Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccc(F)c2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Example 25) gave 324. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.07 (dd, J=8.3, 6.5 Hz, 1H), 7.87 (s, 1H), 7.52 (s, 2H), 7.48-7.38 (m, 1H), 7.31-7.22 (m, 1H), 4.87-4.80 (m, 1H), 4.56-4.38 (m, 1H), 4.36-4.23 (m, 1H), 4.16-3.99 (m, 1H), 3.76 (s, 3H), 2.09-2.01 (m, 1H), 1.87-1.66 (m, 5H). LCMS (ES+) m/z 467 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH2:10]([C:12]1[NH:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[CH3:11]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:13]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:12]2[CH2:10][CH3:11])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: CCc1nc(C)c[nH]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: CCc1nc(C)cn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A dry round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole-4-sulfonylchloride and 180 ml of THF. The stirred solution was treated with 11.10 g of 2-ethyl-4-methylimidazole in one portion and stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate concentrated at reduced pressure to a foam. The foam was dissolved in ethyl acetate and the filtered solids partitioned between water and ethyl acetate. The combined organic layers were washed with water, dried with Na2SO4 and concentrated to give a waxy solid. Recrystallization was carried out using ethyl acetate and a small amount of hexane to give 8.13 g of 1-(4-imidazolylsulfonyl)-2-ethyl- 4-methylimidazole, mp 147°-8°, which recrystallized to mp 149°-50°, λmaxnujol 3.26 (NH), 7.30 (SO2N) and 8.68 μ (SO2N). NMR (DMSO, d6) 466 Hz, d, J = 2 Hz, 1H; 450 Hz, d, J = 2 Hz, 1H; 403 Hz, q, J = Hz, 1H; 170 Hz, q, J ~ 7.5 Hz, 2H; 116 Hz, d, J = 1 Hz, 3H; 66 Hz, t, J ~ 7.5 Hz, 3H.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)C.[CH3:14][N:15](C)[C:16](=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:15]([CH3:16])[CH3:14]
Reactant: O=Cc1cccc(I)c1
Reactant: CC(=O)N(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution of 3-iodo-benzaldehyde (3 g, 12.9 mmol) in anhydrous dichloromethane (130 ml) were added acetic acid (1.9 ml) and N,N-dimethylacetamide. The yellow solution is stirred 10 minutes at 0° C. and sodium triacetoxyborohydride (6.85 g, 32.33 mmoles) is added by portions. The resulting mixture is stirred at room temperature for 90 minutes and evaporated to dryness under reduced pressure. Ethyl acetate and a saturated aqueous hydrogen carbonate solution were added to the residue and the two layers were separated The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield (3-iodo-benzyl)-dimethyl-amine (3.05 g, 90%) as a brown oil.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][N:16](CC)[CH2:15]2)[CH2:11]1)[C:4]1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:14][CH2:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11]1)[CH3:4]
Reactant: CCN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC2(CCNC2)C1
Yield: 195.4 %

Procedure:
A solution of 9.50 g (0.030 mole) 2-benzyl-7-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 100 ml methanol was hydrogenated with 1.0 g 20% palladium on carbon catalyst at 4.5×105Pa for 22 hours. After filtration, the solution was concentrated to a syrup and crystallized from acetonitrile to afford 6.66 g of the title compound, mp 168°-172° C.
Reaction SMILES: [C:1]1(=O)OC(=O)C2=CC=CC=[C:2]12.[CH3:12][O:13][C:14](=[O:33])[CH2:15][S:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][C:28]1S[CH:30]=[CH:31][CH:32]=1.[CH2:34](N)C1C=CC=CC=1>>[CH2:12]([O:13][C:14](=[O:33])[CH2:15][S:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][C:28]1[CH:2]=[CH:1][CH:30]=[CH:31][CH:32]=1)[CH3:34]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)CSC1c2ccccc2C(=O)N1Cc1cccs1
Reactant: NCc1ccccc1
Product: CCOC(=O)CSC1c2ccccc2C(=O)N1Cc1ccccc1

Procedure:
Compound 17 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of commercially available phthalic anhydride to compound 13 using benzylamine instead of thiophene-2-methylamine in the first step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21].Cl>O.C(O)C>[ClH:1].[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Cc1ccc(C)c(N)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethylaniline (36 μl, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a white solid (28 mg, 42%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.27 (dd, J=1.5, 4.5 Hz, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=1.8, 7.8 Hz, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [H][H].[NH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:8]1[CH2:13]CC[CH2:10][CH2:9]1>>[N:3]1([CH2:4][CH2:5][CH2:6][NH2:7])[CH:10]=[CH:9][CH:8]=[CH:13]1
Reactant: [H][H]
Reactant: C1CCCCC1
Reactant: NCCCN
Product: NCCCn1cccc1

