Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:11]([CH3:38])[CH:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[O:39]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:11]([CH3:38])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of methyl [(3S)-6-({4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.427 g, 0.775 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from hexane-ethyl acetate to give the title compound (0.352 g, yield 85%) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])=[O:5])[CH3:2].Cl[C:15]1[N:20]=[C:19](Cl)[C:18]([F:22])=[CH:17][N:16]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([NH:10][C:15]2[N:20]=[C:19]([NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:8]=3)[C:18]([F:22])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCNC(=O)Nc1cccc(N)c1
Product: CCNC(=O)Nc1cccc(Nc2ncc(F)c(Nc3cccc(NC(=O)NCC)c3)n2)c1
Yield: 66.3 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine, the reaction of 1,3-diaminobenzene (2 g, 18.5 mmol), ethyl isocyanate (0.5 mL, 6.3 mmol) and potassium carbonate (4.36 g, 31.5 mmol) gave 3-(ethylaminocarbonylamino)aniline (940 mg, 83%). The reaction of 3-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine (180 mg, 66%) as a white solid. 1H NMR (CD3OD): δ 1.14 (t, J=6.9 Hz, 3H), 1.15 (t, J=7.5 Hz, 3H), 3.21 (q, J=7.2 Hz, 2H), 3.22 (q, J=7.5 Hz, 2H), 7.06 (ddd, J=0.9, 2.1, 7.8 Hz, 1H), 7.10-7.28 (m, 5H), 7.53 (t, J=2.1 Hz, 1H), 7.80 (m, 1H), 7.92 (d, J=5.7 Hz, 1H); LCMS: ret. time: 17.17 min.; purity: 89.63%; MS (m/e): 453.38 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2.O.[C:29](OC(=O)C)(=O)[CH3:30]>S(=O)(=O)(O)O>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]([C:3]2[C:2]3[N:1]=[C:29]([CH3:30])[O:13][C:12](=[O:14])[C:11]=3[C:10]3[CH:9]=[C:8]([F:15])[CH:7]=[CH:6][C:5]=3[N:4]=2)=[CH:17][CH:18]=1
Reactant: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc2c(-c3ccc(-c4ccccc4)cc3)nc3ccc(F)cc3c2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4 g of 3-amino-2-[1,1'-biphenyl]-4-yl-6-fluoro-4-quinolinecarboxylic acid in 30 ml of acetic anhydride was added 10 drops of concentrated sulfuric acid. The mixture was heated at 90° C. for 2 hours, then cooled and poured into 200 ml of water. This solution was stirred at 20° C. for 30 minutes, then the resulting solid was collected and washed with water. The residue was dissolved in 150 ml of dichloromethane and washed with 100 ml of saturated aqueous sodium bicarbonate. The organic layer was separated, dried and the volatiles removed in vacuo. The residue was dissolved in a small amount of dichloromethane and passed through a short pad of hydrous magnesium silicate, eluting with dichloromethane:hexane 1:1). The solids which were obtained were recrystallized from dichloromethane/hexane, giving 4.1 g of the desired intermediate as yellow crystals, mp 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].NC1C=CC([F:41])=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([F:41])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(F)cn1

Procedure:
The product from Example 11, Part D (100 mg, 0.3 mmol) and 2-amino-5-fluoropyridine (110 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using 2; 1 THF/CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (120 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.13 (m, 1H), 7.92 (d, J=3 Hz, 1H), 7.65 (d, J=8, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.17 (t, J=9 Hz, 1H), 7.00 (t, J=9 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.23 (d, J=15 Hz, 1H), 2.57 (m, 2H), 1.97 (m, 2H). MS: m/z (MH+) 426.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[F:35][C:36]([F:43])([F:42])[CH2:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:37][C:36]([F:43])([F:42])[F:35])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: NS(=O)(=O)CC(F)(F)F
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)CC(F)(F)F)cnn12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.12 g, 0.27 mmol) obtained in Example 39, step 2 and 2,2,2-trifluoroethanesulfonamide (WO1984/02650, 0.21 g, 1.33 mmol), the title compound (0.07 g, 43%) was obtained.
