Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:11]=[C:10]([CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:28]([OH:30])=[O:29].[OH-].[Na+]>C1COCC1.CO>[C:21]([N:13]([CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:28]([OH:30])=[O:29])=[CH:2][CH:11]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1cc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)c2ccccc2c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
The compound obtained in Example 43-1 (1.60 g) was dissolved in THF (16 ml) and methanol (16 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (16 ml), the mixture was stirred for 16 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water and 1 mol/l aqueous solution of hydrochloric acid was added to produce a precipitate. The precipitate was collected by filtration and dried to obtain the title compound (1.3537 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]3=[N:10][C:9]=2/[CH:23]=[CH:24]/[C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[CH:4][CH:3]=1.[N:35]1[N:36]=[C:37]([SH:40])[NH:38][CH:39]=1.CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[N:35]1[N:36]=[C:37]([S:40][C:2]2[N:7]=[CH:6][C:5]([C:8]3[N:12]4[N:13]=[CH:14][CH:15]=[C:16]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[C:11]4=[N:10][C:9]=3/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:4][CH:3]=2)[NH:38][CH:39]=1
Reactant: Sc1nnc[nH]1
Reactant: Clc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Sc2nnc[nH]2)nc1)\c1ccc2ccccc2n1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A solution of compound 49a (0.50 g, 1.1 mmol) in DMA (3 mL) was treated with 4H-1,2,4-triazole-3-thiol (0.16 g, 1.6 mmol) and potassium tert-butoxide (0.24 g, 2.1 mmol). The resulting mixture was stirred at 140° C. for 3 h, allowed to cool to rt and treated with water (10 mL). The solids obtained were collected by filtration and purified by RP Prep-HPLC. The title compound 22 was obtained as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 14.65 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08-8.05 (m, 1H), 7.99-7.92 (m, 3H), 7.81-7.70 (m, 3H), 7.58-7.52 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 6.44 (d, J=6.0 Hz, 1H), 4.15-4.05 (m, 4H), 3.85-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9OS: 534.2 (M+H). Found: 534.2.
Reaction SMILES: NN.[CH3:3][O:4][C:5]1[C:27]([O:28][CH3:29])=[CH:26][C:8]([C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10])=[C:7]([N+:30]([O-])=O)[CH:6]=1.O=[Al]O[Al]=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[NH2:30][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[C:27]([O:28][CH3:29])=[CH:26][C:8]=1[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][CH:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10]
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1OC
Agent: [Ni]
Agent: NN
Agent: O=[Al]O[Al]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(N)c(C(=O)N2C[C@H](O)CC2CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of hydrazine (6.59 g, 6.40 mL, 205.5 mmol) in MeOH (110 mL) was added dropwise to a solution of the nitro-compound 35 (18.1 g, 41.1 mmol), over anti-bumping granules and Raney Ni (2.6 g) in MeOH (325 mL) and heated at reflux. After 1 hour at reflux TLC (95% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (2.6 g) and hydrazine (6.40 mL) in MeOH (50 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed reaction completion. The reaction mixture was then treated with sufficient Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 h. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (300 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the amine 36 as a green oil (16.03 g, 95%): [α]22D=−116.32° (c=0.31, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ6.70 (s, 1H), 6.28 (s, 1H), 4.51-4.49 (m, 1H), 4.36-4.34 (m, 1H), 4.06-3.77 (m, 10H), 3.61-3.50 (m, 3H), 2.23-2.21 (m, 1H), 2.01-1.98 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ170.2, 151.5, 141.2, 140.5, 112.2, 112.0, 101.1, 70.4, 62.6, 59.0, 56.9, 56.6, 55.8, 35.7, 25.9 and 25.7, 18.2, −5.4 and −5.5; MS (EI), m/z (relative intensity) 412 (M+. +2, 3), 411 (M+. +1, 10), 410 (M+., 32), 354 (6), 353 (23), 263 (3), 212 (5), 181 (11), 180 (100), 179 (3), 165 (3), 164 (6), 152 (10), 137 (4), 136 (4), 125 (5), 120 (3), 100 (3), 94 (6), 75 (9), 73 (7), 57 (3); IR (CHCl3) 3353 (br), 2953, 2930, 2857, 1623, 1594, 1558, 1517, 1464, 1435, 1404, 1260, 1234, 1215, 1175, 1119, 1060, 1005, 915, 836, 777, 755, 666 cm−1; exact mass calcd for C20H34N2O5Si m/e 410.2237, obsd m/e 410.2281.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][CH:28]=[CH:27][C:26]=2[CH:30]=1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:28]1[O:29][C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:30][C:26]=2[CH:27]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc2occc2c1
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3cc(Cl)ccc3o2)C1

Procedure:
The title compound (0.98 g) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (1.60 g) and 5-chloro-benzofuran (0.86 g, FP1.537.206) using the method of Description 2.
