Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>>[CH:8](/[S:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: C(=C\c1ccccc1)\SCc1ccccc1

Procedure:
A solution of phenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the Procedure 2, part A, to form (Z)-styryl benzylsulfide. The title compound was obtained in 65% yield by oxidation of the sulfide according to the Procedure 2, part B. 1HNMR (CDC13) δ4.50 (2H, s),6.65(1H, d, JH,H=11.2),7.18-7.74 (10H aromatic+1H ethylenic).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CN(C)C=O.ClC(Cl)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:20][C:21]([CH3:22])=[O:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC(=O)COC(=O)C(C)c1ccc(O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
After 49.9 g of 4-hydroxyphenylpropionic acid was dissolved in 160 ml of dimethylformamide, 21.8 g of potassium carbonate was added to the solution at room temperature. Then 29.1 g of monochloroacetone was added dropwise to the solution at 60° C. and the reaction with 4-hydroxyphenylpropionic acid was carried out at 80°-90° C. for 1 hour. After the reaction, dimethylformamide was distilled off from the reaction solution to give a residue. After the residue was dissolved in dichloroethane, the solution was washed with water. The layer of dichloroethane was removed and the solvent was distilled off to give 64.7 g (yield 97%) of acetonyl 4-hydroxyphenylpropionate. After recrystallization from isopropylether, the product was a colorless crystalline material having a melting point of 64.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=O)=[CH:4][CH:3]=1.O1CCCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[C:11]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][CH:7]=1
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nn2ccccc2c1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
3.7 g of the product obtained in Example 1 were then introduced at ambient temperature and the mixture was stirred at ambient temperature for about 2 hours. Tetrahydrofuran with 20% water was introduced at a temperature of about 0° to 10° C., and the mixture was taken up in water, filtered, decanted and extracted with ethyl acetate. The organic phase was dried, filtered and the solvents were eliminated under reduced pressure at a temperature of about 50° C. to obtain 3.7 g of the expected product melting at <50° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]([OH:27])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)C(O)c1ccccc1
Product: CON=C1C[C@@H](c2noc(C(O)c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2RS)-hydroxy(phenyl)ethanoic acid, the title compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=469.3.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH:1]1([CH2:7][CH2:8][C:9]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC2CCCCC2)cc1
Temperature: -5 °C
Yield: 79.1 %

Procedure:
To a 250 ml three-necked flask were added 5.00 g (28.74 mmol) in theoretical amount of 3-cyclohexylpropionyl chloride prepared in the step 1, 3.11 g (28.74 mmol) methylphenyl ether and 150 ml dichloromethane. The resulting mixture was cooled in ice salt bath to −5° C., added portionwise 3.83 g (28.74 mmol) anhydrous AlCl3 under stirring, upon the completion of addition. The mixture was stirred at room temperature for 2 hours, poured into a mixture (150 g ice+5 ml concentrated hydrochloric acid), the organic layer was separated, concentrated under a reduced pressure to about 10 ml, the aqueous layer was extracted with ethyl acetate 2×50 ml, the organic phase was combined, washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether to obtain a 5.6 g product as a white solid in a yield of 79.1%, mp: 64-65 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.00 (2H, m, CH2), 1.10˜1.40 (4H, m, 2×CH2), 1.61˜1.1.82 (7H, m), 2.92 (2H, t, J=7.56 Hz, COCH2), 3.87 (3H, s, OCH3), 6.23 (2H, d, J=8.68 Hz, ArH), 7.94 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 269.2 (M+Na, 100), 247.2 (M+1, 71).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[CH2:8][CH2:7]1
Reactant: O=C(O)CCCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h
Yield: 70.9 %

Procedure:
The non-polar diastereoisomer of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (232 mg, 1.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmol.) were added to a solution of 5-(1H-indol-3-yl)pentanoic acid (217 mg, 1.0 mmol.) in abs. methanol. Stirring was then carried out for 24 h at RT. For working up, the mixture was concentrated, the residue was suspended in water (10 ml), the pH was adjusted to 11 with 5M NaOH, and extraction was carried out with EE (4×10 ml). The organic phase was washed with 1M NaOH, dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (50 g) with methanol/EE (1 ml/3.5 l) and the non-polar diastereoisomer of 5-(1H-indol-3-yl)pentanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide (306 mg) was isolated. 190 mg (0.44 mmol.) thereof were dissolved in 2-butanone; chlorotrimethylsilane (84 μl, 0.7 mmol.) was added, and stirring was carried out for 2 h. The solvent was decanted off, and the tacky solid was washed with cold 2-butanone (2×1 ml) and cold ether (3×1.5 ml) and dried in vacuo. The hydrochloride of the non-polar diastereoisomer of 5-(1H-indol-3-yl)pentanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was obtained in a yield of 184 mg (pale-pink solid, m.p. 120–130° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2cccnc2)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2cccnc2)cs1

