Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[N:14]=[C:13]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[O:12]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[N:14]=[C:13]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[O:12]1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN)c1ccccc1
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a solution of {3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (60 mg, 0.123 mmol) in DCM (2 mL) at 0° C. was added TFA (1 mL). After stirring for 10 minutes, the reaction was concentrated and the residue was purified by preparative thin layer chromatography (10:1:0.2 EtOAc/MeOH/30% NH4OH) to provide the desired product (25 mg, 53%). MS ESI (+) m/z 388 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 2H), 7.50 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 3.17 (m, 1H, J=7 Hz), 3.02 (m, 1H), 2.8 (br, 2H), 2.56 (m, 1H), 1.8 (br, 2H), 1.6 (m, 2H), 1.2 (d, 3H, J=7 Hz), 1.13 (d, 3H, J=7 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:39].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:38]([O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:44][CH:43]=1)[CH3:39]
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred solution of 2-(4-hydroxycyclohexyl)isoindole-1,3-dione (8.0 g, 32.6 mmol) in dry THF (100 mL) was added triphenyl phosphine (12.8 g, 48.8 mmol) and 4-hydroxy benzoic acid ethyl ester (5.44 g, 32.7 mmol). The reaction mixture was cooled to 0° C. and DIAD (9.6 g, 47.4 mmol) was added dropwise from an addition funnel over a period of 3 h. The reaction was gradually brought to room temperature and stirring continued for 3 h. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography over neutral alumina (8% AcOEt in hexane) to give 5.13 g (42%) of 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OC)=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:56]=[CH:55][C:18]([C:19]([N:21]([CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)=[CH:36][CH:35]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1)=[O:13].[CH3:57][OH:58].[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:58][CH3:57])[C:4]=1[CH2:11][C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:21]([CH2:47][C:48]([OH:50])=[O:49])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)[N:30]=3)=[CH:25][CH:24]=2)=[O:20])=[CH:55][CH:56]=1)=[O:13]
Reactant: CO
Reactant: COc1ccc(OC)c(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CC(=O)Nc1ccc(C(=O)N(CC(=O)O)Cc2ccc(-c3nc(-c4ccc(-c5ccc(C)cc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
Prepared using General Procedure 9. To a stirring solution of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-66 (45 mg, 0.060 mmol) in THF (2 mL) and MeOH (0.25 mL) was added 1 M LiOH (120 μL, 0.120 mmol). The reaction mixture was stirred at room temperature for 20 h and a precipitate was formed. The mixture was filtered under vacuum and the captured solid washed with diethyl ether (5 mL). The captured solid was dried in a vacuum oven to provide 20 mg (48%) of 2-(4-(2-(2,6-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 458. LCMS-ESI (m/z) calculated for C41H36N4O7: 696; found 697 [M+H]+, tR=9.08 min (Method 9). 1H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.22-8.12 (m, 4H), 7.92-7.83 (m, 2H), 7.70-7.64 (m, 2H), 7.63-7.54 (m, 4H), 7.53-7.46 (m, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.22 (t, J=8.3 Hz, 1H), 6.67 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 3.78 (s, 6H), 3.67 (s, 2H), 3.47 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16](O)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@H:16]([C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)[C@@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 8-chloro-11-[(6S,8S)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine (64 mg, 0.173 mmol), benzoic acid (42.3 mg, 0.346 mmol) and triphenylphosphine (91.0 mg, 0.346 mmol) in anhydrous methylene chloride (20 mL) at 0° C. under argon was added diethyl azodicarboxylate (60.3 mg, 0.346 mmol) via syringe. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The product was absorbed onto silica gel and purified by flash column chromatography using 10% acetone in hexanes as the eluent to give 51.6 mg (63%) of 8-chloro-11-[(6S,8R)-8-benzoyl-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine as an off-white solid; mp (succinic acid salt) 92°-94° C.; Rf(25% acetone/hexanes): 0.45; HRMS (FAB): MH+ of C27H24N3O3Cl, calculated 474.1584, found 474.1595.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[S:21][N:20]=[C:19]([NH:22]C(=O)C)[N:18]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[S:21][N:20]=[C:19]([NH2:22])[N:18]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1nsc(C2CCCN2C(=O)OCc2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1nsc(C2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
