Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Li+].[OH-]>CO.O>[CH2:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCN[C@H](C(=O)OC)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCCCN[C@H](C(=O)O)C(C)(C)C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A 0.25M solution of methyl N-hex-5-en-1-yl-3-methyl-L-valinate 99 in a mixture of MeOH:water (3:1) was treated with LiOH (3.0 eq.) at RT. The reaction mixture was stirred at 70° C. for 3 h. The organic solvent was removed under reduced pressure and the residue was acidified with aqueous HCl (1N). The water phase was repeatedly extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product, which was used in the following step without further purification. MS (ES+) m/z 214 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:26]C)=[C:13]([C:15]2[C:23]3[CH2:22][NH:21][C:20]([NH2:24])=[N:19][C:18]=3[N:17]([CH3:25])[N:16]=2)[CH:14]=1.[BrH:28]>O>[NH2:24][C:20]1[N:19]=[C:18]2[N:17]([CH3:25])[N:16]=[C:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[C:11]([Br:28])[C:12]=3[OH:26])[C:23]2=[CH:22][N:21]=1
Reactant: Br
Reactant: COc1ccc(Cl)cc1-c1nn(C)c2c1CNC(N)=N2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1nc(-c2cc(Cl)cc(Br)c2O)c2cnc(N)nc21

Procedure:
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine trifluoroacetate is dissolved in 48% HBr in water (10 ml) and heated using microwave radiation at 120° C. for 2 hours. Purification of the reaction mixture by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as the minor product of the reaction as the trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.C(OC(C)C)(=O)C.[CH3:60][S:61](O)(=[O:63])=[O:62]>O>[CH3:60][S:61]([O:18][C@H:16]1[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]2[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]([C@@H:40]([F:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=3)=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]3)[C:17]1=2)(=[O:63])=[O:62]
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(C)(=O)=O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To 40.7 mg (0.055 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, 0.28 ml of isopropyl acetate and 0.008 ml of ultrapure water were added, and the reaction mixture was stirred at room temperature to obtain a homogeneous solution. Then, 0.004 ml (0.062 mmol) of methanesulfonic acid was added thereto, and the reaction mixture was stirred at the same temperature for 90 minutes. The precipitated solid was obtained by filtration, washed with 0.04 ml of isopropyl acetate three times and then dried under reduced pressure at 40° C. to provide 38.7 mg of the title compound as a white powder (yield: 85%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17]I.[H-].[Na+]>C1COCC1.CS(C)=O.[Cl-].[Na+].O>[CH3:17][O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
170 mg (0.77 mmol) of 4-(4-hydroxy-piperidin-1-yl)-benzoic acid (reference example 113d) were dissolved in 3 ml of THF and 3 ml of DMSO, 120 mg (1.1 equiv) of methyl iodide and 68 mg (1.69 mmol) of NaH were added and stirred 16 h at room temperature. The mixture was poured into brine and extracted with DCM (3×) aqueous phase acidified with HCl to pH 1 and extracted again with DCM (3×). The combined organic extracts were washed with brine, dried with Na2SO4, filtered and evaporated. TLC (DCM/MeOH 10%) showed a mixture of the starting material (Rf˜0.5) and a new product with Rf˜0.6. The two were separated by chromatography on silica with DCM/MeOH (0-10%) as a mobile phase to give 60 mg of the title compound. 1H NMR (CDCl3): d 7.95 (d, 2H), 6.87 (d, 2H), 3.68 (m, 2H), 3.63 (m, 1H), 3.38 (s, 3H), 3.14 (m, 2H), 1.98 (m, 2H), 1.68 (m, 2H). MS (ion spray) m/z 236 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:20][C:19]=3[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]2)[CH:4]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.6 %

