Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH2:31][CH2:32][C:33](=O)[C:34]([O:36][CH3:37])=[O:35])([NH:24]S(C(C)(C)C)=O)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:48][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]3([NH:24][CH:33]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)C(=O)CC[C@@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CC[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Methyl 4-[(2R,4R)-1-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-2-oxobutanoate (Intermediate 6, 62 mg, 0.086 mmol) in DCM (1 mL) was added TFA (4 mL, 51.9 mmol) and the reaction mixture was stirred at 25° C. for 6 hrs. Triethylsilane (1 mL, 6.26 mmol, Aldrich) was added to the reaction mixture and it was stirred for 1 hr. The reaction mixture was left still overnight and the day after it was poured very carefully in a NaHCO3 saturated solution to be neutralised and DCM was added. The two phases were separated, the aqueous layer was extracted with DCM (3×) and the combined organic phases were dried and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the two diastereoisomers:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:8](OC)=[O:9])(=[O:4])=[O:3].CS(C1C=C(C=CC=1Br)C(OC)=O)(=O)=O.FC(F)(F)C([O-])=O.[K+].[NH2:42][C:43]([NH2:45])=[NH:44]>[I-].C[N+](C)(C)C.C1(C)C=CC=CC=1.CO.[Cu]I>[NH2:44][C:43]([NH2:45])=[N:42][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([C:15]([F:18])([F:17])[F:16])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1
Reactant: N=C(N)N
Agent: [Cu]I
Agent: COC(=O)c1ccc(Br)c(S(C)(=O)=O)c1
Agent: C[N+](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1C(F)(F)F
Reaction time: 0.75 h

Procedure:
1.1 g of methyl 3-methylsulfonyl-4-trifluoromethylbenzoate [m.p. 146°-147°; obtainable by reaction of methyl 3-methylsulfonyl-4-bromobenzoate with potassium trifluoroacetate in the presence of CuI and tetramethylammonium iodide in toluene] are added to a solution of 928 mg of guanidine in 15 ml of methanol. The mixture is stirred for 45 minutes at 50° and, after removal of the solvent and customary working up, N-diaminomethylene3-methylsulfonyl-4-trifluoromethylbenzamide, m.p. 233°-234°, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:18][C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[C:13]#[N:14])[C:7](=[O:12])[CH:6]=2
Reactant: Oc1cc2cnc(Br)cc2cn1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc3cc(Br)ncc3cc2=O)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 3-cyanobenzyl bromide (1.31 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.C([O:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:30](Cl)=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:11]1[C:2]2[N:1]=[C:30]([CH:29]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[OH:28])[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: CC(=O)OC(C(=O)Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a stirred solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.01 g, 3.90 mmol) and triethylamine (1.20 mL, 8.58 mmol) in tetrahydrofuran (20 mL) was added a solution of 2-chloro-1-(2,4-dichlorophenyl)-2-oxoethyl acetate (2.20 g, 7.80 mmol) in tetrahydrofuran (10 mL) at 0° C. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was dissolved in acetic acid (20 mL), and the mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and potassium carbonate (539 mg, 3.90 mmol) was added at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on NH-silica gel eluting with a 0-10% methanol/ethyl acetate gradient mixture to afford the desired product as pale yellow solid (745 mg, 1.61 mmol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[CH2:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([Li:18])CCC>CCCCCC>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([Li:18])[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Fc1ccc(CC2=CC=CC2)cc1
Solvent: CCCCCC
Product: [Li]C1(Cc2ccc(F)cc2)C=CC=C1
Temperature: 0 °C
Yield: 90 %

Procedure:
7 g of 4-fluorobenzylcyclopentadiene (40 mmoles) and 50 ml of hexane are charged, in an argon atmosphere, into a tailed test-tube equipped with magnetic stirring. The solution is cooled to 0° C. and 16 ml of a 2.4M solution of butyllithium in hexane are added. The temperature is then allowed to rise to room temperature and the mixture is left under stirring for a night. A precipitate is formed which is filtered, washed twice with 10 ml of hexane and finally dried. 6.5 g of the desired salt are obtained with a yield of 90%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]=O.Cl.[NH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: O=CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNCCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 μL (0.54 mmol) of triethylamine and 70 mg (0.18 mmol) of N-[3-chloro-4-(2-oxo -ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide was added to a suspension of 45 mg (0.36 mmol) of methyl amino-acetate hydrochloride in 2 mL dichloromethane/THF (1:1). 114 mg (0.54 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred for 3 hours at RT. 100 mL of 2 N aqueous sodium carbonate solution was added and the aqueous phase was exhaustively extracted with chloroform. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and purified by column chromatography (silica gel, EtOAc/MeOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)(Cl)(Cl)Cl.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:26])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Four point five grams of 3-chloro-4-hydroxybenzoic acid were dispersed in a mixed solvent of 30 ml of carbon tetrachloride and 5 ml of pyridine and then heated. 3.7 g of nonanic acid chloride was dropped into the mixture with refluxing. After heating 3 hours the solvent was removed from the mixture. After decomposing unreacted nonanic acid chloride by adding a small amount of water, the residue was washed with methanol to obtain 3-chloro-4-octylcarbonyloxybenzoic acid (AE). After dispersing the compound (AE) into 20 ml of carbon tetrachloride, (AE) was reacted with 5 ml of thionyl chloride with refluxing for 3 hours. 6.5 g of 3-chloro-4-octylcarbonyloxybenzoic acid chloride (AF) was obtained after removing solvent.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCNCC
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N(CC)CC