2-(3-Acetylamino-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester hydrobromide (14.0 g, 37.8 mmol) was dissolved in ethanol (80 mL). The reaction mixture was cooled to 0° C. and a solution of K2CO3 (15.0 g, 108.7 mmol) in H2O (40 mL) was added. The solution was allowed to return to room temperature while stirring for 30 mins. The solution was concentrated down, redissolved in water (100 mL) and extracted with DCM (3×50 mL). The organic layers were combined and washed with brine (3×50 mL). The organic layer was partitioned from the aqueous layer, dried over MgSO4 and concentrated under vacuo to afford 9.4 g (94%) of 2-(3-amino-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]([N:5]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])[S:6]([CH3:9])(=[O:8])=[O:7])[CH3:4].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].[I-].[K+]>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH:3]([N:5]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[S:6]([CH3:9])(=[O:8])=[O:7])[CH3:4])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: Cc1cccc(C)c1N(C(C)CCl)S(C)(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(C(C)CN1C(=O)c2ccccc2C1=O)S(C)(=O)=O
Reaction time: 7 h
Yield: 26.4 %

Procedure:
45.3 g (0.164 moles) of 1-chloro-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are dissolved in 700 ml of dry dimethyl formamide, 61 g (0.33 moles) of potassium phthalimide and 1 g (6 mmoles) of potassium iodide are added, and the mixture is stirred at 140°-145° C. for 7 hours. The reaction mixture is processed as described in Example 21 for the preparation of the starting substance. The resulting 46.6 g of crude, honey-like substance is triturated with 50 ml of diethyl ether, the separated crystalline substance is filtered off, washed with diethyl ether and dried. 23.05 g of a crystalline substance are obtained; m.p.: 155°-160° C. This substance is purified further by stirring it with 50 ml of diethyl ether at room temperature. Thereafter the crystals are filtered off, washed with diethyl ether and dried. 16.75 g (26.4%) of 1-phthalimido-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained; m.p.: 188°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH2:16]OC)=[N:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[N:21]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)CO
Reactant: COCc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 1.7 %

Procedure:
In a round bottom flask charged with 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methoxymethylimidazo[1,2-a]pyrazine (˜2-3% impurity within 3.05 g, 7.95 mmol of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine) was dissolved in ACN (70 mL) to which was added 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 4.1 g, 96.8 mmol) at ambient temperature followed by heating to about 80° C. for about 3 h. After this time the reaction was cooled to ambient temperature and purified in 200-300 mg batches using RP-HPLC (Table 1, Method i). The pure fractions were combined and concentrated to remove the organic solvent. The resulting precipitate was filtered from the aqueous layer and dried in a vacuum overnight to give the title compound as a white solid (0.054 g, 1.5% yield). LC/MS (Table 1, Method b) Rt=1.77 min; MS m/z: 414.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH:10]([CH2:13][NH2:14])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:14][CH2:13][CH:10]1[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[O:11]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 38.2 %

Procedure:
Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.2 g, 9.66 mmol) with diisopropylethylamine (3.12 g, 24.15 mmol) and benzyl chloroformate (1.81 g, 10.63 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C20H23NO3 C, 73.82; H, 7.12; N, 4.3. Found C, 73.32; H, 7.33; N, 4.15. Chiral HPLC separation of (±)-benzyl(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=9.319 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=11.868 min, Chiralcel OJ, ethanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:21])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])[CH:8]=[CH:9][CH:10]=1.[H][H]>C1COCC1.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:6]2=[O:21])=[C:12]([CH3:20])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCCO)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1-n1cccc(CCCO)c1=O

Procedure:
475 mg (1.65 mmol) of the compound from Example 49A are dissolved in 48 ml of THF. 50 mg (0.05 mmol) of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product is reacted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=[CH:13][C:12]=2[OH:24])=[O:10])[CH:5]=[CH:6][CH:7]=1.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1>C(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:16]=3)[O:24][CH:30]2[C:29]2[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Br)c1)c1cc(OC2CCCCO2)ccc1O
Reactant: O=Cc1ccc(I)cc1
Solvent: C1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCC(C)O
Product: O=C1c2cc(OC3CCCCO3)ccc2OC(c2ccc(I)cc2)C1c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of 2-(3-bromophenyl)-1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone (5.28 g, 13.5 mmol), 4-iodobenzaldehyde (3.29 g, 14.2 mmol), piperidine (0.66 mL, 4.4 mmol), and DBU (0.44 mL, 4.5 mmol) in s-butanol (27 mL) was heated at reflux. Using a Dean-Stark trap, half (13 mL) of the solvent was removed over 40 min, and the reaction was kept at reflux without further concentration for additional 4.5 h. The reaction mixture was cooled to 90° C., i-propanol (27 mL) was added, and the reaction was allowed to cool to room temperature. The large solid pieces were broken down with spatula, and the suspension was stirred overnight (Note #1). The precipitate was collected by filtration to yield 3-(3-bromophenyl)-2-(4-iodophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one (7.23 g, 88%) as a white solid. 1H NMR (DMSO-d6): δ 7.67 (d, 2H), 7.43 (m, 1H), 7.38 (m, 1H), 7.36-7.30 (m, 2H), 7.21 (dd, 2H), 7.18-7.10 (m, 2H), 7.07 (dd, 1H), 5.95 (d, 1H), 5.47 (m, 1H), 4.76 (d, 1H), 3.73 (m, 1H), 3.55 (m, 1H), 1.93-1.68 (m, 3H), 1.68-1.48 (m, 3H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of (50 g, 0.22 mole) of 2'-deoxyuridine and 62 g (0.22 mole) of trityl chloride in 350 ml of dry pyridine was placed in a preheated (100° C.) flask and stirred at 100° C. under an air condenser for two hours. The reaction mixture was cooled to room temperature and slowly poured into 4 L of vigorously stirred ice-water. The solid obtained was filtered, washed with water until free from pyridine, and dissolved in chloroform and dried (Na2SO4 or MgSO4). Filtration and evaporation of chloroform yielded the 5'-O-trityl-2'-deoxyuridine product as an syrup (96 g, 93%), which was used for the next reaction without further purification.
Reaction SMILES: C(SSCC)C.B(F)(F)F.CCOCC.[S:16]([C:26]1[C:31]([OH:32])=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=1)[S:17][C:18]1C(O)=C(C)C=C[CH:19]=1>ClCCl>[CH2:18]([S:17][S:16][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([CH3:33])[C:31]=1[OH:32])[CH3:19]
Reactant: Cc1cccc(SSc2cccc(C)c2O)c1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCSSCC
Product: CCSSc1cccc(C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 144.2 %

Procedure:
Diethyl disulfide (14.24 ml, 116 mmol) and BF3.OEt2 (14.66 mml, 16.42 mmol) were added to a solution of 6,6′-disulfanediylbis(2-methylphenol) (Compound 104) (1.61 g, 5.78 mmol) in dichloromethane (30 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then quenched by slowly adding a saturated NaHCO3 solution dropwise thereto at 0° C., after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to afford 2-(ethyldisulfanyl)-6-methylphenol (Compound 105) (1.67 g, 72%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:28]([CH3:29])=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=3[CH3:30])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6]1.CO>O.C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][C:28]=3[CH3:29])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(CO)C3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(CO)C2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A solution of NaOH (0.16 g) in H2O (1 ml) is added to a stirred solution of methyl 4-[[6-[3-(hydroxymethyl)pyrrolidin-1-yl]-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.35 g, 0.88 mmol) in THF:MeOH (5 ml:1 ml). After 8 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 3 with aqueous citric acid solution, and extracted with ethyl acetate (2×10 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as an off-white solid (73 mg, 33.7%). Mass spectrum (m/z): 384.