Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([CH:22]=1)[NH2:21].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:21][C:20]2[CH:22]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=2[O:23][CH3:24])(=[O:13])=[O:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Reactant: COc1ccc(C)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol; Intermediate 56) in dichloromethane (200 mL) was added 5-methyl-2-methoxyaniline (4.25 g, 31 mmol) and pyridine (7.4 mL, 93 mmol) and allowed to stir at ambient temperature overnight. The dark red solution was washed with water, separated, dried and filtered through a plug of silica to remove most of the red impurity, and finally concentrated. Yield: 13.51 g (99%) red solid. HPLC 90% RT=2.58 min (System A; 30-80% MeCN over 3 min), 1.75 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz, CDCl3) δ ppm 2.23 (m, 3H) 3.52 (s, 3H) 6.54 (d, J=8.30 Hz, 1H) 6.79 (dd, J=8.42, 1.59 Hz, 1H) 6.86 (d, J=2.20 Hz, 1H) 6.96 (s, 1H) 7.31 (d, J=1.71 Hz, 1H) 7.71 (d, J=2.20 Hz, 1H) 7.95 (d, J=1.71 Hz, 1H) 8.04 (d, J=1.71 Hz, 1H). MS (ESI) for C16H14INO4S m/z 444 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C@H:22]([OH:25])[CH2:23][OH:24])[CH:20]=3)[CH:15]=[N:14]2)=[CH:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:25][C@@H:22]([C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)=[CH:17][CH:18]=1)[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2ncc3ccc([C@H](O)CO)cc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3ccc([C@@H](COS(C)(=O)=O)OS(C)(=O)=O)cc32)cc1
Yield: 83.2 %

Procedure:
Methanesulfonyl chloride (0.88 mL, 11.3 mmol) was added dropwise to a solution of (S)-1-(1-(4-methoxybenzyl)-1H-indazol-6-yl)ethane-1,2-diol (1.68 g, 5.63 mmol), Et3N (2.0 mL, 14.1 mmol) and CH2Cl2 (30 mL) at 0° C. After 1 h diluted with CH2Cl2 (100 mL) and washed with 0.5 M HCl, saturated aqueous NaHCO3, brine, and then dried over MgSO4. After the solvent was removed, purification using Biotage Isolera (silica gel, 50-66% EtOAc in hexane) gave the title compound as a sticky white solid (2.13 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.18-7.12 (m, 3H), 6.82 (d, J=8.5 Hz, 2H), 5.90-5.87 (m, 1H), 5.59-5.50 (m, 2H), 4.55-4.50 (m, 1H), 4.42-4.38 (m, 1H), 3.76 (s, 3H), 3.04 (s, 3H), 2.77 (s, 3H); MS ESI 455.1 [M+H]+, calcd for [C19H22N2O7S2+H]+ 455.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure D, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone (32 mg, 0.079 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (32 mg, 0.118 mmol) to afford the desired product (24.0 mg, 65%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 7.97 (dd, J=8.7, 1.9 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J=11.8 Hz, 1H), 4.27-4.18 (m, H), 2.69 (s, 3H), 2.59-2.55 (m, 2H), 2.52 (s, 6H), 2.34 (d, J=12.7 Hz, 2H), 1.99 (d, J=13.2 Hz, 2H), 1.84-1.74 (m, 1H), 1.67-1.55 (m, 2H), 1.28-1.17 (m, 2H). ESI MS m/z 470 [C26H29ClFN3O2+H]+; HPLC>99% (AUC), tR=10.56 min.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino)-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-chlorobenzylamine (19 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was then slurried in a 1:1 methanol-dichloromethane solution, and the solid collected by vacuum filtration to afford the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[N:9][CH:10]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2ccnc2C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Methylimidazole (2.0 g, 24 mmol) and 2-Fluoro-5-methylpyridine (5.41 g, 49 mmol) were dissolved in 40 ml dimethyl formamide. Cesium carbonate (23.8 g, 73 mmol) was added, and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was poured into 100 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The desired compound was obtained as a brown oil (4.0 g, 95%), MS: m/e=174.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:13]2[S:20][CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:5][CH:6]=1
Reactant: NCCc1ccc(N)cc1
Reactant: Clc1ncnc2ccsc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1ccc(CCNc2ncnc3ccsc23)cc1

Procedure:
