Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:31]([NH:38][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(NCc3ccccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140 mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500 μL, excess) was added to it and the reaction mixture was stirred at 80° C. for 1 hour. Solvent was distilled and the crude product was purified over silica gel column to afford the title compound as light yellow solid (112 mg, 83%); 1H NMR (300 MHz, CDCl3) δ: 9.27 (b, 1H, NH), 7.39-7.32 (m, 5 Hs, Ar Hs), 6.96 (s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.47 Hz), 6.50 (d, 1H, J=8.10 Hz), 4.83 (d, 2H, J=4.95 Hz, Benzyl Hs), 3.91 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:13][CH2:14][CH2:15][C:16]([OH:19])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1

Procedure:
A solution of the product of Example 50 (0.1 g) in aqueous sodium hydroxide (1N, 0.8 ml) and ethanol (2 ml) was kept for 2 hours. The solution was evaporated and the residue dissolved in water (5 ml). Hydrochloric acid (1N, 0.8 ml) was added and the precipitate was filtered and washed with water and ether to give the title compound as a solid: m.p. 305°-306° C.; m/e 342(M+H)+ ; NMR(d6DMSO) δ 8.0(2H,d); 6.72(6H,m); 3.74(2H,t); 3.3(4H,m); 2.94(4H,m); 2.19(2H,t); 1.72(2H,m); calculated for C19H23N3O3 : C, 66.8; H, 6.8; N, 12.3. Found: C, 67.0; H, 6.8; N, 12.2%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the thus-prepared reducing agent was added 298 mg (1.0 mmol) of [1(S)-benzyl-2-oxo-3-chloropropyl]carbamic acid t-butyl ester, and the mixture was stirred at 25° C. for 16 hours. After hydrolysis with 1 N hydrochloric acid, the reaction mixture was extracted with ethyl acetate.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([F:11])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.[CH:12]12[O:17][CH:16]1[CH2:15][CH2:14][CH2:13]2>C1COCC1.[Cu]I>[F:9][C:7]1[CH:8]=[C:3]([C@H:15]2[CH2:14][CH2:13][CH2:12][C@@H:16]2[OH:17])[CH:4]=[C:5]([F:11])[C:6]=1[F:10]
Reactant: C1CC2OC2C1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: O[C@H]1CCC[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a suspension of magnesium (2.88 g, 118 mmol) in THF (110 mL) was slowly added 5-bromo-1,2,3-trifluorobenzene (25 g, 118 mmol). After the addition, the reaction mixture was heated at reflux for 2 h. To this reaction mixture, copper (I) iodide (1.506 g, 7.91 mmol) and 6-oxabicyclo[3.1.0]hexane (9.93 g, 118 mmol) dissolved in THF (20 mL) were added dropwise. The reaction mixture warmed upon the addition of the epoxide. The reaction was stirred at rt for 2 h at rt. The reaction mixture was quenched by the addition of a solution of ammonium chloride. Ether was added and the organic layer was collected, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give (1S,2R)-2-(3,4,5-trifluorophenyl)cyclopentanol (20.2 g, 93 mmol, 79% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(OCC)(=O)C>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCCO4)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)CCCO6)CC3)c2c1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 0.55 g (1.5 mmole) of (2R)-2,3,9,10-tetrahydro-8H-[1,4]-dioxino[2,3-f]chromen-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (4.6 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 6 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0.5% methanol in chloroform to give 0.34 g of the desired product as a pale yellow foam. This was crystallized from ethanol with the addition of 0.10 g of fumaric acid to give 0.24 g of the (S)-enantiomer of the title compound as a pale yellow solid, m.p. 205-206° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[CH:19]=[C:18]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:23])=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[O:12][C:13]3[CH:19]=[C:18]([N:20]([S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:23])=[O:22])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCc2nc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3o2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN(c1ccc2nc(CCc3ccc(C#N)cc3)oc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1d from 2-[2-(4-cyanophenyl)-ethyl]-6-[N-quinoline-8-sulphonylamino]-benzoxazole, methyl bromoacetate and potassium carbonate in acetone.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (3 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].C(N(CC)C(C)C)(C)C.Cl[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2](=[CH2:1])[CH2:3][NH:4][S:18]([CH:17]=[CH2:16])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C=C(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)NCC(=C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a stirred solution of 2-methylprop-2-en-1-amine (0.500 g, 7.0 mmol), N,N-diisopropylethylamine (3.486 mL, 21.1 mmol) and N,N-4-dimethylaminopyridine (0.043 g, 0.4 mmol) in methylene chloride (20 mL) at 0° C. was slowly added 2-chloroethanesulfonyl chloride (0.734 mL, 7.0 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexanes) to afford the product as a colorless oil (0.59 g, 52%). 1H NMR (300 MHz, CDCl3) δ 6.54 (dd, 1H, J=16.5, 9.6 Hz), 6.27 (d, 1H, J=16.5 Hz), 5.96 (d, 1H, J=9.6 Hz), 4.97 (s, 1H), 4.93 (s, 1H), 4.37 (br s, 1H), 3.60 (d, 2H, J=6.3 Hz), 1.79 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][OH:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][O:20][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@@H]1c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-hydroxymethyl-5-(R)-phenylpyrrolidine (1.10 g, 3.97 mmol), triphenylphosphine (1.25 g, 4.76 mmol) and methyl 4-hydroxybenzoate (724 mg, 4.76 mmol) was added diisopropyl azodicarboxylate (955 ml, 4.76 mmol) at rt, and the resulting mixture was stirred at 60° C. for 45 min. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[N-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.31 g, 80%) as a colorless oil. 1H-NMR (CDCl3) δ1.19 and 1.47 (brs, total 9 H), 2.09-2.15 (m, 3 H), 2.33-2.37 (m, 1 H ), 3.94 (s, 3 H), 4.30 (brs, 1 H), 4.41 (brs, 2 H), 4.77 (brs, 1 H), 7.03 (d, J=8.8 Hz, 2 H), 7.24-7.36 (m, 5 H), 8.03-8.06 (m, 2 H); MS (ESI) m/z, 412 (M++H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:21]([O:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37](Cl)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:38][CH:39]=2)[CH2:30]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Cl)nc2)C1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C1

