Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 34, the configuration of the stereocenter is arbitrarily assigned) and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 7. LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17].[C:20]1([NH2:27])[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1>ClCCl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][S:16]([C:4]1[CH:5]=[C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:18])=[O:17]
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 2-methoxy-5-trifluoromethanesulfonyl-1-benzenesulfonyl chloride (5 g) in dry dichloromethane (10 mL), benzene-1,2-diamine (5 g) was added followed by addition of dry pyridine (10 mL) at 0° C. The resulting deep red reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (250 mL). The contents were washed with saturated aqueous sodium chloride solution (50 mL) and saturated aqueous sodium carbonate solution (50 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc (7:1 to 4:1) to give N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (6 g). LC: Tr 0.95 min, MS: 411 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.18 (bs, 2H), 4.21 (s, 3H), 6.43 (m, 2H), 6.57 (bs, 1H), 6.75 (dd, 1H), 7.02 (t, 1H), 7.35 (d, 1H), 8.22 (dd, 1H), 8.40 (d, 1H) ppm.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:35]([NH:42][SH:43](=[O:45])=[O:44])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.[N:71](C(OCC)=O)=NC(OCC)=O>>[C:38]([O:37][C:35](=[O:36])[N:42]([S:43]([NH2:71])(=[O:44])=[O:45])[CH2:33][C@@H:10]1[CH2:11][C@@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[SH](=O)=O
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C)S(N)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol (700.0 mg, 0.001462 mol), N-Boc-sulfonamide (398 mg, 0.00203 mol) and triphenylphosphine (575 mg, 0.00219 mol) were dissolved in ethyl acetate (28 mL, 0.28 mol) at 50° C. under an atmosphere of nitrogen. Diethyl azodicarboxylate (350.0 μL, 0.002223 mol) was added over 2-3 min and the mixture was stirred at 50° C. for 30 minutes. The cooled mixture was evaporated and the residue purified by silica gel chromatography, eluting with 10 to 100% ethyl acetate in hexanes, to yield the product as a white solid, 636 mg (66%). LC/MS: Rt=2.55 min, ES+ 657 (AA standard).
Reaction SMILES: [Br:1][CH:2]1[CH2:31][C@@H:30]([CH3:32])[CH2:29][O:28][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:27])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@H:11]1[O:26][C@@H:10]31.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35]([OH:37])=[O:36]>C1(C)C=CC=CC=1>[Br:1][CH:2]1[CH2:31][C@@H:30]([CH3:32])[CH2:29][O:28][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:27])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:36][C:35](=[O:37])[C:34]([Cl:39])([Cl:38])[Cl:33]
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H]5O[C@H]5[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Reactant: O=C(O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12β,25R)-23-bromo-11,12-epoxyspirostan-3-ol was treated with trichloroacetic acid in toluene at room temperature for 3 days to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.[F:26][C:27]1[C:32]2[CH:33]=[N:34][S:35][C:31]=2[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.[C:45](=O)([O-:47])[O-:46].[K+].[K+].O1CCOCC1>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.O>[CH:45]([OH:47])=[O:46].[CH:45]([OH:47])=[O:46].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:30]3[C:31]4[S:35][N:34]=[CH:33][C:32]=4[C:27]([F:26])=[CH:28][CH:29]=3)[O:8][C:7]=12
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC1(C)OB(c2ccc(F)c3cnsc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccc(F)c6cnsc56)cc34)cn2)CC1
Product: O=CO
Yield: 16 %

Procedure:
A mixture of 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (15.0 mg, 0.0417 mmol), 4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-benzothiazole (23.3 mg, 0.0824 mmol), Pd(PPh3)4 (4.82 mg, 0.00417 mmol), potassium carbonate (17.3 mg, 0.125 mmol) and 4:1 dioxane:H2O (1 mL) was heated in a microwave reactor at 110° C. for 40 min. The crude reaction mixture was purified by preparative HPLC to afford 3.8 mg (19%) the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.97-2.15 (m, 2 H), 2.19 (s, 3 H), 2.19-2.30 (m, 2 H), 2.88 (td, J=13.0, 2.8 Hz, 1 H), 3.33-3.40 (m, 1 H), 4.07-4.16 (m, 1 H), 4.54 (tt, J=11.5, 4.2 Hz, 1 H), 4.65-4.74 (m, 1 H), 7.27 (dd, J=9.3, 8.3 Hz, 1 H), 7.41 (s, 1 H), 7.83 (s, 1H), 7.87 (s, 1 H), 8.09 (s, 1H), 8.20 (s, 2 H), 8.22 (dd, J=8.3, 4.5 Hz, 1 H), 9.06 (s, 1 H); MS (ESI): 477.13 [M+H]+; HPLC tR=1.10 min (TOF: polar—3 min).
Reaction SMILES: Br[C:2]1[C:3]2[N:4](N=N[N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.CC(C)([O-])C.[K+].O1CCOCC1>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.O>[NH2:23][C:3]1[C:2]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3nnnn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c(N)n2)CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 8.7 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(8-bromotetrazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (5.5 g, 14.3 mmol), thiophene-2-boronic acid (2.5 g, 21.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.43 mmol), potassium tert-butoxide (2.4 g, 21.5 mmol), 1,4-dioxane (200 mL) and water (50 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 80° C. under N2 for 10 h. Work-up: the reaction mixture was diluted with 0.1 M HCl (20 mL) and washed with EtOAc (150 mL×3). The aqueous layer was then basified with solid NaHCO3 and extracted with CH2Cl2 (150 mL×3). The combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2 to afford 0.70 g (12%) of the product, and 0.45 g (8.7%) of tert-butyl 4-(4-amino-5-(thiophen-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:20][C:21]1[C:29]2[N:28]=[C:27]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[Cl:20][C:21]1[C:29]2[N:28]=[C:27]([CH2:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CNCCCc1nc2c(Cl)cccc2[nH]1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Product: CN(CCCc1nc2c(Cl)cccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(4-chloro-1H-benzoimidazol-2-yl)-propyl]methyl-amine.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[N+:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]N2)([O-:7])=[O:6].[CH2:18]=O.[OH-].[Na+]>C(O)(=O)C>[CH3:18][N:14]1[C:15]2[C:10](=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:17][CH:16]=2)[N:2]([CH3:1])[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCN2
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 24 h

