Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[C:9](=[O:30])[C@@H:10]([N:18]([CH2:26][CH2:27][CH:28]=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C@H:43]([NH2:48])[CH2:44][C:45]([OH:47])=[O:46])=[CH:34]1>>[CH2:1]([N:8]([CH3:31])[C:9](=[O:30])[C@@H:10]([N:18]([CH2:26][CH2:27][CH2:28][NH:48][C@H:43]([CH2:44][C:45]([OH:47])=[O:46])[CH2:42][C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:33][CH:34]=1)[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCC=O)C(=O)OC(C)(C)C
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using (S)-N-benzyl-N-methyl-2-[N'-(t-butoxycarbonyl)-3-oxo-propylamino]-3-phenyl-propionamide (2 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (2 mmol). Purify by chromatography to give the title compound.
Reaction SMILES: N.C([N:9]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[C:10]1=[O:29])C1C=CC=CC=1.[Li]>C1COCC1.CO>[CH2:14]([C@H:13]1[NH:9][C:10](=[O:29])[C@@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)N(Cc3ccccc3)C2=O)OCCO1
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Reaction time: 0.33 h

Procedure:
Into a 3-necked 500 mL flask at -78° C. was condensed 100 mL of ammonia. Next, 12-2 (470 mg, 1.24 mmol), dissolved in 20 mL of THF, was added. Lithium (19 mg, 2.48 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, the reaction was quenched with NH4Cl; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) gave 12-3 as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:4][C@@H:3]1[CH3:25].[CH3:26]C(O)C>[Pd]>[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C@@H:5]1[CH2:6][C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]([O:1][CH3:26])[C@H:3]([CH3:25])[CH2:4]1.[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C@H:5]1[CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@@H:2]([O:1][CH3:26])[C@@H:3]([CH3:25])[CH2:4]1
Reactant: CC(C)O
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Agent: [Pd]
Product: CO[C@@H]1[C@H](C)C[C@H](c2ccncc2N)C[C@@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %
Yield: 42 %

Procedure:
To a degassed solution of (+/−)-tert-butyl ((1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate (1.0 equiv.) in i-PrOH (0.07 M) was added Pd/C (0.1 equiv.). The solution was degassed and purged to H2 and left stirring under a balloon of H2 at rt for 16 hrs. The solution was degassed and purged to Ar, diluted with CH2Cl2, filtered through a pad of celite, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (20% MeOH, 100 mL/min, AD column) to yield tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (42% yield, 99% ee) and tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (39% yield, 99% ee). LC/MS (m/z)=336.2 (MH+), Rt=0.67 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.08 (d, J=7.04 Hz, 3H), 1.43-1.49 (m, 10H), 1.52-1.64 (m, 2H), 1.70-1.81 (m, 2H), 2.52-2.64 (m, 1H), 3.39 (br. s., 1H), 3.52-3.57 (m, 3H), 3.62 (br. s., 2H), 3.66-3.75 (m, 1H), 4.75-4.87 (m, 1H), 6.98 (d, J=5.09 Hz, 1H), 7.95-8.05 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][C:23]=2[F:30])=[CH:19][C:18]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:2]3[CH:14]=[C:6]4[N:7]([CH:11]5[CH2:13][CH2:12]5)[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:15])[N:3]=3)=[CH:24][C:23]=2[F:30])=[CH:19][C:18]=1[C:33]([F:36])([F:34])[F:35]
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O1CCCC1.[ClH:31]>O.C(O)C>[Cl:31][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:10][CH:11]=2)=[CH:17][CH:18]=1
Reactant: Cl
Reactant: O=Cc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: ClCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of 4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]benzaldehyde (5.00 g), sodium borohydride (620 mg), tetrahydrofuran (50 ml) and ethanol (50 ml) was stirred for 16 hours at room temperature. The reaction mixture was poured into water and acidified with 2N hydrochloric acid. The resulting precipitate was collected by filtration and dried, which was suspended in chloroform (50 ml). To the suspension was added thionyl chloride (2.00 g). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate, followed by washing with saturated aqueous sodium hydrogencarbonate and water. The ethyl acetate layer was separated and dried (MgSO4). The solvent was distilled off to leave crystals, followed by recrystallization from chloroform-isopropyl ether to give 4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole (3.25 g, 61%) as colorless prisms, mp 116-117° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:10][CH:11]([CH3:13])[CH3:12]>CN(C=O)C>[Br-:10].[CH:11]([N+:5]1[CH:6]=[CH:7][C:2]([C:1]([NH2:9])=[O:8])=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Br
Reactant: NC(=O)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[n+]1ccc(C(N)=O)cc1
Product: [Br-]
Yield: 65 %