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (17.6 mg) with purity >90%. MS (pos) m/z 400.0,402.0.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Br)(Br)([Br:19])=O>C1(C)C=CC=CC=1>[Br:19][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(C)c12
Solvent: Cc1ccccc1
Product: CCC(CC)c1cccc2nc(Br)n(C)c12
Yield: 11.1 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.10 g, 10.0 mmol), phosphoric tribromide (5.73 g, 20.0 mmol) and toluene (10 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated in vacuo. The residue was dissolved in saturated sodium hydrogen carbonate solution and ethyl acetate, and extracted. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (312 mg, 1.11 mmol, 11%) as colorless oil.
Reaction SMILES: [CH3:1][CH:2]([C@@H:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:3].[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>C(Cl)Cl>[CH3:17][N:6]1[CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@@H:4]([CH:2]([CH3:1])[CH3:3])[CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H]1CN(C)CCN1C(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
Commercially-available (S)—N-1-Boc-2-isopropylpiperazine (2.0 g, 8.76 mmol), sodium triacetoxyborohydride (2.76 g, 13 mmol), and formaldehyde (37% in H2O, 1.06 mL, 13 mmol) were dissolved and stirred in CH2Cl2 (40 mL) overnight at room temperature. After this time, the reaction mixture was diluted with additional CH2Cl2 and washed with 1 N NaOH and brine. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to provide 1,1-dimethylethyl (2S)-4-methyl-2-(1-methylethyl)-1-piperazinecarboxylate (2.18 g) as a colorless oil.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)=[CH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.Cl.NO>C(#N)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:22][N:6]=[C:7]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)[CH:8]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Dimethylformamide (44 ml), 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (5.5 g) and hydroxylamine hydrochloride (2.0 g) were charged in 300-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 55 to 60° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, and acetonitrile (110 ml) was added to separate the crystals. The inner temperature was made 0 to 5° C., and the crystals were filtered and washed with acetonitrile (28 ml) and water (110 ml). The crystals were dried overnight in vacuo to give methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (5.21 g)
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[I:13]N1C(=O)CCC1=O>CN(C)C=O>[I:13][C:11]1[CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a solution of Example 3b (1.12 g, 6.03 mmol) in dimethylformamide (60.3 mL) was added N-iodosuccinimide (1.49 g, 6.63 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was quenched with 10% sodium thiosulfate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated. Water was added to the residue, and the mixture was stirred at ambient temperature for 10 minutes and filtered to give the title compound (1.55 g, 83%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)cc21
Yield: 87.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (4.5 g), 4.2 g of 5-chloro-2-oxindole, and 2.9 mL of piperidine in 50 mL of ethanol were heated to 95° C. for 5 hours. The reaction mixture was collected and concentrated. The residue was suspended in acetone and the yellow precipitate was filtered, washed with cold ethanol, 2 N aqueous hydrochloric acid and water to pH 6 then dried in a vacuum oven overnight to give 7.2 g of the title compound (88%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1N1CCN(S(C2SC=CC=2)(=O)=O)CC1>>[F:34][C:33]([F:35])([F:36])[C:32]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:13]=1)([OH:41])[C:37]([F:38])([F:40])[F:39]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: OB(O)c1ccc(O)cc1
Product: Oc1ccc(-c2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1

Procedure:
Following the procedure outlined for Example 69, 4-hydroxyphenylboronic acid (19.2 mg, 0.139 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH4OH in CH3CN/H2O (5% to 95% over 8 min)) to afford 2′44-(2-thiophenylsulfonyl)-1-piperazinyl)-5′-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4-biphenylol. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=5.3 Hz, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.38 (s, 1H), 7.36-7.25 (m, 3H), 7.13 (d, J=8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 2.89 (br. s, 8H). m/z (ESI, +ve ion) 567.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.47 μM; GK-GKRP EC50 (LC MS/MS)=1.37 μM.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:7]1=[N:6]2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([NH:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[O:18])[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Nc1nnn[nH]1
Reactant: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc12
Temperature: 105 °C
Yield: 62.6 %