Procedure:
Similarly prepared according to procedure given in Example 1 is the compound of formula I wherein R1, R2 and R3 represent hydrogen, n represents the integer 1, m represents the integer 3 and Het represents ##STR20## and wherein the cyclohexane and pyrrolidone rings are cis fused, m.p. 78°-79°, starting with 1,3-diaminopropane so as to obtain 3-(1-pyrrolyl)-propylamine which is then condensed with ethyl cyclohexanone-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([OH:30])=O.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>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
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: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 58.1 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-ethyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.713 g, 2.29 mmol), 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (0.400 g, 2.29 mmol), HATU (1.133 g, 2.98 mmol), DIPEA (0.520 mL, 2.98 mmol) and DMF (12 mL). Purification was accomplished by silica gel chromatography (0-5% MeOH (2M NH3) in CH2Cl2) to afford the title compound (0.622 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.09 (br. s., 1H), 7.81-7.84 (m, 1H), 7.48-7.53 (m, 2H), 7.45-7.47 (m, 1H), 7.33-7.40 (m, 1H), 4.54 (d, 2H), 2.60 (q, 2H), 1.18 (t, 3H). ES-LCMS: m/z 467.0, 469.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1(F)CCCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Temperature: 130 °C
Yield: 55.5 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.1 g, 4.5 mmol), 3,3-difluoropiperidine hydrochloride (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and 3,3-difluoropiperidine hydrochloride (0.29 g, 1.8 mmol) were added and the mixture was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.BrC1C=CC(F)=CC=1C(O)=O.B.O1CCCC1.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10]
Reactant: COCOCc1cc(F)ccc1Br
Agent: B
Agent: O=C(O)c1cc(F)ccc1Br
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene: To a solution of 2-bromo-5-fluorobenzoic acid (10.3 g, 45.3 g) in tetrahydrofuran (50 mL) was added borane-tetrahydrofuran complex (1M in tetrahydrofuran; 92 mL) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature overnight. Water was carefully added, and the mixture was concentrated under reduced pressure to about 50 mL. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-bromo-5-fluorobenzyl alcohol, which was converted into its methoxymethyl ether in a similar manner to Example 11, step (a) to afford 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene (9.64 g, 85% in 2 steps): 1H NMR (300 MHz, CDCl3) δ 3.43 (s, 3H), 4.62 (s, 2H), 4.78 (s, 2H), 6.88 (td, J=8.5, 3.2 Hz, 1H), 7.25 (dd, J=9.6, 3.1 Hz, 1H), 7.48 (dd, J=8.8, 5.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC1C=CC=CC=1)=[O:9].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:24][C:23]1[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:4]=2[O:5][CH2:6][C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])[N:1]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropanoate (Example 47c) and ethyl 3-oxobutanoate as a brown solid (80%). MS 192 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH:14]([CH2:18][CH3:19])[CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCC1CN(c2nn(N)c(=O)c3ccccc23)CCO1
Product: CCC1CN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CCO1

Procedure:
The product from Example 220B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 8.29 (dd, J=7.8, 1.2 Hz, 1H), 7.96-8.03 (m, 2H), 7.90 (ddd, J=7.9, 6.7, 1.4 Hz, 1H), 7.40-7.41 (m, 4H), 3.91 (dd, J=11.1, 2.6 Hz, 1H), 3.79 (td, J=11.4, 2.3 Hz, 1H), 3.67 (s, 2H), 3.56-3.65 (m, 1H), 3.26-3.32 (m, 2H), 2.76-2.84 (m, 1H), 2.51-2.57 (m, 1H), 1.48 (p, J=7.1 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H); MS (DCI+) M/Z 427 (M+H)+, 444 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:24]([CH3:26])[CH3:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
N-Tertiarybutyloxycarbonyl-L-tyrosine (14.1 g 50 mM) in dry dimethylformamide (200 ml) was treated with sodium hydride (3.45 g, 115 mM) with vigorous stirring under an atmosphere of argon at 10° C. for 1 h. 2-Bromopropane (6.15 g, 50 mM) was added and the stirred solution allowed to warm to 20° C. over 16 h. Water (200 ml) was added and the solution extracted with ethyl acetate (2×200 ml). The reaction was adjusted to pH1 with hydrochloric acid (6M) and extracted with dichloromethane 2×300 ml. The combined extracts were columned on silica in ethyl acetate to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine (13.6 g, 42 mM) as a foam. The foam was dissolved in dichloromethane (200 ml) and treated with methylamine hydrochloride (2.5 g, 80 mM), 1-hydroxybenzotriazole (6.75 g, 44 mM), dicyclohexylcarbodiimide (9.1 g, 44 mM) and N-methyl morpholine (2.5 g, 80 mM) at 0° C. with continuous stirring. The solution was allowed to warm to room temperature over 16 h and filtered. The filtrate was washed with water, aqueous saturated sodium hydrogen carbonate solution and aqueous citric acid (1M), dried over sodium sulphate and concentrated in vacuo to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine-N-methyl amide (6.1 g, 18 mM) which crystallised from ethyl acetate/hexane as needles m.p. 110°-114° C. (Found: C,63.5; H,8.4; N,8.7. C18H28N2O4 0.25 H2O requires: C,63.4; H,8.4; N,8.2%) δ(CDCl3) 1.32 (6H,d,J=7 Hz, (CH3)2CH); 1.4 (9H,s,(CH3)3C); 2.72 (3H,d,J=4 Hz NHCH3); 2.98, (2H,d,J=7 Hz CH2C6H5); 4.26 (1H,m,NHCHCO); 4.5 (1H, heptet, J=5 Hz, CH(CH3)2); 5.08 (1H,m,NH); 5.92 (1H,m,NH); 6.78, and 7.04 (each 2H,each d,each J=8 Hz C6H4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[C:10]([CH3:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Yield: 75.2 %

