Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([O:11][C:20](=[O:21])[C:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=2)[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#C[C@@H](COc1ccc(F)cc1)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (est. 490 mmol) in methylene chloride (1 L) was added 3,5-dinitrobenzoyl chloride (125 g, 539 mmol) at between −5° C. and 0° C., followed by slow addition of triethylamine (10.8 mL, 77 mmol) and a catalytic amount of dimethylaminopyridine (DMAP) (20 mg). After the mixture was stirred at ambient temperature for 40 minutes, the reaction mixture was cautiously partitioned between methylene chloride and aqueous NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and brine, and dried over Na2SO4. The solution was filtered through a pad of silica gel with methylene chloride which gave crude product as a tan solid. Rapid recrystallization from 99:1 mixture of methanol:acetic acid (5 L) gave 101 g of the enantiomerically enriched product, (3S)-4-(4-fluorophenoxy)-3-(3′,5′-dinitrobenzoyl)oxy-1-butyne, a compound of formula (BBa) as fluffy white needles. This material was determined to have greater than 98% ee by analytical HPLC using a Diacel Chiralpak AD® (4.6×250 mm, 60% 2-propanol/hexane, 1 mL/min), which separates the (R) (11.5 min) and the (S) (19.3 min) enantiomers; 1H NMR (CDCl3) δ 2.65 (s, 1H), 4.40 (m, 2H), 6.05 (m, 1H), 6.90 (m, 2H), 7.0 (t, 2H), 9.15 (s, 2H), 9.25 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:22][C:23]([C:14]([F:17])([F:16])[F:15])=[CH:24][CH:25]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccco1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(C(F)(F)F)o1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-2-yl)pyrazole (0.46 g) in dimethylformamide (15 ml) and water (5 ml) was added sodium dithionite (0.286 g) and disodium hydrogen phosphate (0.17 g). The mixture placed in a 400 ml Parr vessel, which was evacuated, then charged with trifluoromethylbromide gas to 40 psi. The mixture was shaken and heated at 45° C., for 3 hours, then left at room temperature for 16 hours. The vessel was then evacuated, then recharged with trifluoromethylbromide to 40 psi, then shaken and heated to 45° C. for a further 9 hours, then left at room temperature for 48 hours. The vessel was then evacuated, then recharged with trifluoromethylbromide to 40 psi, then shaken and heated to 45° C. for a further 7 hours, then left at room temperature for 16 hours. The mixture was filtered and then poured into brine (25 ml) and extracted with ether (25 ml, ×3). The combined organic layers were washed with water (20 ml), dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel (25 g) eluted with hexane:ether (50:50 changing gradually to 20:80). Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 148-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19].[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:28]([Cl:33])([Cl:32])[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:30]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of intermediate 11 (0.0536 mol) in DCM (200 ml) was cooled to 5° C. under N2 flow. A solution of trichloro-acetylchloride (0.0643 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 30 minutes. A solution of triethylamine (0.0643 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour then at room temperature for 2 hours, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 27.4 g (quantitative) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methoxybenzoyl)phenyl]-acetamide (intermediate 12).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1([CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]1[OH:20])C#N>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#CC1(O)C=CC=C(F)C1O
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(Oc2cccc(F)c2Oc2ccc(C#N)cc2)cc1
Yield: 89.4 %

Procedure:
The compound 1,2-bis-(4-cyanophenoxy)-3-fluorobenzene was prepared according to the procedure described in Example 1 by reacting 4-fluorobenzonitrile with 1,2-dihydroxy-3-fluorobenzonitrile. The product was recrystallized from ethanol/water (4:1). The yield was 89.4% of the title compound with the formula: ##STR9##
Reaction SMILES: [Al].II.[CH2:4](Br)[C:5]#C.ClC1C=CC(O[CH:14](N2C=NC=N2)[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=CC=1.[Cl-].[NH4+]>O1CCCC1.[Hg](Cl)Cl>[CH3:19][C:16]([CH3:17])([CH3:18])[CH:15]([OH:20])[CH2:14][C:4]#[CH:5]
Reactant: C#CCBr
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: Cl[Hg]Cl
Agent: II
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)C(C)(C)C
Temperature: -60 °C
Reaction time: 12 h

