Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]1[C:6]2[O:31][CH:30]=[CH:29][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:9]3[N:10]=[C:5]([NH:4][CH2:3][C:2]([F:32])([F:33])[F:1])[C:6]4[O:31][CH:30]=[CH:29][C:7]=4[N:8]=3)[CH:20]=2)[CH:16]=[N:17]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(Nc3nc(NCC(F)(F)F)c4occc4n3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)CNc1nc(Nc2ccc3cn[nH]c3c2)nc2ccoc12
Temperature: 30 °C
Reaction time: 6 h
Yield: 19.1 %

Procedure:
N4-(2,2,2-trifluoroethyl)-N2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (1.08 g, 2.257 mmol) was dissolved in DCM (15 mL). TFA (10 mL, 130 mmol) was added. The resulting mixture was stirred at about 30° C. for about 6 h. The mixture was concentrated in vacuo. The residue was diluted with DCM (30 mL) and the pH was adjusted to about pH=9.0 with concentrated NH4OH. The solvents were removed under reduced pressure and the resulting mixture was purified by preparative-HPLC (Table 2, method w) to afford N2-(1H-indazol-6-yl)-N4-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidine-2,4-diamine (0.15 g, 19%): LC/MS (Table 2, Method h) Rt=1.79 min; MS m/z: 349 (M+H)+. Syk IC50=A
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@@H](N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 2) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+] 525.2290, observed 525.2294.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].C(N(CC)CC)C.Cl.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:46]([N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[O:47])[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)N5CCN(C)CC5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (23.0 mg, 0.058 mmol) and triethylamine (0.016 mL, 0.116 mmol) in CH2Cl2 (2 mL) was added 4-methylpiperazine-1-carbonyl chloride hydrochloride (11.6 mg, 0.058 mmol) and the mixture stirred at rt for 18 h. Diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3(aq) (2 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone (25 mg, 58% yield) as a yellow powder. 1H NMR (400 MHz, CDCl3, 298K) δ ppm 2.17-2.27 (m, 2H) 2.55 (s, 3H) 2.65-2.78 (m, 4H) 3.07 (t, 2H) 3.45-3.73 (m, 9H) 3.86-3.95 (m, 1H) 4.02 (s, 3H) 4.13 (s, 2H) 5.66-5.73 (m, 1H) 7.62 (d, 1H) 8.06 (d, 1H) 8.64 (s, 1H) LCMS: [M+H]+=522.3, Rt(1)=1.21 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.C([O:12][CH:13]([C:19]([CH3:21])=O)[C:14](OCC)=[O:15])(=O)C>CC(N(C)C)=O>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:19]([CH3:21])=[C:13]([OH:12])[C:14](=[O:15])[N:7]2[CH:6]=1
Reactant: CCOC(=O)C(OC(C)=O)C(C)=O
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2sc(Cl)cn2c(=O)c1O
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.2 %