A solution of 4-(2-amino-ethyl)-phenylamine (compound 12.1; 0.1 mmol.), compound 6.2 (1.0 equivalent) and DIEA (2.5 equivalents) was heated in n-butanol (2 mL) at 135° C. for 2 hours. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried and concentrated under reduced pressure to give crude [2-(4-amino-phenyl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine (compound 12.2) which was used without purification for the next step.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]([F:22])([F:21])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH2:19]O>O>[Br:1][CH2:19][C:10]1[C:9]([C:8]([F:22])([F:21])[F:7])=[CH:14][CH:13]=[CH:12][C:11]=1[C:15]([F:18])([F:17])[F:16]
Reactant: OCc1c(C(F)(F)F)cccc1C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CBr
Temperature: 25 °C

Procedure:
To 1 ml of a mixture of 48% aqueous HBr solution and conc. sulfuric acid (2:1 v/v) were added 0.81 g (3.3 mmol) (2,6-bis-trifluoromethyl-phenyl)-methanol and the solution heated to reflux for 6 h. Then the reaction mixture was cooled to rt, diluted with water and extracted with tert-butyl methyl ether. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation provided 2-bromomethyl-1,3-bis-trifluoromethyl-benzene as colourless oil of b.p. 135-140° C./22 mbar: MS (EI): 307.9 and 305.9 (M+.), 227.1 (((M-Br)+.), 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (0.5 g, 1.83 mmol) and commercially available 3-bromo-benzene-boronic acid (0.48 g, 2.39 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.11 g, 15%). MS (ISP) 395.0 [(M+H)+]; mp 102.5° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (135 mg, a white solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (210 mg, 0.72 mmol, Amine-5, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:42])[CH:25]([NH:41][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)O
Product: CC(C)CC(NC(=O)N1CCN(C)CC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
A solution of the product from Example AF (2(S)-[(4-methyl-piperazine-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.25 g, 1.03 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.35 g, 1.03 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, gradient elution 1:1 EtOAc/heptane; 9:1 EtOAc/EtOH; 9:1:0.1 EtOAc/EtOH/NH4OH) to give the title compound as a white foam (0.35 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[N:3]=3)[CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: COc1cc(F)ccc1C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C1CN(c2nc(-c3ccncc3)cc(=O)n2C)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
2-Chloro-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (222 mg, 1.0 mmol) was added to an ice-cooled solution of 2-(4-fluoro-2-methoxyphenyl)piperazine (210 mg, 1.0 mmol), triethylamine (0.15 ml, 1.1 mmol) in N,N-dimethylformamide (10 ml) and stirred at that temperature for 1 hr and then at room temperature for 2 hr. Next day, reaction was quenched by ice-water and the filtrate was washed with water and dried to give 2-(2-(4-fluoro-2-methoxyphenyl)piperazin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (246 mg, 62%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:18]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.[Cu]I.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>[CH2:18]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[O:9])=[C:5]([CH3:7])[N:6]=2)=[N:28]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nnn(COCc3ccccc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a mixture of 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.32 mmol), copper(I) iodide (0.002 g, 0.009 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in anhydrous toluene (3 mL) was added 2-(benzyloxymethyl)-5-(tributylstannyl)-2H-tetrazole (0.018 g, 0.39 mmol, prepared following the procedure described in Tetrahedron Letters, 41, (2000), 2805-2809) and the reaction mixture was heated at 85° C. in a sealed tube for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:methanol, 10:1) to afford the title compound as a clear oil (0.065 g, 48%): 1H NMR (300 MHz, CDCl3) δ 8.53 (br s, 1H), 8.52-8.45 (m, 1H), 7.75-7.69 (m, 1H), 7.36-7.20 (m, 6H), 6.80 (t, J=5.8 Hz, 1H), 5.97 (s, 2H), 4.69 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.4, 160.3, 157.3, 153.3, 149.2, 149.1, 135.9, 135.3, 133.5, 128.7, 128.5, 128.2, 128.0, 123.8, 80.3, 72.4, 41.7, 17.5; MS (ES+) m/z 422.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[CH3:24][C@H:19]1[CH2:20][O:21][CH2:22][CH2:23][N:18]1[C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]([O:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])=[CH:7][CH:6]=2)[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(4-aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (400 mg) was dissolved in dioxane (10 mL) and sodium bicarbonate (154 mg) and phenylchloroformate (0.154 mL) added dropwise. The mixture was stirred at RT for 16 hours then the dioxane removed under reduced pressure and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to give the desired material as a brown foam (624 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([S:7]([O-:10])(=[O:9])=O)=[CH:4][CH:3]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CCOCC>[C:18]([NH:22][S:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)[O-])o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