Procedure:
1.52 g (0.024 mole) sodium cyanoborohydride was added at 25° C., to a mixture of 1.08 g (0.006 mole) of the 1,2,3,4-tetrahydro-6-nitroquinoxaline obtained in accordance with J. Het. Chem. 10, 213 (1973) and 1.5 g (0.005 mole) paraformaldehyde in 300 ml acetic acid. The solution was then left standing for 24 hours at room temperature. The solution was then poured into 60 ml 25% aqueous NaOH solution. The mixture obtained was then extracted three times with methylene chloride. After drying and concentration, N,N'-dimethyl-1,2,3,4-tetrahydro-6-nitroquinoxaline was obtained in a yield of 0.35 g (35% of the theoretical). The melting point of the product was 70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[N+:10]1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:20]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH2:14][OH:20])[C:11]([CH3:15])=[N:10]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1nn(-c2ccc(F)cc2F)[n+]([O-])c1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(F)cc2F)nc1CO
Temperature: 110 °C
Reaction time: 1.25 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-4,5-dimethyl-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 1.78 g, 7.0 mmol) in tetrahydrofuran (14 mL) was added trifluoroacetic anhydride (2.5 mL, 17.5 mmol). The reaction mixture was stirred at 110° C. in the microwave for 75 min. The mixture was diluted with ethyl acetate, washed successively with 1.0 M aqueous sodium hydroxide and 50% aqueous sodium hydroxide, dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to obtain the title compound (0.59 g) as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9])([CH3:3])[CH3:2].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:15][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c(C=O)cc1OC(C)C
Temperature: 61 °C
Yield: 92.8 %

Procedure:
Silver trifluoroacetate (12.3 g, 56.7 mmol) was added to a solution of isovanillin isopropyl ether (10.0 g, 51.5 mmol) in dry chloroform (120 mL) under nitrogen and the resultant slurry stirred and heated to 61° C. Iodine (14.4 g, 56.7 mmol) was then added portionwise (6 portions) over 0.6 h and the reaction allowed to reflux for a futher 6.5 h. The reaction mixture was then cooled and filtered, rinsing with chloroform (50 mL). The filtrate was washed with Na2S2O5 (10% solution in water, 150 mL), NaHCO3 (sat. in water, 150 mL) and water (150 mL) dried (MgSO4) and concentrated under vacuum. The solid residue was suspended in hexane (200 mL) and stirred vigoursly for 1 h, cooled in an ice bath for 1 h and filtered rinsing with ice cold hexane (200 mL) to give the title compound as a cream solid (15.3 g, 93%) mp 75-6° C. IR (KBr disc, cm−1) 3072, 2978, 2932, 1673, 1581, 1503, 1438, 1385, 1332, 1260, 1215, 1174, 1157, 1133, 1105, 1024, 939. 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H,), 7.34 (s, 1H), 7.24 (s, 1H), 4.57 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.31 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 194.7 (−), 155.5 (+), 147.9 (+), 128.2 (+), 122.2 (−), 114.1 (−), 110.8 (+), 92.4 (+), 71.3 (−), 56.4 (−), 21.77 (−). MS (70 eV) m/z (%): 320 (M+·, 43), 278 (100), 249 (17), 207 (12), 150 (40). Anal. Calcd for C11H13O3I: C, 41.27; H, 4.09; I, 39.64. Found: C, 41.06; H, 3.80; I, 39.59.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.ICC>C1COCC1.[Cl-].[Na+].O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:2][CH3:3])[CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Cl)ccn1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(Cl)ccn1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a solution of LDA (0.13 moles) in THF/hexanes (40 mL/40 mL) at −60° C. under argon was added a solution of 4-chloro-2-picoline (15 g) in THF (250 mL) over 20 min. After a further 30 min at −60° C. iodoethane (10.4 mL) in THF (60 mL) was added over 20 min, the reaction stirred at −60° C. for 1.5 h and then allowed to warm to −30° C. The mixture was poured into brine and extracted with dichloromethane. After drying (MgSO4) and purification by chromatography eluting with dichloromethane in petroleum ether (70-100%) followed by dichloromethane containing methanol (0 to 5%) the title compound was obtained as a brown oil (12.35 g). 1H NMR δ (CDCl3) 0.97 (3H, t), 1.75 (2H, m), 2.75 (2H, t), 7.12 (1H, m), 7.16 (1H, d), 8.42 (1H, d).
Reaction SMILES: [C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][OH:33])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:38].O>C1COCC1>[C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][O:33][CH3:38])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CO)c(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1c(-c2cccs2)c2n(c1C(=O)N(C)C(C)(C)C)CCc1cc(OC)c(OC(C)C)cc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 40 (20 mg), sodium hydride (3.3 mg, 60% dispersion in oil) and iodomethane (13 μl) in THF (2.5 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→1/1 (v/v)] as eluent.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[NH3:29].O1CCOCC1>O>[NH2:29][C:7]1[C:2]([Br:1])=[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])[N:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:6]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Reaction time: 48 h
Yield: 40.4 %