Procedure:
2-amino-5-chloro-thiazole hydrochloride (10 g) was reacted with ethyl 2-acetoxy-acetoacetate (22 g) in dimethylacetamide (400 ml) containing polyphosphoric acid (71 g: 29 g of H3PO4 and 42 g of P2O5) under stirring at 100° C. for 6 hours. After cooling, dilution with ice water and neutralization with 37% NaOH, the precipitate was extracted with ethyl acetate and the organic solution was evaporated in vacuo to dryness. The residue was hydrolyzed by treatment with 35% HCl (50 ml) in dioxane (100 ml) at reflux temperature for 2 hours: after cooling the reaction mixture was diluted with ice water and neutralized with 37% NaOH and the precipitate was extracted with ethyl acetate. The organic solution was evaporated in vacuo to dryness and the residue was crystallized from methanol to give 5.85 g of 2-chloro-6-hydroxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 214°-217° C., which was dissolved in dimethylformamide (100 ml) and reacted with methyl iodide (15.4 g) in the presence of anhydrous K2CO3 (15 g) under stirring at 60° C. for 3 hours. After cooling the reaction mixture was diluted in ice water and neutralized with NaH2PO4 : the precipitate was filtered and the aqueous phase was extracted with ethyl acetate for the complete recovering of the product. On the whole it was obtained 5.1 g of 2-chloro-6-methoxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 138°-141° C., which was reacted with N-bromosuccinimide (17 g, added portionwise) in benzene (150 ml) at the reflux temperature for 40 hours. After cooling the reaction mixture was diluted with ethyl acetate and treated with aqueous NaHCO3 and then with water: the separated organic solution was evaporated in vacuo to dryness and the residue was crystallized from ethyl acetate to give 2.8 g of 7-bromomethyl-2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 160°-162° C., which was reacted with triphenylphosphine (2.6 g) in acetonitrile (50 ml ) at the reflux temperature for 3 hours. After cooling and evaporation in vacuo of the solvent, the residue was purified with ethyl acetate to give 3.8 g of (2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium bromide, which was suspended in dimethylsulfoxide (45 ml) and treated with potassium tert-butoxide (0.75 g) dissolved in dimethylsulfoxide (20 ml) at room temperature under stirring for 10 minutes.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[C:8]1([CH:18]=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][C@H:2]2[CH2:3][OH:4])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: OC[C@@H]1CCCN1
Product: OC[C@@H]1CCCN1Cc1cccc2ccccc12

Procedure:
Using (S)-prolinol ((S)-VII1) and α-naphthoaldehyde as the starting materials, a similar operation was carried out to obtain (S)-N-(α-naphthyl)methyl-2-pyrrolidine methanol ((S)-II-2). ##STR316##
Reaction SMILES: C(O[CH:4]=[C:5]([C:19]#[N:20])[CH2:6][CH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:24][C:23]1[N:25]=[C:19]([NH2:20])[C:5]([CH2:6][CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:4][N:22]=1
Reactant: N=C(N)N
Reactant: CCOC=C(C#N)CCCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(CCCc2cccc3ccccc23)c(N)n1
Temperature: 125 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 0.85 gram (0.003 mole) of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene, 1.22 grams (0.013 mole) of guanidine hydrochloride, and 2.65 grams (0.01 9 mole) of potassium carbonate in 20 mL of N,N-dimethylformamide was heated at 110° C. for 20 hours. After this time the reaction mixture was analyzed by thin layer chromatography (TLC) which indicated the reaction was not complete. The reaction mixture was warmed to 125° C. where it was stirred for six hours. TLC analysis of the reaction mixture after this time indicated that the reaction was still not complete. An additional 10 mL of dimethylformamide was added, and the reaction mixture was stirred at 125° C. for an additional 64 hours. The reaction mixture was then poured into water, and the mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure, yielding a yellow solid. The solid was triturated with dichloromethane. The solid was collected by filtration and subjected to column chromatography on silica gel. Elution was accomplished with 10:1 methylene chloride and methanol. The eluate was concentrated under reduced pressure, yielding 0.30 gram of 2,4-diamino-5-[3-(naphth-1-yl)propyl]pyrimidine, mp 179°-181° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:18])=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: Nn1nc(C2CCCCC2)c2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(C2CCCCC2)c2ccccc2c1=O

