1H), 7.65 (d, J=9.6 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=2[N+:17]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:17][C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C2CCCCC2)c(N)c1
Yield: 87.8 %

Procedure:
To a refluxing solution of N-(4-cyclohexyl-3-nitro-phenyl)acetamide (1.8 g, 6.86 mmol) and ammonium formate (1.8 g, 28.55 mmol) in ethanol (50 mL) was added 10% Pd/C (1.3 g, 12.22 mmol). The mixture was refluxed for additional 5 minutes, cooled and filtered through a pad of celite. The solvent was removed by evaporation to give N-(3-amino-4-cyclohexylphenyl)acetamide (1.4 g, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=2.1 Hz, 2H), 7.03 (d, J=8.3 Hz, 1H), 6.67 (dd, J=8.2, 2.1 Hz, 1H), 3.72 (d, J=9.8 Hz, 2H), 2.42 (d, J=8.5 Hz, 1H), 2.15 (s, 3H), 1.88 (d, J=9.5 Hz, 4H), 1.78 (d, J=12.1 Hz, 1H), 1.51-1.33 (m, 5H).