Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[O:2]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[NH:9])[CH2:4][CH2:3]1.C(O)C.[C:14]([CH2:17][C:18](=O)[CH3:19])(=O)[CH3:15]>>[CH3:15][C:14]1[CH:17]=[C:18]([CH3:19])[N:10]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[N:9]=1
Reactant: N=C(N)N1CCOCC1
Reactant: CC(=O)CC(C)=O
Agent: Br
Solvent: CCO
Product: Cc1cc(C)nc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 89.7 %

Procedure:
To a suspension of morpholinoformamidine hydrobromide (2.0 g, 9.52 mmol) in ethanol (6 ml) potassium tert-butoxide (1.068 g, 9.52 mmol) then acetylacetone (2 ml, 20 mmol) were added. The reaction mixture was flashed with argon, sealed in the Emrys process vial and heated under microwave irradiation at 140° C. for 5 min. After cooling it was quenched with ethyl acetate (50 ml), filtered via plug of SiO2 (5 g) and eluted with ethyl acetate. Volatiles were removed in vacuo at 70° C. to furnish 1.65 g of pale brown oil that solidified overnight. Yield 90%. LC-MS (m/z) 193.9 (MH+); tR=0.71. 1H NMR (500 MHz, DMSO-d6): 2.23 (s, 6H), 3.62 (m, 4H), 3.67 (m, 4H), 6.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:27]([N:29]=[C:30]=S)[CH3:28].O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:27]([NH:29][C:30]1[NH:1][C:2]2[CH:3]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=4[CH:26]=3)[CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:28]
Reactant: CCN=C=S
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 60 °C
Yield: 39.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (750 mg, 2.10 mmol) in ethyl acetate (20 mL) was treated with ethyl isothiocyanate (184 uL, 2.10 mmol). The mixture was heated to 60° C. for 4.25 h. After cooling to rt, water was added and the layers were partitioned. The organic phase was washed once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was then dissolved in ethyl acetate (20 mL), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (403 mg, 2.10 mmol) was added. The mixture was heated to 60° C. for 50 minutes before cooling to rt. Water was added, and the biphasic mixture was partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient: 98:2 dichloromethane:methanol to 90:10 dichloromethane:methanol) to provide 1,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (337 mg, 0.83 mmol, 39% yield) as an orange film. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.47-7.38 (m, 2H), 7.32 (s, 1H), 7.20-7.08 (m, 2H), 7.05-6.96 (m, 1H), 6.68-6.58 (m, 1H), 4.55-4.40 (m, 2H), 4.09-3.98 (m, 2H), 3.77-3.65 (m, 2H), 3.33-3.26 (m, 2H), 1.41-1.28 (m, 9H), 1.18 (t, 3H); MS (EI) for C23H28N4O3: 409 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[CH:37]=[C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:34][C:26]=3[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[CH:37]=[C:36]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:34][C:26]=3[C:27]([OH:29])=[O:28])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc2[nH]ccc2c1

Procedure:
Trifluoroacetic acid 5 mL solution of the obtained tert-butyl 2-((1-(tert-butoxycarbonyl)-1H-indol-5-yl)amino)-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((1H-indol-5-yl)amino)-4-phenylbenzoic acid 8 mg of yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.[C:18](OCC)(=O)CC>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC
Product: CCc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 15 from ethyl propionate, mp. 228°-230° C.
Reaction SMILES: [Br:1][C:2]1[C:13]([O:14][CH3:15])=[N:12][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Br:16].CI.[C:19]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:13]([O:14][CH3:15])=[N:12][C:5]2[CH2:6][CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Br:16]
Reactant: COc1nc2c(c(Br)c1Br)C(C)CNCC2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nc2c(c(Br)c1Br)C(C)CN(C)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 561.1 %

Procedure:
A mixture of 3,4-dibromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (32.5 mg, 9.30 μmol), MeI (5.8 μl, 93.0 μmol), Na2CO3 (19.7 mg, 18.3 μmol) and DMF (5 ml) was stirred for 3 d at room temperature. The reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 19.0 mg (56%) of 3,4-dibromo-2-methoxy-5,7-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.63 (m, 1H), 3.25 (m, 1H), 2.88 (m, 3H), 2.30 (s, 3H), 2.28 (dd, 1H), 2.14 (m, 1H), 1.26 (d, 3H) ppm.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[C:42]2[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:44](=[O:49])[O:45][C:46]([CH3:48])([CH3:47])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:47][C:46]1([CH3:48])[O:45][C:44](=[O:49])[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:55])[CH3:56])[C:42]2[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: CC1(C)OC(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)OC3(C)C)cc1