Procedure:
The product of Example 74A and 2-(adamantan-1-yl)acetyl chloride were processed using a method similar to that described in Example 1C, and purified by preparative HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm); a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A)] to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.97-8.01 (m, 1H), 7.89 (t, J=7.5 Hz, 1H), 3.21-3.40 (m, 1H), 1.39-1.98 (m, 26H), 1.13-1.27 (m, 1H); MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: N
Reactant: CCCC(O)c1nc(Cl)c2ncn(C)c2n1
Solvent: O
Solvent: C1COCCO1
Product: CCCC(O)c1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the solution of 1-(6-chloro-9-methyl-9H-purin-2-yl)butan-1-ol (1.8 g, 7.47 mmol) in dioxane (10 ml) was added 30% w/w water solution of ammonia (20 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 95/5).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([N:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]2=[O:27])=[N:11][N:12]([CH3:14])[CH:13]=1)=O)(C)(C)C.C(OCC)(=O)C.CO.[ClH:36]>>[ClH:36].[NH2:8][C:9]1[C:10]([N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:27])=[N:11][N:12]([CH3:14])[CH:13]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(N)c(N2CCNC2=O)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-(4-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-2-oxoimidazolidine-1-carboxylate (7.61 g) was dissolved in 2M hydrogen chloride methanol solution (50 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was ice-cooled, ethyl acetate (50 mL) was added thereto, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (4.15 g).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]([OH:17])[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: O=c1cc[nH]c(=O)[nH]1
Product: Cc1ccc(C(O)c2c[nH]c(=O)[nH]c2=O)cn1

Procedure:
reacting in a mineral acid medium at a pH up to 5 uracil and 6-methyl-3-formylpyridine to form 5-[(6-methyl-3-pyridinyl)hydroxymethyl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.O=[C:22]([CH2:28][C:29](=O)[CH3:30])[C:23]([O:25]CC)=[O:24]>CCO>[CH2:3]([N:10]1[C:29]([CH3:30])=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(=O)O)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a solution of 1-benzylhydrazine dihydrochloride (Aldrich, 0.98 g, 5.0 mmol) in EtOH (30 mL) were added DIEA (2.0 mL) and ethyl 2,4-dioxopentanoate (0.70 mL, 5.0 mmol). The mixture was stirred at room temperature for 12 h and was concentrated in vacuo. The residue was dissolved in 1 N NaOH (10 mL). The solution was heated at 60° C. for 1 h. After cooling down, the solution was extracted with DCM (3×50 mL). The aqueous layer was neutralized to pH 2.0 and then was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. It was filtered and concentrated to give 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (1.0 g, 92% yield). MS(ESI+): m/z 217.12 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.FC(F)(F)C(O)=O.[Cl:37][C:38]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:39]=1[CH2:40][C:41]([N:43]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH2:44][CH3:45])=[O:42]>>[Cl:37][C:38]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:39]=1[CH2:40][C:41]([N:43]([CH:46]1[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:48][CH2:47]1)[CH2:44][CH3:45])=[O:42]
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Reactant: CCN(C(=O)Cc1ccc(F)cc1Cl)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Cc1ccc(F)cc1Cl)C1CCN(C[C@H]2CN([C@H](CC3CCC3)C(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 14.7 %

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester (25 mg, 0.07 mmol, Aldehyde 1) and 4-(N-((2-chloro-4-fluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate (41 mg, 0.1 mmol, from Example 14 , Step A) according to the method described in Example 14 , Step B to give 6.0 mg (15%) of the title compound. ESI-MS: 584.3 (M+H); HPLC A: 2.70 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:18][O:19][P:20]([O:23]C)[O:21][CH3:22]>>[C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:20](=[O:23])([O:21][CH3:22])[O:19][CH3:18])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Yield: 86 %