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[C@:22]([CH3:26])([CH2:24][CH3:25])[NH2:23])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([N:20]4[C:21](=[O:27])[C@:22]([CH2:24][CH3:25])([CH3:26])[NH:23][C:29]4=[O:31])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:2][CH2:3]2
Reactant: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3cccc4c3C3(CCO4)CC3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 155.5 %

Procedure:
To a solution of N1-[2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-pyrimidinyl]-D-isovalinamide (Intermediate 225, 4 mg, 10.86 μmol) in dry Dichloromethane (1 mL) TEA (3.78 μL, 0.027 mmol) was added. The reaction was cooled in an ice-bath, then a solution of triphosgene (1.450 mg, 4.89 μmol) in dry Dichloromethane (0.250 mL) was added once then two other times with 10 minutes in between. The reaction was stirred at 0° C. for 40 minutes, then it was quenched with water (5 mL) maintaining the reaction in the ice-bath. The organic layer was separated, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using a column isolute 2 g and cyclohexane to cyclohexane/ethyl acetate 1:1 as eluent affording the title compound (3 mg,) as a white solid.
Reaction SMILES: [CH2:1]([CH:7](O)[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.C([O-])(=[O:17])C.[Na+]>C(O)(=O)C>[CH2:1]([CH:7]1[CH:8]([OH:12])[CH:9]=[CH:10][C:11]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)[O-]
Reactant: CCCCCCC(O)c1ccco1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC1C(=O)C=CC1O

Procedure:
In an autoclave, there were charged α-n-hexylfurfuryl alcohol (I-4) (18.2 g), water (910 g) and a buffer solution (0.6 g) comprising sodium acetate and acetic acid adjusted to pH 4.7. The resultant mixture was stirred at 110° C. under a nitrogen stream. After completion of the reaction, the reaction mixture was cooled and extracted with toluene. Removal of toluene from the extract gave a mixture (15.65 g) of 2-n-hexyl-3-hydroxy-4-cyclopentenone (II-4) and 2-n-hexyl-4-hydroxy-2-cyclopentenone (III-4). Yield, 86%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (26.00 mg; 0.15 mmol; 1.00 eq.) in DMF were added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (35.01 mg; 0.14 mmol; 0.90 eq.), 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (41.33 mg; 0.13 mmol; 0.88 eq.), and N-ethyl-N-isopropylpropan-2-amine (0.07 ml; 0.38 mmol; 2.50 eq.). The reaction mixture was stirred overnight at RT. Purified the crude by HPLC to obtain 20 mg of the title product in 28% yield. MS (M+1) 460
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.CN(C)C=O.Cl>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:30])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-[4-(benzyloxy)-2-bromophenyl]prop-2-enoate (950 mg, 2.63 mmol, 1.00 equiv), tributyl(1-ethoxyethenyl)stannane (1.434 g, 3.97 mmol, 1.51 equiv), Pd(PPh3)2Cl2 (184.8 mg, 0.26 mmol, 0.1 equiv), N,N-dimethylformamide (15 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The mixture was cooled to 0° C. before 2N hydrogen chloride (10 mL) was carefully added dropwise. The resulting solution was stirred for an additional 1.0 h at 15° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The solution was then diluted with 10 mL of H2O. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The combined extracts were washed with 1×20 mL of water and 1×20 mL of aqueous saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 800 mg (89%) of ethyl (2E)-3-[2-acetyl-4-(benzyloxy)phenyl]prop-2-enoate as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34]>O.C(#N)C>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH2:21][CH3:22])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:23][CH2:24]2)=[CH:25][CH:26]=[CH:27][C:28]=1[CH2:29][CH2:30][O:31][CH2:34][CH2:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Solvent: CC#N
Solvent: O