Procedure:
4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile (0.00250 mol) and NH3/1,4-dioxane 0.5M (0.015 mol) were heated in a pressure vessel at 150° C. for 4 days. The sample was allowed to sit at ambient conditions for 2 days. Water was added slowly to the mixture until a precipitate formed. The mixture was stirred for 2 hours and filtered. The solid was recrystallized from CH3CN to obtain 0.58 g (fraction 1). The filtrate was evaporated (fraction 2). Both fractions were combined and purified by column chromatography, eluting with CH2Cl2. The resulting residue of the desired fraction was recrystallized from CH3CN to yield 0.44 g of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile (40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (comp. 46).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:15])([F:16])[F:14])=[C:8]([Br:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate B) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the contents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5 ml) were added, followed by the addition of sodium carbonate ((15 mg, 0.14 mmol). The remaining solution of bromine in acetic acid was added and the reaction mixture was left to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under vacuum to afford the title compound.
Reaction SMILES: C(NCC)C.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22]I)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>[Cu](I)I.O>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#CI)cc2)CC1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(C#CC#C[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of dichlorobistriphenylphosphine palladium (4.2 mmol) and copper iodide (0.64 mmol) was added diethylamine, and stirred at room temperature under argon gas atmosphere for 30 minutes. Then, 4-(trans-4-propylcyclohexyl)-1-(2-iodoethynyl)benzene (0.12 mol) was added thereto, and further stirred at room temperature for 15 minutes. To this reaction mixture was added (trimethylsilyl)acetylene (0.14 mol), and stirred at room temperature overnight. After completion of the reaction, water was added thereto and extracted with toluene twice. The organic layer thus obtained was washed with water, and then dried over anhydrous magnesium sulfate. After it was subjected to filtration, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography (silica gel/heptane) and recrystallization (ethanol) to obtain colorless crystals of 4-(trans-4-propylcyclohexyl)-1-(4-trimethylsilyl-1,3-butadiyne-1-yl)benzene. (Yield 24%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[F:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([O:26]C)=O)[C:15]2=[O:30])=[CH:11][CH:10]=1.Cl>C1COCC1.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([N:2]([CH3:3])[CH3:1])=[O:26])[C:15]2=[O:30])=[CH:31][CH:32]=1
Reactant: CNC
Reactant: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−10° C.) solution of dimethylamine (2M in THF, 0.002 g, 0.035 mmol) was slowly added trimethylaluminum (2M in toluene, 0.002 g, 0.035 mmol) and stirred for 30 minutes at room temperature. The reaction mixture was cooled to −10° C. and methyl 6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.004 g, 0.012 mmol, Example 1, Step 8) in THF (5 mL) was added. The reaction stirred at room temperature for 2 hours, then transferred via syringe to a solution of 1:1 CH2Cl2:0.5 N aq. HCl at 0° C. and stirred for 1 hour. The product mixture was separated, and the aqueous was extracted three times with CH2Cl2. The aqueous layer was treated with saturated Na2CO3 solution to pH 5 and extracted three times with CH2Cl2 again. The organic combined extracts were dried with Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a light yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(O)cc1)C(=O)OC
Yield: 83.3 %

Procedure:
A suspension of methyl 3-[4-benzyloxyphenyl)-2-ethoxypropanoate (3.7 g, 11.78 mmol; preparation 2) and 10% Pd-C (0.37 g) in ethyl acetate (50 mL) was stirred at 25° C. under 60 psi hydrogen pressure for 24 h. The catalyst was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) as an eluent to afford the title compound (2.2 g, 84%) as an oil.