Procedure:
A stirred solution of 200 mg (0.303 mmol) of 2-(2-bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) in 3.5 mL of THF was cooled to 0° C. and treated dropwise with a solution of 542 mg (2.4 mmol) of stannous chloride dihydrate in 1.5 mL of concentrated hydrochloric acid. After 45 minutes, the mixture was added to a vigorously stirred mixture of 50% NaOH and ice. Ethyl acetate (15 mL) was added, and the mixture was stirred at 0° C. for 1.5 hours. The phases were separated, and the aqueous fraction was re-extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine and dried over anhydrous Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed on silica gel to give 131 mg (68%) of the title compound as a stiff, off-white foam, mp 103°-105° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 629, 631 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[N:7]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:6]=1[CH3:27])=[O:4].[OH-].[Na+]>O1CCOCC1.O.C(OCC)C>[CH3:27][C:6]1[N:7]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:18])([F:20])[F:19])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccccc2OC(F)(F)F)n(C[C@@H]2CCCO2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)O)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of 171 mg of 2-methyl-1-[(S)-1-(tetrahydro-furan-2-yl)methyl]-5-(2-trifluoromethoxy-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester in dioxane (4 ml) and water (4 ml) was added 1.3 ml of a 1N solution of sodium hydroxide. The reaction mixture was heated at reflux for 20 hours. After such time the reaction mixture was allowed to cool down to room temperature. The mixture was diluted with diethyl ether and extracted with 1N sodium hydroxide solution. Water phases were pooled, acidified with 2N solution of hydrochloride acid and extracted twice with diethyl ether. The organic phases were pooled, washed with brine and dried with MgSO4. Solvent was removed to give 154 mg of the title compound as brownish oil; MS (ISP) 368.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23].C([O-])(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine (1.0 eq) was dissolved in 1,2-dichloroethane (0.1 M). 1-methylsulfonylpiperazine (1.1 eq) and sodium acetate (1.1 eq) were added. The solution was stirred for 2 h at 70° C. and the solvent was removed in vacuo. The residue was purified by silica gel chromatography to give 5-chloro-2-(4-methylsulfonylpiperazin-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidine. This intermediate, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 eq), trans-dichlorobis(triphenylphosphine)palladium(II) (0.10 eq), 1M KOAc (3.0 eq) and a 6× volume of acetonitrile were microwaved at 150° C. for 15 minutes. Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give 145. MS (Q1) 477 (M+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C@H:10]([C@@H:12]2[N:16]([CH3:17])[C:15](=[O:18])[CH2:14][C@@H:13]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:11])=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1(S)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@H:10]([C@@H:12]2[N:16]([CH3:17])[C:15](=[O:18])[CH2:14][C@@H:13]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:11])=[CH:6][CH:7]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)/C=C\c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Sc1ccccc1
Solvent: c1ccccc1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)/C=C/c1ccc(F)cc1
Yield: 26.3 %

Procedure:
A mixture of (±)-5-[(2Z)(1R*)-3-(4-fluorophenyl)-1-hydroxyprop-2-enyl](4R*,5R*)-1-methyl-4-phenylpyrrolidin-2-one (115 mg, 0.35 mmol), AIBN (10 mg, 0.06 mmol) and thiophenol (12 mg, 0.11 mmol) in benzene (10 mL) was heated at the reflux temperature for 4 h. The resulting mixture was concentrated under reduced pressure and purified by preparatory TLC (90% EtoAc/hex) to give (±)-(4R*,5R*)-5-[(2E)(1R*)-3-(4-fluorophenyl)-1-hydroxyprop-2-enyl]-1-methyl-4-phenylpyrrolidin-2-one (30 mg, 26%) as a white solid: mp 189-191° C.; 1H NMR (CDCl3) δ 2.49-2.57 (m, 1H), 2.98 (s, 3H), 3.12-3.21 (m, 1H), 3.84-3.89 (m, 2H), 4.09-4.14 (m, 1H), 6.07 (dd, J=16.2, 5.0 Hz, 1H), 6.40 (dd, J=16.2, 1.7 Hz, 1H), 6.97-7.03 (m, 2H), 7.21-7.42 (m, 7H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[CH2:27][CH2:28][OH:29])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[CH2:27][CH2:28][O:29][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Tert-butyl-dimethyl-silyl chloride (3.62 g, 24.02 mmol) and imidazole (3.27 g, 48.03 mmol) were added to a solution of the compound of step 2 (4.609 g, 20.01 mmol) in 75 ml of DCM and the resulting solution was stirred at room temperature for 3 h. The mixture was washed with 50 ml of water and then 50 ml of brine. The aqueous phase was extracted once with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6.90 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[C@:16]([C:18]#[CH:19])([OH:17])[C@H:15]([OH:20])[C@@H:14]([CH2:21][OH:22])[O:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN(C=O)C.[CH2:28](N(CC)CC)[CH3:29].C[Si](C#C)(C)C>C1COCC1.CO.N.[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>[NH2:1][C:2]1[C:3]2[C:10]([C:28]#[CH:29])=[CH:9][N:8]([C@H:12]3[C@:16]([C:18]#[CH:19])([OH:17])[C@H:15]([OH:20])[C@@H:14]([CH2:21][OH:22])[O:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCN(CC)CC
Reactant: C#C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@]2(O)C#C)c2ncnc(N)c12
Reaction time: 0.5 h