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Triton-B (0.3 molar equivalents of a 40% solution in water) was added to a solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4-yl)methanone (limiting reagent) (step c) and tert-butyl acrylate (5 molar equivalents) in acetonitrile (3.4 volumes). The reaction was stirred at ambient temperature for 1 hr. The solvent was evaporated and the residue was partitioned between water (2 volumes) and 2-MeTHF (2 volumes). The layers were separated and the organics were dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield: 94% of theoretical.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@H:8]1[CH2:25][C:24]2[CH2:23][C:22](=O)[CH2:21][CH2:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[CH2:27])[CH2:12][CH2:11]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:7][C@@H:8]1[CH2:25][C:24]2[CH2:23][C:22](=[CH2:1])[CH2:21][CH2:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[CH2:27])[CH2:12][CH2:11]1
Reactant: C=C1CC[C@H]2[C@@H]3[C@H](C)CC4=C(CCC(=O)C4)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC2=C(C1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Methyltriphenylphosphonium bromide (2.2 g, 6 mmol) was added to a stirred solution of potassium t-butoxide (680 mg, 6 mmol) in 25 ml dry THF under a nitrogen atmosphere. The yellow suspension was stirred for 30 minutes at room temperature. A solution of (7α)-7-methyl-3-keto-17-methyleneestr-5(10)ene (850 mg, 3 mmol) in 25 ml dry THF was added rapidly (approx. 30 seconds) to the suspension, resulting in a slightly exothermic reaction. The reaction mixture was stirred for 30 minutes at room temperature, poured on ice-water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), dried (Na2SO4) and evaporated to dryness to give (7α)-7-methyl-3,17-dimethyleneestr-5(10)ene (680 mg, 80%) as a colorless oil. [α]D +115° (c 0.185 in ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24]([OH:26])=O)[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:51][CH2:52][CH2:53][CH2:54][NH:55]C(=O)OC(C)(C)C>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24](=[O:26])[NH:51][CH2:52][CH2:53][CH2:54][NH2:55])[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCCN)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from 55 (170 mg) and TBTU (150 mg) was dissolved in ACN (5 ml). TEA (150 μl) was added to the mixture. The mixture was stirred for 15 min. at rt. Then tert-butyl N-(3-Aminopropyl)carbamate (200 mg) was added. The mixture was stirred at 50° C. for 2 days. Afterwards the mixture was diluted with water and filtrated. The solid was washed with water and dried in an oven
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([CH:15]=[CH2:16])[C:8]=1[O:17][CH3:18].[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:18][O:17][C:8]1[C:9]([CH:15]=[CH2:16])=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: C=Cc1c(SC)ccc(Br)c1OC
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1c(SC)ccc(C(=O)O)c1OC
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
At −100° C., n-BuLi (25 ml, 15% strength in n-hexane, 4.1 mmol) was added to a solution of 1-bromo-2-methoxy-4-methylsulfanyl-3-vinylbenzene (7 g, 31.3 mmol) in THF (300 ml), and the mixture was stirred at −100° C. for 20 min. At −100° C., CO2 was then introduced (exothermic reaction up to −60° C.). At -80 to −90° C., the mixture was then stirred for another 1 h, and NaOH (100 ml) was added dropwise at −40° C. The solution was stirred into EtOAc (400 ml), and the mixture was extracted 3× with 5% strength NaOH and acidified to a pH=1 using 10% strength HCl. The H2O phase was extracted with EtOAc (300 ml), and the combined organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:9])[N:14]([C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][CH2:11][Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)NCCCCl