Procedure:
A solution of 200 mL of DMF, containing 50.0 g of isonicotinamide and 60 mL of 2-bromopropane, was refluxed 5.75 h. A white insoluble solid filtered from this cool solution gave 64.9 g (65%) of 1-isopropylpyridinium-4-carboxamide bromide. m/e=165, NMR. Catalytic reduction of this salt, with PtO2 in MeOH, gave 65.2 g (98%) of 1-isopropylpiperidine-4-carboxamide hydrobromide, m/e=171. An aqueous solution of this salt was gasified, evaporated to dryness, and extracted with EtOAc to give 39.7 g (90%) of 1-isopropylpiperidine-4-carboxamide free base.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:27]([C:31]([O-:33])=[O:32])[C:28]([O-:30])=O.[C:34]1([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)=NC(Cl)=O>>[CH3:25][CH:24]([C:11]1[N:12]=[C:13]([CH2:22][O:23][C:28]([NH:27][C:31]([O:33][C:43]2[CH:44]=[CH:45][C:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:41][CH:42]=2)=[O:32])=[O:30])[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH3:26]
Reactant: O=C([O-])NC(=O)[O-]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C=NC(=O)Cl
Product: CC(C)c1nc(COC(=O)NC(=O)Oc2ccc(-c3ccccc3)cc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Yield: 55 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the iminodicarboxylate with N-4-biphenyloxycarbonyl isocyanate prepared from 4-phenylphenol (187 mg, 1.1 mmol) and N-chlorocarbonylisocyanate (106 mg, 1 mmol) in the same manner as the example 82 to give the compound 103 (215 mg, 55%). Mp 105-107° C. Rf 0.40 (EtOAc). 1H-NMR (CDCl3): δH1.32 (6 H, d, J 6.9 Hz, (CH3)2CH), 3.21 (1 H, sep, J 6.8 Hz, (CH3)2CH), 5.31 (2 H, s, NCH2), 5.33 (2 H, s, OCH2), 6.72 (2 H, d, J 1.5 Hz, arom 2- and 6-H), 6.78 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.06 (1 H, t, J 1.5 Hz, arom 4-H), 7.18 - 7.60 (9 H, m, 4-phenylphenyl), 7.82 (1 H, bs, NH), 8.46 (2 H, d-like, 4-pyridyl 3- and 5-H). IR(CHCl3)cm-1 : 3418 (NH), 1817 and 1747 (OOCNCOO). Elementary analysis (for C33H28N4O4SCl2) Calcd.: C, 61.21% H, 4.36% N, 8.65% S, 4.95% Cl, 10.95% Found: C, 61.06% H, 4.38% N, 8.64% S, 4.94% Cl, 10.78%
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)C.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH2:20]([Mg]Br)[CH3:21].Cl>C1(C)C=CC=CC=1>[CH2:20]([CH:7]1[CH2:8][C:3](=[O:1])[CH:4]=[CH:5][N:6]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:21]
Reactant: CC[Mg]Br
Reactant: COc1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC1CC(=O)C=CN1C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of 4-methoxylpyridine 81 (4.41 g, 40.5 mmol) in toluene (200 mL) at −20° C. was added CbzCl (5.7 ml, 40.5 mmol) in toluene (200 mL) dropwise. After 15 min, ethylmagnesium bromide (23 mL, 2M in THF, 46 mmol) was added dropwise. After 1 hr, 10% aqueous HCl (100 mL) was added and the mixture stirred overnight. The mixture was separated and the organic layer was washed with sat. NaHCO3 and brine. It was dried and concentrated to afford 82 (9 g, 36.4 mmol, 89.9%) that was used directly in the next reaction.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[K+:5].[K+].O.[S:8]([O-:12])([OH:11])(=[O:10])=[O:9].[K+]>>[Si:2]([OH:9])([OH:4])([OH:1])[OH:3].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[K+:5].[K+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: O[Si](O)(O)O
Reaction time: 0.06 h