Procedure:
A mixture of 0.6 g (0.0022 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (Example 48) and 0.84 g (0.005 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 90 ml of dimethylformamide is stirred and heated in a wax bath at 105° C. for eighty five minutes under nitrogen. The mixture is allowed to stand at room temperature for thiry minutes and then 0.225 g (0.0022 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for three and one-half hours. The solvent is evaporated and the residue suspended in hot methanol, cooled and 0.71 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.47 g of 1,3-dimethyl-10-oxo-N-1H-tetrazol-5-yl- 10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with pyridine (1:0.2); mp >300° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH:18]1([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:23][CH3:24])[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(NC(=O)C(C)(C)C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.16 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one (Example 29) and 78 mg (0.77 mmol) triethylamine are dissolved in 4 ml dichloromethane. 37 mg (0.31 mmol) 2,2-dimethylpropanoyl chloride are added dropwise. The mixture is stirred for 2 hours at room temperature and then washed with 1 N potassium hydrogensulfate solution and with saturated sodium hydrogencarbonate solution. The organic layers are dried and evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH:35]=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:50]CC1>C(OCC)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:12]([CH2:34][CH:35]=[O:50])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H]1C[C@](COCc2ccccc2)(n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOCC
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CC=O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
A solution of 18 (1 mmol), OsO4 (0.1 mmol) and 4-methylmorpholine N-oxide (2 mmol) in diethyl ether and water are stirred overnight. A solution of NaIO4 is added and the solution further stirred. The aqueous layer is extracted with diethyl ether and the combined organic layer is evaporated under vacuum to yield the crude product, compound 55.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:42])[CH:25]=[C:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(C)=O>[CH2:1]([N:8]([C@H:16]([C:24](=[O:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Reaction time: 9 h
Yield: 83.5 %

Procedure:
An autoclave was charged with (2S)-2-(N,N-dibenzylamino)-5-tert-butoxycarbonylamino-1,6-diphenyl-4-hexen-3-one (0.56 g, 1 mmol), 25 mg of 3%-Pd-alumina and 5 ml of acetone. After introducing hydrogen under a pressure of 10 atm, the contents were stirred at 50° C. for 9 hours. The reaction mixture was filtered through a celite pad to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain 0.47 g (yield: 83%) of the title compound. 1H-NMR indicated that the purity of the (2S,5S) isomer was 95% or higher.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:10]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O)=[N+:11]=[N-:12]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)CCN=[N+]=[N-]
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCN=[N+]=[N-]
Yield: 98.9 %

Procedure:
Step C In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.32 g, 2.45 mmol) was reacted with 5-azido-3,3-dimethyl-pentanal (0.38 g, 2.45 mmol) in CH2Cl2 at room temperature for 18 h to give [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (0.65 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:14])[CH3:15]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 57.1 %

Procedure:
{2-[2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine (0.128 g, 0.35 mmol) was treated with SnCl2.2H2O (0.319 g, 1.39 mmol, 4.0 equiv.) in EtOH (20 mL), in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.067 g, 0.20 mmol, 56%) as an oil. LCMS m/z (%)=339 (M+H79Br, 78), 341 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 7.68 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (s, 1H), 7.45-7.51 (m, 2H), 4.62-4.82 (m, 2H), 3.76 (s, 3H), 3.65-3.76 (m, 2H), 2.87 (s, 6H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[N:9]=2)[CH2:7][CH2:6]1>C(O)(=O)C>[CH:5]1([C:8]2[N:13]=[C:12]([OH:14])[C:11]([N+:1]([O-:4])=[O:2])=[C:10]([OH:15])[N:9]=2)[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(C2CC2)n1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(C2CC2)nc1O
Temperature: 30 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Glacial acetic acid (90 ml) is added to fuming nitric acid (40 ml) at 0° C. The solution is warmed to 30° C. and 2-cyclopropyl-4,6-pyrimidinediol 4 (35 g, 0.25 mol) is added in portions. The temperature is kept between 30 and 40° C. After 1 h, the mixture is poured onto crushed ice and filtered. The filtrate is concentrated to 50 ml in vacuo. Methanol is added and the precipitate is filtered and dried. Pure 2-cyclopropyl-5-nitro-4,6-pyrimidinediol 17 (39.8 g, 81%) is obtained and used in the next step without further purification.