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)N(CCCCl)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Phenyl isocyanate (2.8 g) was added to a solution of the above crude ethyl 2-(3-chloropropylamino)isobutyrate (5 g) in toluene (30 mL) which was cooled to 0° C., and the mixture was stirred overnight at 0° C. to room temperature. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 7.4 g of crude ethyl 2-[3-phenyl-1-(3-chloropropyl)ureido]isobutyrate.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:8]([CH3:13])([CH3:12])[C:9](O)=O)#[N:7].O=P(Cl)(Cl)Cl>O1CCOCC1.Cl.C(Cl)Cl>[NH2:5][C:3]1[S:4][C:9]([C:8]([CH3:13])([CH3:12])[C:6]#[N:7])=[N:1][N:2]=1
Reactant: NNC(N)=S
Reactant: CC(C)(C#N)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C#N)c1nnc(N)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
300 mg (3.29 mmol) of thiosemicarbazide and 370 mg (3.27 mmol) of 2-Cyano-2-methylpropanoic acid are dissolved in dioxane (10.0 mL) and heated to 90° C. 300 μL (3.29 mmol) of POCl3 are added dropwise. The reaction is stirred at 90° C. for 1 h, cooled to RT and diluted with 1 N aq. HCl and DCM. The aq. layer is separated, 4 N aq. NaOH is added to reach pH 8 and then extracted with DCM. Then combined organic layer is washed with brine and dried. The solvent is removed under reduced pressure to afford 180 mg of 2-(5-amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile. Yield: 32%; ESI-MS: 169 [M+H]+; HPLC (Rt): 0.24 min (method B)
Reaction SMILES: [Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@H:21]([OH:26])[C@@H:20]1[OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl>C(Cl)Cl.N1C=CC=CC=1>[Si:1]([CH:18]([OH:28])[C@H:19]1[O:25][C@@H:22]([O:23][CH3:24])[C@:21]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:26])[C@:20]1([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 14.5 h

Procedure:
To a solution of 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (579 mg, 1.44 mmol) in methylene chloride-pyridine (4:1, 12.5 ml) was added dropwise benzoyl chloride (0.367 ml, 3.16 mmol) at 0° C. The reaction mixture was stirred for 2.5 h at 0° C. and for 14.5 h at room temperature. Ice was added to quench the reaction and the mixture was stirred for 1 h. Methylene chloride (100 ml) was added and two phases were separated. Organic layer was washed with water, saturated ammonium chloride, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in crude form, which was then purified by silica gel column chromatography (Hx-EtOAc, 5:1→1:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside in more pure form [Rf =0.75 (CHCl3 --MeOH, 10:1), 869 mg, 99%] as a thick syrup. 1H NMR (CDCl3) d 1.05 (s, 9H, t-Bu), 3.42 (s, 3H, --OCH3), 3.86 (dd, J=11.1 and 4.8 Hz, 1H, H-5a), 3.92 (dd, J=11.1 and 4.7 Hz, 1H, H-5b), 4.48 (dd, J=10.6 and 4.6 Hz, 1H), 5.15 (s, 1H), 5.63 (d, J=5.0 Hz, 1H), 5.82 (pseudo t, J=5.8 and 5.4 Hz, 1H), 7,29-8.18 (m, 20H, Ar). Anal. Calcd for C36H38O7Si1 : C, 70.79; H, 6.27; Found: C, 71.01; H, 6.20.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH:5]([CH2:7]CS([O-])(=O)=O)[CH2:4][O:3]1.[NH2:14][CH2:15][CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:13][C:2]1([CH3:1])[CH2:6][CH:5]([CH2:7][NH:14][CH2:15][CH2:16][NH2:17])[CH2:4][O:3]1
Reactant: NCCN
Reactant: CC1(C)CC(CCS(=O)(=O)[O-])CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(CNCCN)CO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
A suspension of 4.00 g of [(2,2-dimethyl-4-tetrahydrofuryl) methyl]methanesulfonate, 10.4 g of 1,2-diaminoethane and 2.87 g of potassium carbonate in 40 ml of acetonitrile was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction with dichloromethane, The organic layer was dried over magnesium sulfate, anhydrous, and then concentrated under a reduced pressure to obtain 1.38 g of N-[(2,2-dimethyl-4-tetrahydrofuryl) methyl]-1,2-diaminoethane as a pale yellow oil.