Procedure:
Alternatively, the title compound and the compounds of Examples 9 and 10 are prepared from (2R,3R,4R,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol (Example 7). To a dried and precooled 25 ml round-bottomed flask are added (2R,3R,4R,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol (0.060 g, 0.144 mmol), copper(I) iodide (0.006 g, 0.028 mmol), tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) dissolved in anhydrous THF (1.0 ml) and anhydrous DMF (0.5 ml), triethylamine (0.04 ml, 0.288 mmol), trimethylsilylacetylene (0.024 ml, 0.173 mmol). The reaction mixture is stirred at 0° C. to room temperature under argon for 30 mins. The solvent is removed in vacuo, and the residue obtained is dissolved in methanol (0.60 ml) and 30% ammonia solution (0.60 ml). The resulting reaction mixture is allowed to stir at room temperature for one hour. The solvent is removed in vacuo. The crude residue obtained is purified by reverse phase preparative HPLC on Atlantis C18 column (250×20 mm) in gradient from 5 to 95% of acetonitrile in water. Fractions containing the desired products are isolated, evaporated and lyophilized from water to give (2R,3R,4R,5R)-2-(4-amino-5-ethynyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol (Example 8), (2R,3R,4R,5R)-2-(4-amino-5-ethynyl-pyrrolo[2,3-d]pyrimidin-7-yl)-3-buta-1,3-diynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol (Example 9), and (2R,3R,4R,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-buta-1,3-diynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol (Example 10) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=[O:21])=[O:20].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1cnc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (8.00 g) in THF (50 mL) was added 1.6 M n-butyllithium-hexane solution (30.6 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added an excess amount of dry ice, and the mixture was allowed to warm to room temperature. 1 M Hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.30 g).
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6]1
Reactant: CSc1ccccc1C=NO
Solvent: Clc1ccccc1
Solvent: O=S(Cl)Cl
Product: c1ccc2sncc2c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was heated to room temperature and subjected to distilling off of the solvent and then to distillation under reduced pressure to give 26.2 g of 1,2-benzisothiazole (boiling point: 115° to 116° C./15 mm Hg, melting point: 39° to 40° C.). The yield was 97% to the 2-(methylthio)benzaldehyde oxime.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][S:28]([N:25]1[CH2:24][CH2:23][N:22]([C:20]([N:11]2[CH2:12][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:9]([NH:7][CH3:6])[CH2:10]2)=[O:21])[CH2:27][CH2:26]1)(=[O:30])=[O:29]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 96.9 %

Procedure:
To a solution of rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (640 mg, 1.38 mmol) in CH2Cl2 (10 ml) was added TFA (2 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq. NaHCO3 and the organic phase dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.49 g (98%) of the title compound as a white solid. ES-MS m/e: 367.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=O)[N:5]=1)(=[O:3])[NH2:2].CO.[NH3:33]>>[NH2:33][C:26](=[O:28])[C@@H:25]([NH:24][C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:7]=1)[CH3:30]
Reactant: COC(=O)[C@H](C)Nc1nc(C(N)=O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: N
Solvent: CO
Product: C[C@H](Nc1nc(C(N)=O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Yield: 81 %

Procedure:
A solution of (S)-methyl 2-((4-carbamoyl-6-(4-(4-fluorophenoxy)phenyl)pyrimidin-2-yl)amino)propanoate (0.911 g, 2.22 mmol) in 7M ammonia in methanol (20 mL, 140 mmol) was heated in a sealed tube for 4 days at 50° C. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 10 mL 1:1 acetone/hexanes. The solid was filtered, rinsed once with 5 mL 1:1 acetone/hexanes, and dried under vacuum at 40° C. to give (S)-2-((1-amino-1-oxopropan-2-yl)amino)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a white powder (0.713 g, 1.80 mmol, 81% yield). 1H NMR (400 MHz, CD3OD): 8.20 (2H, d, J=8.8 Hz), 7.76 (1H, s), 7.21-7.08 (4H, m), 7.06 (2H, d, J=8.8 Hz), 4.47 (1H, br s), 1.54 (3H, d, J=7.2 Hz). LC/MS: m/z=396.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]2)[CH2:2]1.[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31](O)=[O:32])(=[O:19])[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10]2)[CH2:4]1)=[O:32])(=[O:19])[CH3:18]
Reactant: O=C(N1CCN(C2CNC2)CC1)C(F)(F)F
Reactant: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of compound 1g (228 mg, 0.74 mmol), compound 25c (22 mg, 0.74 mmol), and Et3N (0.3 mL, 2.22 mmol) in CH2Cl2 (7 mL) was added HATU (338 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 25d (265 mg). LC/MS m/z (M+H+), 517.0 (M+2H+), 519.0.
Reaction SMILES: [CH:1]([Si:3]([CH2:10][CH2:11][CH3:12])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])=[CH2:2].[C:13]1([PH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([Si:3]([CH2:1][CH2:2][P:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH2:11][CH3:12]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](CCC)(CCC)CCC
Product: CCC[Si](CCC)(CCC)CCP(c1ccccc1)c1ccccc1

Procedure:
The vinyl tripropyl silane was then reacted with diphenyl phosphine with u.v. initiation for 86 hours in a manner described in the previous example. The conversion was about 95%. The mixture was fractionally distilled to yield the pure product as a clear, colorless, mobile liquid (see Table I.)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26](OC)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>Cl>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH2:26][OH:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)C1(c2cccc(Sc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(CO)CCOCC3)c2)cc1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a stirred solution of methyl 4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate(359 mg,0.9 mmol) was added LAH (80 mg, 2.0 mmol) at 0° C. After completion of addition, the mixture was allowed to warm to room temperature. To the reaction mixture was carefully added water (1 ml), and the resulting solids were dissolved in 1N aqueous HCl and the aqueous solution was basified with 1N aqueous NaOH. The aqueous mixture was extracted with ethyl acetate (30 ml×3), and the combined extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography {LiChroprep NH2 (Merck), 20 g; eluted with ethyl acetate} to afford 231 mg (69%) of the desired compound as white solids.