Procedure:
Using a procedure analogous to Example A1, 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na2CO3 (0.84 g, 6.6 mmol) and Pd(PPh3)4 (0.25 g, 0.2 mmol) were combined to give 2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (0.74 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.4 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.68-6.61 (m, 2H), 6.45 (dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]+.
Reaction SMILES: C(F)(F)=C(Cl)[F:3].[NH:7]1[CH:14]=[CH:13][C:11](=[O:12])[NH:10][C:8]1=[O:9].FF>F>[F:3][C:13]1[C:11](=[O:12])[NH:10][C:8](=[O:9])[NH:7][CH:14]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)=C(F)Cl
Agent: F
Agent: FF
Product: O=c1[nH]cc(F)c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
In a 200 ml volume flask made from "Daiflon Resin" (trifluorochloroethylene resin manufactured by Daikin Kogyo Co., Ltd.) which is equipped with a stirrer, a cooler, an inlet for gas and a thermometer, a designed amount of uracil and an aqueous solution of hydrofluoric acid (50 g) are charged, and the contents are stirred at a temperature lower than the reaction temperature to dissolve uracil in the aqueous solution of hydrofluoric acid. A designed amount of fluorine gas diluted or not with nitrogen gas is introduced therein over a period of 30 minutes to 1 hour. Then, nitrogen gas is made to pass through the flask for about 10 minutes to remove fluorine present in the reaction system. The reaction solvent is distilled off with heating to obtain crude 5-fluorouracil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Yield: 22.2 %

Procedure:
A mixture of (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-one (398 mg, 2.12 mmol), PdCl2(Ph3P)2 (70 mg), Cs2CO3 (1.5 mL, 3.0 mmol) in 1,4-dioxane (15 mL) was heated under reflux for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (150 mg, 22%). 1H NMR (CDCl3): δ=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t, 3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41 (m, 1H), 2.92 (m, 1H), 3.63 (s, 3H), 5.69 (q, 1H), 6.69 (m, 1H), 6.99 (m, 4H), 7.18 (m, 2H) δ7.27 (m, 2H) δ 7.42 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][O-])[CH2:5][CH2:4][O:3]1.[Na+].[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:7]=[C:6]2[CH2:5][CH2:4][O:3][C:2]2=[O:1])[CH:12]=1
Reactant: Nc1cc(Br)ccn1
Reactant: O=C1OCCC1=C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1=CNc1cc(Br)ccn1

Procedure:
A solution of sodium (2-oxodihydrofuran-3(2H)-ylidene)methano-late (134 mg, 1 mmol), 4-bromopyridin-2-amine (173 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid (50 mg, 0.29 mmol) in toluene was stirred at 150° C. for 1 hr. After the suspension was diluted with water, the solution was adjusted to pH 8 and extracted with ethyl acetate. Then, the organic layers were dried over Na2SO4 and concentrated to give crude product, which was used for then next reaction without further purification. MS (ESI): 269, 271 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](Br)[C:5]2OC[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.[C:26](=[O:29])([O-])[O-].[K+].[K+]>CC(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([NH:8][CH2:7][C:6]1[CH:5]=[C:4]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH:3]=[C:2]([C:15]2[CH:11]=[N:8][CH:7]=[CH:6][CH:5]=2)[C:26]=1[OH:29])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)N1COc2c(Br)cc(Br)cc2C1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)NCc1cc(-c2cccnc2)cc(-c2cccnc2)c1O
Temperature: 72 °C
Yield: 50.6 %

Procedure:
A mixture of 6,8-dibromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 6) (0.621 g, 1.79 mmol), pyridine-3-boronic acid [purchased from Boron Molecular Limited] (0.660 g, 5.37 mmol) and potassium carbonate (1.979 g, 14.3 mmol) in 2-propanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (107 mg, 0.09 mmol) was added and the resulting mixture was heated at 72° C. for 30 minutes then the cooled reaction mixture concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford a dark brown oil. The product was purified by flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give 2-((tert-butylamino)methyl)-4,6-di(pyridine-3-yl)phenol (151 mg) as an off-white solid.