Procedure:
Compound 280 was prepared from compound 245 and (S)-5-(3-(tert-butyldimethylsilyloxy)-pyrrolidin-1-yl)-2-chloropyridine using methods described in Example 186a.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:24])([F:23])[CH:13]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:14][OH:15]>>[F:24][C:12]([F:11])([F:23])[CH:13]([CH2:14][O:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC(OC1CCCCO1)C(F)(F)F
Product: O=[N+]([O-])c1ccc(OCC(OC2CCCCO2)C(F)(F)F)cc1

Procedure:
On reaction of 1-fluoro-4-nitro-benzene and 3,3,3-trifluoro-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol according to the procedure described in example 33 i) there was obtained 2-[2,2,2-trifluoro-1-(4-nitro-phenoxymethyl)-ethoxy]-tetrahydro-pyran. This compound was then treated with THF/1N HCl (20 min RT) to take off the tetrahydropyranyl protecting group and alkylated with methyl iodide in DMF and with NaH as a base at RT (2 h) to give 1-nitro-4-(3,3,3-trifluoro-2-methoxy-propoxy)-benzene, which was then hydrogenated as described in example 33 ii) to give the desired compound, (rac)-4-(3,3,3-trifluoro-2-methoxy-propoxy)-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH3:25])=[N:23][N:24]=2)[N:21]=1>>[CH3:25][C:22]1[N:20]2[N:21]=[C:16]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: Cc1nnc2ccc(Cl)nn12
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc2nnc(C)n2n1
Yield: 41 %

Procedure:
As described for example 86, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) was converted, using 6-chloro-3-methyl-1,2,4-triazolo[4,3-b]pyridazine instead of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine, to the title compound (70 mg, 41%) which was obtained as a white solid. MS: m/e=322.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]=[N:7]O)([O-])=O.C(O)(=O)C.[H][H].[OH-].[Na+]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH2:7]
Reactant: O=[N+]([O-])c1ccccc1C=NO
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NCc1ccccc1N
Reaction time: 7 h
Yield: 79.4 %

Procedure:
16.6 g (0.1 mol) of this o-nitrobenzaldoxime, 0.83 g of a 5% Pd-C catalyst, 12 g (0.2 mol) of glacial acetic acid and 100 ml of tetrahydrofurane were charged into a hermetically sealed glass container and stirred vigorously while charging hydrogen. Reaction was continued at temperatures of 25°-35° C. for 7 hours. After the reaction, the resulting mixture was filtered to remove the catalyst, was added with 8 g (0.2 mol) of sodium hydroxide and was subject to distillation. Thus, 9.7 g of o-aminobenzylamine was obtained. Yield 79.4%; Purity 99.4%; B.P. 91°-93° C./1 mmHg. M.P. 58°-61° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21](Cl)=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1.[Br:28]Br>C1COCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21]([Br:28])=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Reaction time: 1 h
Yield: 17.2 %