Procedure:
Analogously to Method D, 0.30 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.28 g of 8-bromomethyl-4,4-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.68.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:13]1[C:22]2[C:21](=O)[CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:21]1[C:22]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:18][CH2:19][CH2:20]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21

Procedure:
Using General Procedure B, reaction of (3-amino-propyl)-carbamic acid tert-butyl ester, 6,7-dihydro-5H-quinolin-8-one and NaBH(OAc)3 in CH2Cl2 gave [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester as a light brown oil plus ˜15% impurity. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.77 (m, 4H), 2.00 (m, 2H), 2.80 (m, 4H), 3.24 (m, 2H), 3.74 (t, 1H, J=7.5 Hz), 5.36 (br, 1H(NH)), 7.06 (m, 1H), 7.37 (d, 1H, J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Cl:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Br:17]Br.C[O-].[Na+]>CO>[Br:17][C:2]([Cl:1])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: BrBr
Reactant: COC(=O)C(Cl)c1ccc([N+](=O)[O-])c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cl)(Br)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of methyl 2-chloro-2-(3-methyl-4-nitrophenyl)acetate (6 g) in methanol (20 cm3) was stirred at room temperature and the solutions of bromine and sodium methoxide were added dropwise and simultaneously. The methanol was removed from the reaction mixture under vacuum and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, separated and evaporated to have a residue which was recrystallised from ethanol to give yellow methyl 2-bromo-2-chloro-2-(3-methyl-4-nitrophenyl)acetate (4.0 g, 50%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Yield: 98.7 %

Procedure:
A mixture of 6-chloro-3-trifluoromethylpyridazine (0.666 g, 5.09 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P; Tarbit B. Tetrahedron 1999, 55, 15067-15070), N-Boc-piperazine (1.138 g, 6.11 mmol) and diisopropylethylamine (1.95 ml, 1.12 mmol) in acetonitrile (10 ml) was stirred at 180° C. for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; hexane/ethyl acetate) to yield D9 (1.67 g, 99%) as a light yellow solid. C14H19F3N4O2 requires 332; Found 333 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:14])=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 68 %

Procedure:
The title compound was prepared from reaction of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica (50% EtOAc/Hexane as eluant) to give 2-(4-butyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (68%); m.p. (EtOAc/Hexane) 163–165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH2:27]([N:29]1[C:33]([CH:34]=[O:35])=[CH:32][C:31]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[N:30]1)[CH3:28]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:34]([C:33]3[N:29]([CH2:27][CH3:28])[N:30]=[C:31]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH:32]=3)[OH:35])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(O)c1c[nH]c2ncc(Cl)cc12
Temperature: -20 °C
Yield: 55.9 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.15 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) and the solution was cooled to −20° C. 2M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise and the reaction was stirred and allowed to warm to −5° C. After the reaction was cooled to −20° C., 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.043 g, 0.17 mmol, prepared as described in Example 47, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The reaction was stirred to −5° C., then concentrated, ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave the desired compound (630, 0.038 g, 40%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH:26][C:46](=[O:47])[CH2:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])=[CH:44][CH:43]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[N:11]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3csc4ccccc34)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2csc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 63.5 %