Procedure:
26 g (0.96 mol) of aluminum flakes were covered with a layer of 120 ml of tetrahydrofuran, and a few grains of iodine and a pinch of mercury (II) chloride were added. After 12 hours, a solution of 169 g (1.42 mol) of propargyl bromide in 170 ml of tetrahydrofuran was added dropwise at 60° C., while stirring vigorously. The mixture was then cooled to -60° C., and in the course of 2 hours, a solution of 293.8 g (1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-one in 330 ml of tetrahydrofuran was stirred in. 340 ml of a saturated ammonium chloride solution were then added to the reaction mixture at 0° C. The bulk of the solvent was distilled off under reduced pressure, and the residue was extracted with twice 600 ml of ethyl acetate. After the organic phase had been washed with water, it was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The precipitated crystalline product was filtered off and washed with isopropanol and diethyl ether. 131.1 g (39.3% of theory) of 4-(4-chlorophenoxy)-(1-H-1,2,4-triazol-1-yl)-methyl)-5,5-dimethyl-1-hexyn-4-ol of melting point 124° to 125° C. were obtained.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=2[S:51]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=2[C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[C:62]([N+:67]([O-])=O)[CH:61]=2)=[O:52])=[CH:40][C:39]=1[N+:70]([O-])=O>>[NH2:67][C:62]1[CH:61]=[C:60]([C:54]2[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]=2[S:51]([C:45]2[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([NH2:70])[CH:40]=2)=[O:52])[CH:65]=[CH:64][C:63]=1[Cl:66]
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(Cl)c([N+](=O)[O-])c2)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(Cl)c(N)c2)c(-c2ccc(Cl)c(N)c2)c1
Yield: 88 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-chloro-3-nitrophenyl)-4-methylphenyl sulfoxide, the title compound is obtained; M.P.=119°-121° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7]O)[CH3:5].[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2S(C)(=O)=O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[CH:12][CH:11]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)n1ccc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a powdered suspension of NaH (55 mg, 4.8 mmol) in toluene (4 mL) was added 2-(N,N-dimethylamino)ethanol (321 mg, 3.6 mmol). The mixture was stirred for 10 minutes, after which compound (i), above, (751 mg, 2.4 mmol) was added and the mixture refluxed 16 h. The mixture was allowed to cool to room temperature and then diluted with CH2Cl2. The organic extract was washed with water and brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a white solid (390 mg, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.CO[CH:19]1[CH2:23][CH2:22][CH:21](OC)O1>>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[CH:19]=[CH:23][CH:22]=[CH:21]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Product: O=c1[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc2[nH]c1=O

Procedure:
23.2 mmol of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione were reacted with 23.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:30]([F:41])([F:29])[F:40])=[N:32][CH:33]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccc(C(F)(F)F)nc1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl}-pyrimidin-2-ylamino]-ethyl)-phenol (compound 132) was coupled with 6-trifluoromethyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 570. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.5 (s, 1H)) 8.6 (d, 1H) 8.5 (s, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 7.9 (m, 2H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 3.0 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11](O)=[O:12])=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[C:35]([NH:39][C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:39]([C:35]([CH3:37])([CH3:36])[CH3:38])[C:40](=[O:47])[C@H:41]([C@H:43]([CH2:45][CH3:46])[CH3:44])[NH2:42])=[O:12])=[CH:5][CH:6]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NC(C)(C)C
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1)C(C)(C)C
Yield: 15.7 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (50 mg, 0.16 mmol, 1.0 eq), N-ethylmorpholine (125 uL, 0.98 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (170 uL, 0.27 mmol, 1.6 eq) followed by L-isoleucine tert-butylamide (49 mg, 0.19 mmol, 1.1 eq). Purification by HPLC provided 12 mg (16%) of L-isoleucine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] tert-butylamide.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Reactant: O=C1CCCN1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(N3CCCC3=O)ccc2n1
Yield: 51 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (135 mg, 0.34 mmol) was converted, using 2-pyrrolidone instead of benzamide, to the title compound (61 mg, 51%) which was obtained as a light brown solid. MS: m/e=359.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].I[C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:16]=1>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[N:16]=1
Reactant: N#Cc1ccc(-c2coc(I)n2)cc1
Reactant: CC1(C)COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)co1
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 3.7 %