Procedure:
n-Butyllithium (2.5 mmol) was slowly added to a solution of 3-(2,6-dichlorophenyl)-5-(3,4,5-trichlorothien-2-yl)-1-methyl[1,2,4]triazole (325 mg, 1.0 mmol) in THF at -78° C., and the mixture was stirred one hour. Bromine (3.0 mmol) was added and the reaction stirred two hours, then diluted with water, extracted with ether, washed with brine, and dried over magnesium sulfate. The product was concentrated to 620 mg of dark oil. This was chromatographed (SiO2, 10% EtOAc-Hex) to give 79 mg of the title product as a pink solid. MP 197-199° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)([C:21](OCC)=[O:22])=[O:20]>O1CCCC1>[CH:9]([N:8]1[C:19](=[O:20])[C:21](=[O:22])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2)([CH3:11])[CH3:10]
Reactant: CC(C)Nc1ncccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(=O)[nH]c2cccnc21
Reaction time: 2 h

Procedure:
To a stirred solution of 3-amino-2-isopropylamino-pyridine (2.0 g, 10.6 mmole) and triethylamine (4.8 ml, 34.6 mmole) in tetrahydrofuran (30 ml) was dropwise added ethoxalyl chloride (2.68 ml, 24 mmole). Stirring was continued for two hours after the addition. The mixture was filtered through a glass filter funnel and the filtrate was evaporated to give the title compound as white crystals. M.p. 246°-247° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+].C(Cl)Cl>[NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH:14][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cc1cnc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A flask was charged with (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (150 mg, 0.302 mmol), benzaldehyde (0.031 mL, 0.30 mmol), methylene chloride (5 mL), acetic acid (0.140 mL, 2.45 mmol) and sodium triacetoxyborohydride (22 mg, 0.45 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then diluted with 2N sodium hydroxide (10 mL). The dilution was extracted with ethyl acetate (20 mL) and the extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 173, (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (47 mg, 0.091 mmol, 30%), as an off-white solid. 1H-NMR (400 MHz, DMSO-D6): 11.94 (s, 1H), 10.09 (s, 1H), 7.60 (d, 2H), 7.34-7.28 (m, 4H), 7.25-7.17 (m, 3H), 7.03-6.96 (m, 6H), 4.48 (t, 1H), 3.60-3.32 (m, 7H), 2.12-1.99 (m, 2H). MS (EI) for C29H28FN5O3. found 513.9 (MH+).
Reaction SMILES: [Cl:1][C:2]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].Cl.[NH2:19][CH2:20][C:21]#[C:22][CH2:23][OH:24].C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:24][CH2:23][C:22]#[C:21][CH2:20][NH:19][C:3](=[O:4])[C:2]([Cl:1])([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCC#CCO
Reactant: O=C(Cl)C(Cl)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC#CCO)C(Cl)(c1ccccc1)C1CCCCC1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of 2-chloro-2-cyclohexyl-2-phenylacetyl chloride (9.0 g) in methylene chloride (50 ml) was added dropwise to a solution of 4-amino-2-butyn-1-ol hydrochloride (5.38 g) and triethylamine (30.8 ml) in methylene chloride (120 ml) at 0° C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for an additional 3.5 hours and 1N hydrochloric acid was added thereto. The organic layer was separated, washed with saturated sodium bicarbonate, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (6:1) as an eluent to give N-(4-hydroxy-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide (7.32 g).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([CH2:15][N:16]=[C:17]=[S:18])[N:12]=[N:11]2)[CH:7]=[C:6]([F:19])[C:5]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl>O>[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([CH2:15][NH:16][C:17]([NH:2][CH3:1])=[S:18])[N:12]=[N:11]2)[CH:7]=[C:6]([F:19])[C:5]=1[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: Fc1cc(-n2cc(CN=C=S)nn2)cc(F)c1N1CCOCC1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNC(=S)NCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40% methylamine (10 mL) was added 4-[2,6-difluoro-4-(4-isothiocyanatomethyl-[1,2,3]triazol-1-yl)-phenyl]-morpholine (0.2 g), obtained in Example 33, and stirred at room temperature for 30 min. The reaction mixture was neutralized with 1N HCl and diluted with water. Water layer was extracted with ethyl acetate (20 mL×2) and the combined organic layer was washed with brine and dried over sodium sulfate. Upon concentration and purification of the resulting residue by silica gel column chromatography (eluent; chloroform/ethylacetate, 8:2), the title compound was obtained as pale yellow crystals (0.12 g, 50%). Mp. 181° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH3:27]>C1COCC1.CS(C)=O>[CH2:22]([O:21][P:19]([CH2:18][O:17][CH2:16][C:5]1[N:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:27])[N:10]=[CH:9][N:8]=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: N
Reactant: CCOP(=O)(COCc1nc2c(Cl)ncnc2n1CC(C)(C)C)OCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CC(C)(C)C)OCC

Procedure:
A solution of 6-chloro-8-diethylphosphonomethoxymethyl-N9-neopentylpurine (1 mmol) in THF-DMSO was treated with liquid ammonia (10 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 8-diethylphosphonomethoxymethyl-N9-neopentyladenine as a white solid. TLC: Rf=0.44,25% MeOH-EtOAc.