Procedure:
Under an argon atmosphere, to a mixture of 3-(benzo[b]thiophen-3-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7i) (505 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11i (505 mg, 740 μmol, 63.5%) as a yellow solid. Rf=0.19 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.15 (s, 6H), 0.20 (s, 6H), 0.91 (s, 9-H), 0.93 (s, 9H), 3.41 (s, 2H), 6.65-6.71 (AA′BB′, 2H), 6.93-7.00 (2AA′BB′, 4H), 7.35-7.42 (m, 2H), 7.80 (s, 1H), 7.95-8.07 (m, 4H, includes AA′BB′), 9.01 (s, 1H), 10.49 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (4C), 17.89, 17.93, 25.47 (3C), 25.54 (3C), 41.6, 119.5 (2C), 120.4 (2C), 122.6, 123.5, 124.4 (2C), 127.3, 127.9, 128.1 (2C), 128.9, 130.3 (2C), 132.3, 137.5, 137.5, 139.4, 143.7, 143.8, 147.6, 153.8, 156.7, 169.4; IR (KBr, cm−1) 683, 700, 735, 758, 781, 804, 839, 914, 1169, 1261, 1331, 1362, 1435, 1472, 1508, 1605, 1670, 2857, 2886, 2930, 2955; HRMS (ESI+) m/z 704.2781 ([M+Na]+, C38H47N3NaO3SSi2+ requires 704.2769).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 119.9 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (660 mg, 2.08 mmol) in tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (297 mg, 1.04 mmol) in 3 portions over 10 min. The mixture was allowed to stir (−20° C.) for 1 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (10 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and evaporated. The crude material was purified by ISCO® chromatography using a gradient of 75 to 100% ethyl acetate in hexanes to afford 494 mg (60%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.64 (s, 1H), 4.10-3.96 (m, 2H), 3.29-3.19 (m, 1H), 1.90 (d, 2H), 1.55-1.42 (m, 2H), 1.41 (s, 9H); ES-MS m/z 396.1 [M+H]+, HPLC RT (min) 2.79.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:34](=[O:35])[N:33]([CH:36]([C:46]([O:48]C(C)(C)C)=[O:47])[CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:31](=[O:32])[C:30]2=[CH:53][CH:54]=1)=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>FC(F)(F)C(O)=O>[C:1]([O:18][CH:19]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:34](=[O:35])[N:33]([CH:36]([C:46]([OH:48])=[O:47])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:31](=[O:32])[C:30]2=[CH:53][CH:54]=1)=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)C(=O)N(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)C(=O)N(C(CCC(=O)O)C(=O)O)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 4-(6,7-bis(palmitoyloxy)-4-thiaheptanoyl)amino-N-(1,3-bis(t-butyloxycarbonyl)propyl)phthalimide as obtained in Example 64 (191 mg) in trifiuoroacetic acid (5 ml) was stirred at room temperature for 4 hours, followed by concentration, to yield the title compound (170 mg, yield 100%) as a colorless crystal.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([OH:24])=O)=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:24])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: C1CCNC1
Reactant: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Product: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Yield: 84.3 %

Procedure:
The product was prepared in the same manner as described in example 70f using 5-(2-((2-fluoroethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 277 μmol) and pyrrolidine (68.7 μl, 830 μmol) as starting materials. The reaction affords 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide (96.8 mg, 84.4%) as white solid. MS: m/z=415.0 (M+H+).
Reaction SMILES: [OH2:1].[O:2]1[C@H:4]2[CH2:5][C@H:6]3[C@:19]([CH3:21])([CH2:20][C@@H:3]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:22])[C@@H:12]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:11]2)[CH2:8][CH2:7]3>N1CCOCC1>[N:23]1([C@H:3]2[CH2:20][C@@:19]3([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@H:12]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[C@@H:13]3[OH:22])[CH2:5][C@@H:4]2[OH:2])[CH2:24][CH2:25][O:1][CH2:11][CH2:12]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: O
Solvent: C1COCCN1
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
Water (50 ml) was added to a solution of (2α,3α,5α,16β,17β)2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (85.2 g) in morpholine (500 ml) and the reaction mixture was heated at reflux temperature for 3 d. Evaporation of the reaction mixture gave a crude product, which was crystallised from acetone. Recrystallisation from methanol gave pure (2β,3α,5α,16β,17β)-2(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol (71.2 g), m.p. 212°-219° C.; [α]D20 =+87.9° (c 1.02 in CHCl3).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(OC([N:67]([CH2:76][CH2:77][S:78][S:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:68][CH2:69][C:70](OCC#N)=[O:71])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[C:80]([S:79][S:78][CH2:77][CH2:76][NH:67][CH2:68][CH2:69][C:70]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:71])([CH3:83])([CH3:82])[CH3:81]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CCC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)SSCCNCCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h, 44.6 mg, 0.314 mmol) and cyanomethyl 3-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)propanoate (Compound 6g-B, 236 mg, 0.628 mmol) were dissolved in DMF under ice-cooling, followed by addition of triethylamine (0.088 ml, 0.628 mmol). After stirring at room temperature for 1 hour, the reaction solution was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=70:30). TFA (1.5 ml) was added to the resulting residue, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=80:20) to afford the title compound (66.9 mg, 25%).