Procedure:
A 5 mL flask was charged with 4,4-dimethyl-oxazolidin-2-one (1.0 g, 8.7 mmol) and sodium hydride (60% wt suspension in mineral oil) (40 mg, 1.2 mmol) was added and the mixture was stirred for 20 min. 4-(2-Iodo-1,3-oxazol-4-yl)benzonitrile (0.257 g, 0.87 mmol), prepared in the previous step, was added and the mixture was heated to 170° C. for 2 h then cooled and diluted with ethyl acetate. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (15% acetone in hexane) afforded the title compound (9 mg, 4%). HRMS: calcd for C15H13N3O3+H+, 284.10297; found (ESI, [M+H]+), 284.1024; Analytical HPLC: purity 95.3% at 210-370 nm, 8.1 min; 98.3% at 278 nm, 8.1 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1Cl

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,4-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.43 (d, J=5.0 Hz, 1H); 8.01 (br s, 1H); 7.85 (d, J=8.7 Hz, 1H); 7.52 (d, J=1.6 Hz, 1H); 7.25 (m, 1H); 6.87 (d, J=5.5 Hz, 1H); 6.00 (br s, 1H); 4.71 (d, H=6.0 Hz, 2H).
Reaction SMILES: N([CH:4]([OH:20])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:18][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][OH:20])[C@@H:6]([OH:19])[CH2:7]1
Reactant: [N-]=[N+]=NC(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br

Procedure:
The 5'-azido derivative of 5-bromo-2'-deoxy uridine is prepared via the method described above. The 5'-azido-5-bromo-2'-deoxyuridine (1 mmol) is treated with triphenyl phosphine (1.5 mmol) in pyridine at room temperature for 2 h. Concentrated ammonia (1 ml) is added to the reaction vessel. After 14 h the solvent is removed under vacuum. The residue is dissolved in chloroform/ methanol containing one equivalent of p-toluene sulfonic acid, and this solution is added to hexanes. The 5'-amino-5-bromo-2'-deoxyuridine precipitate is collected and dried.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: ClCCBr
Reactant: c1ccc2[nH]nnc2c1
Product: ClCCn1nnc2ccccc21
Yield: 35.8 %

Procedure:
1-(2-Chloroethyl)-1H-1,2,3-benzotriazole (164 mg, 36%) was prepared from benzotriazole (300 mg, 2.52 mmol) and 1-bromo-2-chloro ethane (397 mg, 2.77 mmol) according to the procedure of Example 291. The title compound was isolated as a yellow oil (48 mg, 98%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(2-chloroethyl)-1H-1,2,3-benzotriazole (44 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.69-2.20 (m, 4H), 2.39-2.45 (m, 1H), 2.61-2.68 (m, 1H), 2.72-2.81 (m, 1H), 2.84-3.01 (m, 2H), 3.03-3.12 (m, 2H), 3.20-3.27 (m, 1H), 3.49-3.60 (m, 1H), 3.74-3.84 (m, 1H), 4.06 (t, 1H, J=6.7 Hz), 4.76 (t, 1H, J=6.6 Hz), 4.96 (t, 1H, J=6.2 Hz), 6.61 (t, 1H, J=7.5 Hz), 6.82 (d, 1H, J=7 Hz), 6.95 (dd, 1H, J=1.1, 7.7 Hz), 7.34-7.62 (m, 3H), 8.08 (t, 1H, J=7.6 Hz) ppm.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: c1ccc(OCc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(COc3ccccc3)nc3ccccc32)c1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
A 50 mL flask fitted with a stir-bar and a septum with an Ar inlet was charged with 2-(phenoxymethyl)-1 H-benzimidazole (61) (1.00 g, 4.46 mmol), K2CO3 (1.23 g, 8.92 mmol), and DMF (12 mL). 3-Methoxybenzyl chloride (769 mg, 4.91 mmol) was added, and the suspension was heated in a 100° C. bath for 2 hr. The mixture was cooled, and the solids were filtered off and rinsed with EtOAc (50 mL). The filtrate was then washed with sat'd NH4Cl (2×30 mL), H2O (2×30 mL), and brine (20 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. Upon standing the oil crystallized, and was subsequently collected with hexanes:EtOAc 30:1 (15 mL). Upon drying, 1.41 g of Compound #11 were obtained as an off-white crystalline solid (92%). 1H NMR (300 MHz, CDCl3): δ 7.84 (m, 1H), 7.36-7.25 (m, 5H), 7.21 (t, 1H), 6.82 (dd, 1H), 6.68 (d, 1H), 6.62 (m, 1H), 5.52 (s, 2H), 5.36 (s, 2H), 3.64 (s, 3H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 4.8 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].Cl>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[N:21][OH:22])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)Oc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ccc(C=NO)cc2)cc1
Yield: 98.1 %