Reaction SMILES: [C:1]([CH:4]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]=[CH2:7])(=O)[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:5]([C:4]1[N:8]=[C:9]([CH:10]([CH3:11])[CH3:12])[O:13][C:1]=1[CH3:2])[CH:6]=[CH2:7]
Reactant: C=CCC(NC(=O)C(C)C)C(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCc1nc(C(C)C)oc1C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
6.63 g of the above prepared N-(1-acetyl-but-3-enyl)-isobutyramide(33.61 mmol) were treated with 37 ml of trifluoroacetic acid (483 mmol) and 28.03 ml of trifluoroacetic anhydride (6 eq.) and kept for 3 h at 40°, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/NaHCO3, the aqueous layer (pH ˜8) extracted twice with AcOEt, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=92/8) yielded 3.92 g of the title compound as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH:32]([Sn](C=C)(C=C)C=C)=[CH2:33]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH:32]=[CH2:33])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(Nc3ccc4cn[nH]c4c3)c12
Temperature: 60 °C
Yield: 29.6 %

Procedure:
To a solution of 2-chloro-N-(1H-indazol-6-yl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.45 g, 0.8 mmol) in dimethylformamide (2.0 mL) was added tetravinyltin (0.29 mL, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (0.092 g, 0.08 mmol). After degassing, the mixture was heated at 60° C. for 15 h. before it was diluted with EtOAc, and washed sequentially with Sat. NaHCO3 and brine. The organic extract was dried over Na2SO4 and concentrated to give a crude residue. Purification by flash column chromatography (Hexane/EtOAc=1:1) gave 2-chloro-N-(1H-indazol-6-yl)-5-vinyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.11 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][OH:48])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][O:48][S:59]([CH3:58])(=[O:61])=[O:60])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCO)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOS(C)(=O)=O)c2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 113e (163 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (174 μL, 1.0 mmol) followed by methanesulfonyl chloride (39 μL, 0.50 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.12 min, m/z 731 [MH+].
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH2:33][CH3:34])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=O
Reactant: CCC/C(=C\c1ccc(-c2cccc(NC)c2)cc1)C(=O)OCC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CCC)C(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
172 μL (1 mmol) of heptyl isocyanate are added to 251 mg (0.8 mmol) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]pentanoate (prepared according to Example 8a). The reaction mixture is heated at 100° C. in an Emrys Optimizer microwave oven for 20 minutes. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 361 mg (100%) of ethyl 2-[1-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]pentanoate are obtained in the form of a yellowish oil.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([OH:22])=O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([Cl:4])=[O:22])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5° C.) solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10° C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17]C(OC1C=C2C(=CC=1)NC=C2CCC(OC(C)(C)C)=O)=O.[CH:40]([OH:42])=[O:41]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][C:40]([O:42][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13])=[O:41]
Reactant: CC(C)(C)OC(=O)CCc1c[nH]c2ccc(OC(=O)CCCC(=O)NCCc3c[nH]c4ccc(O)cc34)cc12
Reactant: O=CO
Solvent: ClCCl
Product: NCCc1c[nH]c2ccc(OC(=O)CCCC(=O)NCCc3c[nH]c4ccc(O)cc34)cc12
Reaction time: 1 h

Procedure:
To a solution of 6b (90 mg, 0.164 mmol) in CH2Cl2 (200 μL) at 0° C., 96% formic acid (400 μL) was added drop wise. After 30 mM the cooling bath was removed and stirring continued at room temperature for another 1 h. Formic acid was removed under a vacuo; residue was dissolved in MeOH (1 mL). The pH of the solution was then adjusted to 8 with 30% aqueous NH3, The alcoholic portion was removed under reduced pressure. 6c was isolated as semi solid (60 mg, 81.66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32])=[O:11]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 140 mg of 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in 2.5 ml of 0.2M sodium hydroxide solution, the mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 5 ml of water and 50 ml of diethyl ether, and then recrystallized from acetone to give 60 mg of 5'-[2-(2,6-dichlorophenyl)-acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of a white solid of melting point 249°-250° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[CH:48]=[CH:47][CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[N:16]=1>C(Cl)Cl>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[N:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:49])[C:20]([C:21]([F:23])([F:22])[F:24])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A47) (58 mg, 0.099 mmol) in DCM (5 mL) and the resulting solution stirred for 18 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue partitioned between 2 M aqueous NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated and washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 13 as a white solid (41 mg, 85%); 1H NMR (400 MHz, d4-MeOH) δ 8.78 (d, J=2.1 Hz, 1H), 8.61 (d, J=0.6 Hz, 1H), 8.19 (dd, J=8.6, 2.6 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.24-7.15 (m, 3H), 3.67 (s, 2H), 3.22-3.15 (m, 4H), 3.14-3.05 (m, 2H), 2.90-2.70 (m, 3H), 1.93 (d, J=13.9 Hz, 2H), 1.75 (m, 2H). LCMS-A: rt 4.552 min; m/z 485 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:42].Cl.[NH4+]>C1COCC1.C(OCC)C>[I:42][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:10][C:9]=2[CH:11]=1