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12].[OH-].[Na+]>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[N:5]=[C:6]([NH:13][CH2:10][CH2:11][CH3:12])[N:7]=1
Reactant: CCCN
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCNc1nc(N)nc(Cl)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6-Amino-2,4-dichloro-[1,3,5]triazine (XXXVII) (30.0 g, 187 mmol) was dissolved in acetone (100 mL) and poured into ice-water (100 mL) to form a very fine suspension. To this mixture, a solution of propan-1-amine (11.0 g, 187 mmol) in acetone (20 mL) was added at 0° C. To this reaction, 2 N NaOH (94 mL, 187 mmol) was added dropwise at a rate to keep the temperature between 0° C. and 5° C. The mixture was stirred for 30 min at ambient temperature and for an additional 60 min at 50° C. The mixture was concentrated and then the precipitate was filtered off and washed with water (3×100 mL). After drying over calcium chloride under high vacuum, 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) was isolated as a white powder (35 g, 100% yield). LCMS (ESI) m/z=188 (M+H)+.
Reaction SMILES: C(O)(C)(C)C.C([Li])CCC.C(O[C@@:20]1([C:30]#[C:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34][OH:35])[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[CH2:22][C:21]1([CH3:29])[CH3:28])(=O)C1C=CC=CC=1>CCCCCC.C1(C)C=CC=CC=1>[OH:27][C@H:23]1[CH2:22][C:21]([CH3:28])([CH3:29])[C:20]([C:30]#[C:31][CH:32]([CH3:36])/[CH:33]=[CH:34]/[OH:35])=[C:25]([CH3:26])[CH2:24]1
Reactant: C/C(C#C[C@]1(OC(=O)c2ccccc2)[C@H](C)C[C@@H](O)CC1(C)C)=C\CO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC1=C(C#CC(C)/C=C/O)C(C)(C)C[C@H](O)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
In a sulphonation flask equipped with a stirrer, a thermometer, a dropping funnel, a reflux condenser and an apparatus for inert gasification 16 ml of tert.butanol and 20 ml of absolute toluene were placed under argon and cooled to -25° C. This solution was treated dropwise at -30° C. to -20° C. within 10 minutes with 52 ml of a 1.56M solution of butyl lithium in hexane and the mixture was stirred for a further 30 minutes without cooling. There was subsequently added to the thus-prepared solution of lithium tert.-butylate at about 20° C. in one portion a solution of 14.4 g of (1S,4R,6R)-4-hydroxy-1-(5-hydroxy-3-methyl-3E-penten-1-ynyl)-2,2,6-trimethylcyclohexyl benzoate in 120 ml of absolute toluene. The suspension obtained was heated carefully to 65° C. with the aid of an oil bath and stirred at this temperature for 1.5 hours. Thereafter, the mixture was poured on to 150 ml of ice/water. The aqueous phase was separated and extracted twice with 150 ml of diethyl ether each time. The organic phases were washed with 150 ml of saturated sodium chloride solution, combined, dried over sodium sulphate and concentrated on a rotary evaporator at about 40° C. and the residue was then dried at room temperature for 1 hour in a high vaccum. The crude product obtained (12.0 g) was chromatographed on silica gel with diethyl ether/hexane (vol. 1:1). From the product-containing fractions there was obtained a total of 7.5 g (80%) of (4R)-5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2E-penten-4-yn-1-ol as yellowish crystals (purity 98.8%, content of 2Z isomer 1.1%).
Reaction SMILES: OCCCCCC[CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]1CCN[CH2:61][CH2:60]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>>[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]1[CH2:8][CH2:9][N:10]([C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:61][CH2:60]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCN1CCNCC1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 25 in place of 8-aminooctanol. ES/MS calcd. for C41H56N5O6SSi+ 774.4. Found m/z=774.5 (M+H)+.