Procedure:
To a solution of Example 17B (1.42 g, 5.56 mmol) in pyridine (10 mL) was added hydroxylamine hydrochloride (3.30 g, 47.5 mmol). The mixture was heated to reflux with a heat gun. After cooling, the mixture was poured into 10% HCl. The precipitates were collected and washed with 10% HCl followed by water, and then dried under vacuum at 50° C. overnight to give the desired product as a white solid (1.48 g, 98%).
Reaction SMILES: C([N:8]1[C:12]([SH:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1)C1C=CC=CC=1.N.[Na]>>[C:16]([CH2:15][CH2:14][C:11]1[N:10]=[N:9][NH:8][C:12]=1[SH:13])([OH:18])=[O:17]
Reactant: O=C(O)CCc1nnn(Cc2ccccc2)c1S
Agent: N
Agent: [Na]
Product: O=C(O)CCc1nn[nH]c1S
Reaction time: 0.67 h

Procedure:
1-Benzyl-4-carboxyethyl-1,2,3-triazole-5-thiol (1.1 g., 4 mmol.) is suspended in 50 ml. of anhydrous liquid ammonia and sodium is added until a permanent blue color results. The reaction mixture is allowed to stir for 40 minutes then allowed to warm to ambient temperature while the ammonia evaporates. The residue is triturated with ether and the solid formed is collected and dissolved in water. The aqueous solution is acidified and extracted with ethyl acetate. The extract is dried (MgSO4) and evaporated to dryness to give 4-(2-carboxyethyl)-1,2,3-triazol-5-thiol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH:12]=[CH2:13])=[O:5])C.[H][H]>CO.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:9]2[O:8][CH:7]([C:19]([F:21])([F:20])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH2:12][CH3:13])[C:10]=2[CH:14]=1
Reactant: C=CC1=C(C(=O)OCC)C(C(F)(F)F)Oc2ccc(Cl)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1=C(C(=O)O)C(C(F)(F)F)Oc2ccc(Cl)cc21
Reaction time: 0.42 h
Yield: 70.7 %

Procedure:
Ethyl-6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 142,Step 5) (0.433 g, 1.30 mmol) was dissolved in methanol (10 mL). Palladium(5 wt % on activated carbon)(0.150 g) was slowly added. The reaction vessel was charged with hydrogen (25 psi) and was stirred for 25 minutes. Gas chromatographic analysis indicated that the reaction was complete. The reaction mixture was filtered through Celite and evaporated to yield a orange oil. The oil was purified by flash column chromatography(100% hexanes) to yield the desired product as a yellow oil (0.282 g, 65%): 1H NMR (CDCl3/300 MHz) 7.43 (d, 1H, J=2.4 Hz), 7.25 (dd, 1H, J=2.4, 8.7 Hz), 6.92(d, 1H, J=8.7 Hz), 5.75 (q, 1H, J=7.0 Hz), 4.38-4.24 (m, 2H), 3.05-2.95 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.25, (t, 3H, J=7.6 Hz).