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-methylformamide containing diethylamine (146 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (14 mg, 0.038, 38%). ESI-MS m/z calc. 365.1, found 366.2 (M+1)+ Retention time 2.18 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([O-:20])(=O)=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[K+].CN(C)C=O.S(Cl)([Cl:29])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:29])(=[O:20])=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (102.3 g, 308 mmol) was added in portions over 15 minutes to a room temperature solution of dimethylformamide (2.4 mL, 31 mmol) in thionyl chloride (112 mL, 1.54 mol). The reaction mixture was gradually brought to 80° C. (oil bath temperature) over 30 minutes and heated at 80° C. for 90 minutes, then cooled to room temperature and stirred at room temperature for 60 minutes. The reaction mixture was partitioned between ice water (500 mL) and ethyl acetate (500 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a cream colored solid. The crude product was triturated with pet ether to afford 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonyl chloride as a pale tan solid (77.47 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[CH:27])[CH:12]=2)=[CH:7][CH:6]=1)(C)(C)C.I[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][CH:25]([C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=2)[C:20]2[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=2[CH:14]=1)[C:26]#[C:27][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1ccc(-c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 72 %

Procedure:
In a similar manner to that of Example 1g, by reacting 300 mg (0.8 mmol) of 1-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 166 mg (0.7 mmol) of 4-iodobenzoic acid in the presence of 7 mg of copper iodide and 12 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=280 mg; yield=72%; m.p.=180° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([N+:20]([O-])=O)=[CH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH2:20])=[C:16]([O:18][CH3:19])[CH:17]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1N
Reaction time: 0.75 h

Procedure:
Step BA suspension of 2-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methoxy-5-nitropyridine (0.9 g, 2.7 mmol) and Pd/C (Aldrich, 10%, 0.15 g) in ethyl acetate (10 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 45 min. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-methoxy-pyridin-3-ylamine as a off white gum (0.6 g, 73%).
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8](=[O:10])[NH:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(CNC(=O)c2ccc(B(O)O)cc2F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
A mixture of 4-borono-2-fluorobenzoic acid (218 mg, 1.2 mmol), (3-(methylsulfonyl)phenyl)-methanamine (200 mg, 1.08 mmol), DIEA (0.754 mL, 4.32 mmol) and TBTU (381 mg, 1.2 mmol) in DMF (2 mL) was stirred at room temperature for 2 days, then the reaction mixture was diluted with water (10 mL), and product precipitated out as gum, and the supernatant was separated via centrifugation, and the gummy residue was sonicated with water (3 mL), and the gummy residue was further dried under high vacuum yielding 3-fluoro-4-(3-(methylsulfonyl)benzylcarbamoyl)-phenylboronic acid (335 mg, 88%) as white foam. LCMS (m/z): 352.1 (MH+), 0.51 min.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 108 %

Procedure:
To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:41]O>ClCCl.O1CCCC1>[CH3:41][O:33][C:32](=[O:34])[CH2:31][CH2:30][CH2:29][N:13]1[C:12]2[N:11]=[C:10]([CH2:9][C:8]3[CH:35]=[CH:36][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)[NH:18][C:17]=2[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:14]1=[O:28]
Reactant: CO
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)O)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21

Procedure:
Prepared by reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid with thionyl chloride in dichloromethane/tetrahydrofuran at room temperature and then reaction with excess methanol. Crystallization from methanol gave the product as a colorless solid. MS, m/z(M+H)=508.1986.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:25]([O:28]CC=C)[CH:26]=[CH2:27].C(C1C=C(C2C=CC=CC=2)C=C(Br)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:7]2[O:8][CH:26]([CH2:25][OH:28])[CH2:27][C:6]=2[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(-c2ccccc2)cc1Br
Reactant: C=CCOCC=C
Agent: C=CCc1cc(-c2ccccc2)cc(Br)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: C=CCBr
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2cc(-c3ccccc3)cc(Br)c2O1
Yield: 84 %

Procedure:
Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:38][C:39]1[C:40]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=2)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=1>ClCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([NH:38][C:39]2[C:40]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=3)=[O:46])=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoic acid (201 mg, 0.55 mmol) was diluted with dichloromethane (5 mL), pyridine (52 μL, 0.64 mmol), and DMF (2 drops). Oxalyl chloride (52 μL, 0.60 mmol) was added and vigorous bubbling occurred. After about 30 minutes, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (5 mL) and the 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (123 mg, 0.50 mmol) was added, followed by pyridine (72 μL, 0.64 mmol). The reaction was stirred overnight and then diluted with dichloromethane (50 mL) and washed with water (3×5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (CH2Cl2 through 5% EtOAc/CH2Cl2) to give the desired product as a pale yellow amorphous solid (214 mg, 0.36 mmol, 72%).