Procedure:
About equal parts by weight of a dry potassium metasilicate, containing less than 6 mols of water per mol of potassium metasilicate and potassium hydrogen sulfate, are mixed. The mixture is agitated at ambient pressure, the chemical reaction starts in 2 to 5 minutes and considerable heat is produced. The chemical reaction is complete in 1 to 2 hours, thereby producing white granules of a silicic acid compound and potassium sulfate. The mixture is washed with water and filtered to remove the salt. The silicic acid compound is air dried at 25° to 75° C.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=1[F:31]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)c(F)c3)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.38 g (5.90 mmol) of potassium cyanide was added to 1.30 g (2.95 mmol) of the compound from Example 110A in 27 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.95 g (86% of theory) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:19])([F:18])[S:13]([O:16]C)(=[O:15])=[O:14]>ClCCl>[F:11][C:12]([F:19])([F:18])[S:13]([O-:16])(=[O:15])=[O:14].[CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:12]
Reactant: Cc1nc2ccccc2[te]1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[te]c2ccccc2[n+]1C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
2-Methylbenzotellurazole (Example 18) (10.5 g, 0.043 mole) was dissolved in dry dichloromethane (75 ml). Freshly distilled methyl trifluoromethanesulfonate (7.5 g, 0.045 mole) was added to the solution. An exothermic reaction occurred immediately. After a few minutes a crystalline product separated which was collected by filtration, washed with diethyl ether, and dried. Yield 16.86 g (96%). The pale yellow powder was dissolved in acetone (100 ml) and reprecipitated by adding diethyl ether to the solution until it became turbid. Colorless plates separated on chilling. Yield 15.33 g (87% of theory); mp 160°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14]C(=O)C2C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=2)[CH3:13])[CH2:11][O:10]1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 98.5 %

Procedure:
[(1R)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoate (50 g) was dissolved in methanol (2 liters). To the solution was added dropwise 1N sodium hydroxide aqueous solution (255 ml) at room temperature. The mixture was stirred for an hour at room temperature and neutralized with 1N hydrochloric acid (127 ml). Methanol was distilled off under reduced pressure. To the residue were added ethyl acetate (1 liter) and water (200 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline (200 ml), dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1:3) to give (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (25 g) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][NH2:26]>C1COCC1.Cl[Hg]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:26][CH3:25])=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Reactant: CN
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CNC(Nc1ccc(OC)c(OC)c1)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.50 g, 1.4 mmol), methylamine (2 M in THF, 0.75 mL. 1.5 mmol), HgCl2 (0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid (0.48 g, 99% yield) and this compound was used without further purification. LCMS: m/z 335 (M−H)−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[C@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(COC)OC>[ClH:3].[Cl:3][C:4]1[C:21]([O:22][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:7]2[C@H:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)Oc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Product: Cl

Procedure:
Add 430 mg (0.01 moles) of sodium hydride (50% in minerl oil) in small portions, to a stirred suspension of 2.88 g (0.01 moles) of (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (obtained in step E of Example 1) in 60 ml of dry dimethoxyethane and stir until the evolution of gas ceases. Add dropwise a solution of 1.08 g (0.01 moles) of ethyl chloroformate in 10 ml of dimethoxyethane with stirring and then stir the reaction mixture at room temperature for 16 hours. Evaporate to dryness at 100° C. and treat the residue with a mixture of 50 ml each of water and ethyl ether. Dry the ether layer over anhydrous sodium sulfate and precipitate (S)-7-chloro-8-ethoxycarbonyloxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride with 1N ethereal hydrogen chloride. Obtain an analytical sample by crystallization from 2-propanol, m.p. 196°-197° C., [α]D26 =+27.1° (c=1, dimethylformamide).
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Cl-].[Cl-].[Al+3]>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:20])=[CH:8][CH:7]=1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C