Reactant: CCCCCc1nc2cc(CCO)ccc2o1
Reactant: [I-]
Agent: Cl
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCc1nc2cc(CCI)ccc2o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, a 0° C. solution of 2-(2-pentyl-benzoxazol-5-yl)-ethanol (1.63 g, 6.99 mmol) in dry THF (49 ml) was treated with triphenyl phosphine (2.018 b, 7.693 mmol) and imidazole (1.05 g, 15.38 mmol). After complete dissolution iodide (1.95 g, 7.69 mmol) was added in small portion so that the reaction temperature never exceeded 4° C. After stirring for 3 hours at 0° C. the reaction mixture was distributed between diethyl ether and saturated aqueous ammonium hydrochloride. The organic layer was evaporated in vacuum, suspended in diethyl ether, filtered and the filtrate concentrated in vacuum. Silica gel chromatography (eluent: pentane/diethyl ether 4/1) followed by crystallization from pentane provided the title compound as colorless crystals. mp: 47.7/48.7° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[Li+].O1CCCC1.O>CO>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCOC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A 250 mL round-bottom flask was charged with ethyl 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate (2.3 g, 5.0 mmol), lithium hydroxide (0.48 g, 20.0 mmol), tetrahydrofuran (30 mL), water (50 mL) and methanol (30 mL). The reaction mixture was stirred under nitrogen at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in water (100 mL) and acidified to pH 1 by the addition of 10 M hydrochloric acid, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and recrystallized from ethanol (50 mL) to afford 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (1.96 g, 91%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.45 (m, 1H), 8.33-8.26 (m, 1H), 7.42 (dd, J=7.82, 4.77 Hz, 1H), 7.21-6.83 (m, 4H), 6.49-6.44 (m, 2H), 5.39 (ABq, 2H), 4.72 (ABq, 2H), 4.24-4.00 (m, 4H).
Reaction SMILES: Cl.[NH:2]([C:4]1[N:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)[NH2:3].C(OCC)(=O)C.[CH3:22][C:23](=O)[CH2:24][CH2:25][C:26](=O)[CH3:27]>C(O)(=O)C>[CH3:27][C:26]1[N:3]([NH:2][C:4]2[N:5]=[N:6][C:7]([N:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:8][CH:9]=2)[C:23]([CH3:22])=[CH:24][CH:25]=1
Reactant: NNc1ccc(N2CCNCC2)nn1
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CCNCC2)nn1
Reaction time: 48 h

Procedure:
A mixture of 9.2 g (40 m moles) of 3-hydrazino-6-(1-piperazinyl)-pyridazine hydrochloride (m.p. 257° C.; prepared according to the procedure of U.K. Pat. No. 1.157.642), 3.28 g (40 m moles) of ethyl acetate and 4.82 g of 2,5-hexanedione in 100 ml of acetic acid is heated at 75° C. for 2 hours and then allowed to stand for two days at room temperature.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][N:13]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[N:15]=[CH:14]1.S(Cl)(Cl)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][S:18]([C:16]1[N:15]=[CH:14][N:13]([CH3:12])[CH:17]=1)(=[O:20])=[O:19])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Product: Cn1cnc(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
Mono-N-Boc-ethylenediamine (5; 5 g, 31.2 mmol, 1 eq) was sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride (6.76 g, 37.4 mmol, 1.2 eq). The appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. After 16 h, the solvent was reduced and then the reaction mixture was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 1092:7:1) to give the title compound as a white powder (9 g, 95%): δH (500 MHz, CD2Cl2) 1.37 (s, 9H, C(CH3)3), 2.99 (t, J=5.8 Hz, 2H, CH2NHSO2), 3.11 (q, J=5.8 Hz, 2H, CH2NHBoc), 3.71 (s, 3H, CH3), 5.53 (s, 1H, NHSO2), 5.68 (s, 1H, NHBoc), 7.48 (s, 1H, Im), 7.56 (s, 1H, Im); δC (125 MHz, CD2Cl2) 27.6, 33.5, 39.8, 42.6, 78.9, 124.0, 127.2, 139.2, 156.1; HRMS (ES+) calcd for [C11H20N4O4S+H] 305.1284. found 305.1294.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C2CCCCO2)=[C:7]([CH3:22])[C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2].Cl.O>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH3:22])[C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(OC2CCCCO2)c(C)c1C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
1-Acetoxy-2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxybenzene (4.09 g) was dissolved in tetrahydrofuran (20 ml). After adding 10% HCl (3 ml), the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and subjected to extraction with diethyl ether. The extract was washed with 5% aqueous sodium hydrogen carbonate and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from n-hexane to afford 4-acetoxy-3,5-di-tert-butyl-2-methylphenol (3.1 g) as a colorless needle.