At a temperature of 30° to 50° C., 248 gm (1.35 mol) of sodium 5-methyl-furan-2-sulfonate were admixed in portions with 281 gm (1.35 mol) of phosphorus pentachloride and the mixture was stirred for 15 minutes at 50° C. The reaction mixture was then poured over ice and extracted with ether. The ether phase was washed until neutral, dried and evaporated. The residue (200 gm of 5-methyl-furan-2-sulfonic acid chloride) was dissolved in 500 ml of ether, and the solution was added dropwise to a solution of 280 ml (2.7 mol) of tert.-butylamine in 500 ml of ether at a temperature of 5° to 10° C. After stirring at room temperature and at reflux temperature, each for 2 hours, the reaction mixture was washed with ice water, dilute hydrochloric acid and water and then evaporated. The residue was recrystallized from cyclohexane, yielding 180.5 gm (61.5L % of theory) of N-tert.-butyl-5-methyl-furan- 2-sulfonamide.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
A solution of 4-[(2-naphthalenyl)methoxy]-alpha-oxobenzeneacetic acid methyl ester (0.58 g) in methanol (3 mL) and tetrahydrofuran (8 mL) was treated with 1N sodium hydroxide (2.0 mL) and a white precipitate formed immediately. After 5 minutes, the reaction mixture was concentrated, the residue was acidified with excess hydrochloric acid and partitioned between dichloromethane (100 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated. The resulting residue was crystallized from dichloromethane-hexane-tetrahydrofuran to give 0.315 g of 4-[(2-naphthalenyl)methoxy]-alpha-oxobenzeneacetic acid, mp 145°-146° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1O
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2ccccc2OC)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-methoxy phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:23])[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate as a TFA salt (73 mg, 0.17 mmol) in DCM (4.0 mL) was added TFA (1.0 mL). The solution was stirred at room temperature for 2 h and the solvent was removed in vacuo to give 4-(4-amino-2-fluorobenzyl)pyridin-2-amine, bis-trifluoroacetic acid (70 mg, 93% yield). MS(ESI+): m/z 218.12 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=[O:16].O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([NH:10][C:7]1[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=1)=[O:16]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
To 5-nitropyrimidin-2-amine (1.0 g, 7.1 mmol) in pyridine (10 mL) was added 3-chloro-4-fluorobenzoic acid (1.7 g, 9.7 mmol). The reaction mixture was heated at 100° C. for 4 hrs and allowed to cool to rt. 15 mL H2O was added. A precipitate was collected by filtration and purified by silica gel chromatography, eluting with CH2Cl2 followed by 10% EtOAc/CH2Cl2 to give 1.16 g (55% yield) 1C. RP HPLC ret. t.: 2.22 min. and (M+H)+: 297.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with Solvias catalyst (7 mg), tripotassium phosphate (84 mg) and 4-bromo-1H-pyrrolo[2,3-b]pyridine (commercial from Sinova, 29 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (65 mg) in 1,4-dioxane (0.5 ml) was added, followed by water (0.1 ml) and the reaction was heated under microwave irradiation for 10 min at 120° C. The reaction was washed through a silica cartridge, preconditioned with methanol, with methanol. The solvent was removed under a stream of nitrogen, then washed with DCM and water. The resultant solution was evaporated under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol, 2 M HCl (aq) (3 drops) was added and the solution was left to stand for 30 min. The solvent was removed under a stream of nitrogen and the residue was dissolved in methanol, washed with methanol through an aminopropyl cartridge preconditioned with methanol and dried under a stream of nitrogen to give title compound, 20 mg.