Procedure:
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with DCE (480.8 mL), chlorobenzene (1) (90.4 mL, 888.5 mmol) and 4-nitrobenzoylchloride (111.4 g, 600.3 mmol), and the resulting mixture stirred and warmed to 40° C. Aluminum trichloride (97.0 g, 720.4 mmol) was added portionwise over 1 h and then the reaction was heated to 60° C. and stirred for 10 h. The reaction was cooled to 20° C., poured into ice-water (2 L) and stirred for 10 min. The resulting aqueous mixture was extracted with DCM (600 mL×2). The combined organic extracts were was washed with deionized water (1 L×3). The solvent was concentrated at 40° C. to remove DCM and then at 66° C. to yield a pale to slight yellowish solid, which was dissolved in hot EtOH (500 mL) at 76° C., stirred for 30 min, and then gradually cooled to 4° C. over 1 h. The resulting solid was collected by filtration to yield (4-chlorophenyl)(4-nitrophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 262 (M+H)+, 284, 286 (M+Na)+
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:24].[I:25]I>[O-]S([O-])(=O)=O.[Ag+].[Ag+].C(O)C>[NH2:1][C:2]1[C:23]([I:25])=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:24]
Reactant: II
Reactant: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(N)c(F)c2)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC(C)(C)c1ccc(CNC(=O)NCc2cc(F)c(N)c(I)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the 50 ml of round bottom flask were put 1-(4-amino-3-fluoro-benzyl)-3-(4-t-butyl-benzyl)-urea (0.25 g, 0.76 mmol) and Ag2SO4 (1.1 eq, 0.26 g) and then cooled to 0° C. And to this mixture was poured 20 ml ethanol and added I2 (1.0 eq, 0.193 g) portionwise and stirred for 3 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was filtered through celite and concentrated under reduced pressure.
Reaction SMILES: [C:1]([OH:4])#[C:2][CH3:3].[CH2:5]([OH:8])[C:6]#[CH:7].[C:9]1([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:5]([OH:8])[C:6]#[C:7][C:3]#[C:2][CH2:1][OH:4].[C:9]1([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCO
Reactant: CC#CO
Agent: CCOC(=O)Nc1ccccc1
Product: OCC#CC#CCO

Procedure:
The monomer 2,4-hexadiyn-1,6-diol-monophenylurethane is synthesized by the unsymmetrical coupling reaction of propyne-1-ol and 2-propyne-1-ol-phenylurethane and is purified by recrystallization of the crude product from ethyl acetate/petroleum ether. Recrystallization of a 0.4 gm sample from 100 ml of a 10:90 acetone/petroleum ether solvent mixture by slow evaporation at room temperature gives approximately 5 cm long needle-like crystals which turn pink upon exposure to light.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:8]([F:11])([F:10])[F:9])(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.O>[N:23]([CH2:6][CH:7]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([F:11])([F:10])[F:9])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate (213 g, 625 mmol) in DMF (2500 mL) was added sodium azide (91.1 g, 1.40 mol). The reaction mixture was heated to 80° C. After 16 hours, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (3×500 mL). The organics were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to afford benzyl (3-azido-1,1,1-trifluoropropan-2-yl)carbamate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:12]1[S:11][C:9]2[N:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]=2[CH:13]=1
Reactant: CCCOc1nc2sccc2c(=O)n1CCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCOc1nc2sc(Cl)cc2c(=O)n1CCC
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
In a sulfonation flask, 10.1 g (0.04 mol) of 2-propoxy-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are added with stirring to 50 ml of absolute pyridine. The internal temperature is then raised to 70-75° C. and 9.0 g (0.07 mol) of N-chlorosuccinimid (NCS) are added over about 10 minutes in smallish portions. After stirring for 2 hours at 70-75° C., the pyridine is removed in a water-jet vacuum and the residue taken up in ethyl acetate. After washing twice with cold dilute aqueous hydrochloric acid, drying over sodium sulfate and removing the solvent in a water-jet vacuum, the crude product is obtained. The purification of the crude product is accomplished by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5), giving 7.8 g 6-chloro-2-propoxy-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one in the form of a white powder having a melting point of 62-65° C.