Procedure:
1-(Bromomethyl)-4-(phenylsulfonyl)benzene (Step 1, 10.1 g, 32.5 mmol) was heated to reflux in trimethylphosphite (40 mL) for 16 hours. The cooled reaction was azeotroped with xylene then purified by flash column chromatography on silica, eluting with ethyl acetate to give dimethyl [4-(phenylsulfonyl)benzyl]phosphonate (9.5 g, 86%). δH (360 MHz, CDCl3): 7.92–7.84 (4H, m), 7.55–7.39 (5H, m), 3.64 (6H, d, J=10.9 Hz), 3.16 (2H, d, J=21.6 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[3,4-dihydro-2(1H)-isoquinolinylcarbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 19) (343 mg, 0.71 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (281 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
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+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)cc3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 (520 mg, 1.1 mmol), 2-fluoropyridin-4-ylboronic acid 178-1 (237 mg, 1.6 mmol), Pd(PPh3)4 (65 mg, 0.055 mmol), saturated Na2CO3 (5 mL), ethanol (5 mL) and toluene (15 mL). The reaction was heated to 110° C. and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 178 as off-white solid. MS m/z 434.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.58 (s, 1H), 8.30 (d, 1H, J=5.6 Hz), 8.04 (d, 1H, J=2.8 Hz), 7.94 (d, 1H, J=9.2 Hz), 7.84-7.82 (m, 2H), 7.71-7.69 (m, 1H), 7.53-7.49 (m, 3H), 7.44 (dd, 1H, J1=9.2 Hz, J2=2.8 Hz), 3.76 (s, 2H), 3.59 (b, 4H), 3.16 (t, 2H, J=2.8 Hz), 3.09 (t, 2H, J=2.8 Hz), 2.04 (s, 3H).
Reaction SMILES: CC(S([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])=O)(C)C.Cl>CO.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][NH2:7])(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)S(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
2-Methyl-N-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzyl]propane-2-sulfinamide (Example 177, 285 mg, 0.6 mmol) was dissolved in methanol (5 mL) and 4N HCl in dioxane (5 mL) and stirred overnight at room temperature. The solvent was removed in vacuo and the residue triturated with diethyl ether to give the title compound as the hydrochloride salt (221 mg, 90%). δH (500 MHz, d6 DMSO): 8.46–8.38 (3H, m), 8.13 (1H, d, J=7.8 Hz), 7.89 (2H, d, J=8.3 Hz), 7.84–7.78 (3H, m), 7.71–7.67 (4H, m), 7.45 (1H, d, J=16.5 Hz), 7.30 (1H, d, J=16.5 Hz), 7.23 (2H, t, J=8.7 Hz), 4.28 (2H, s).
Reaction SMILES: O([C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)[Si](C(C)(C)C)(C)C.[CH3:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.ClCCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CO>[CH3:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: Cc1cnc(O[Si](C)(C)C)nc1O[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CO
Product: Cc1cn(C(=O)C(F)(F)[C@H](O)[C@H](O)CO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.59 g. of 3,5-bis(t-butyldimethylsiloxy)-1-methanesulfonyloxy-2-desoxy-2,2-difluororibose was added 1.60 g. of 5-methyl-2,4-bis(trimethylsilyloxy)pyrimidine and 45 ml. of dry 1,2-dichloroethane. To this mixture was added 1.45 g. of trifluoromethanesulfonyloxytrimethylsilane, and the clear solution was stirred under nitrogen at reflux for about 2-3 hours. The reaction was then cooled to ambient temperature and 1.35 ml. of methanol were added and the suspension was stirred for 30 minutes. The precipitate was filtered and the filtrate was reduced to one-half its volume under vacuum and then diluted with an equal volume of dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was saturated with anhydrous hydrogen bromide. The reaction mixture was stirred for 30 minutes and was then concentrated under vacuum. The residue was dissolved in methanol and the solution was evaporated to dryness under vacuum. The residue was dissolved in water and the solution was extracted twice with diethyl ether. The water layer was then evaporated to dryness. The residue was taken up in ethanol and evaporated repeatedly to azeotrope off all water. One g. of crude product was obtained, and was chromatographed on 30 g. of Woelm silica gel (70-150 mesh), eluting with ethyl acetate to yield 0.76 g. of desired product. It was further purified by recrystallization from ethyl acetate to obtain 0.37 g. of white crystalline product. nmr (CD3OD, 90 MHz) δ1.93 (s, 3H); 3.5-4.67 (series of m, 4H); 4.83 (bs, 3H); 6.3 (t, J=9Hz, 1H); 7.47 (m, 1H); mass spec. m/e=278=Parent.