Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(Cl)(Cl)[Cl:13].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:13][C:6]1[S:2][C:3]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[C:4]=2[CH:5]=1
Reactant: NC1CCCc2sccc21
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: NC1CCCc2sc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A sample of 11.4 grams 4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine hydrochloride is stirred in 150 ml. of chloroform at about 10° C., and 6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirred for 3.5 hours at room temperature, and then about 20 ml. of 50% sodium hydroxide solution is added gradually to dissolve the suspended solid. The mixture is then poured into water and extracted with chloroform twice. The extracts are dried, evaporated to dryness, and the residue is distilled to give 7.4 grams of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, boiling point 94° C. to 98° C./0.5 Torr.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH2:17][C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH3:7])[CH:10]=1)=[O:19]
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
2 ml of pyridine is added to 30 ml of a solution of 3-methoxyaniline (4.92 g, 40 mmol) in dichloromethane and the mixture is stirred for 5 minutes, while maintaining the temperature inside vessel at lower than 0° C., and thereto 20 ml of a solution of chloroacetyl chloride (6.78 g, 60 mmol) in dichloromethane is drop-added slowly. A reaction is carried out at room temperature for 12 hours after completion of drop-addition, and then terminated. The reaction solution is washed with 5% of HCl (30 ml×3), 5% of NaOH (30 ml×3), water (30 ml×3), and saturated saline (30 ml) successively, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to remove the solvent to obtain 6.43 g of 2-chloro-N-(3-methoxyphenyl)acetamide, with a yield of 80.7%.
Reaction SMILES: O[CH2:2][C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)=[CH:23][C:22]=1[C:37]([F:40])([F:39])[F:38])#[N:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(N(C)C)=O.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:2][C@@H:3]3[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:6][CH2:7][N:8]3[C:28]2=[O:29])=[CH:23][C:22]=1[C:37]([F:38])([F:39])[F:40])#[N:20]
Reactant: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N2C[C@@H]3CN(C(=O)OCc4ccccc4)CCN3C2=O)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
To (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg, 1.02 mmol) in DMA (1 mL) was added phenyl 4-cyano-3-(trifluoromethyl)phenylcarbamate (250 mg, 0.82 mmol), and the mixture was heated to 40° C. for 5 h. The reaction was cooled to RT, and PPh3 (321 mg, 1.22 mmol) followed by DIAD (241 μL, 1.22 mmol) were added to the reaction. After stirring for 15 min at RT, the reaction was diluted with EtOAc (20 mL) and washed twice with 0.5 N NaOH (10 mL), then twice with sat'd brine (10 mL). The EtOAc was dried over MgSO4 then concentrated in vacuo. The residue was taken up in CH2Cl2 (5 mL) and cooled to −10° C., and Et2O (5 mL) was added. The resulting precipitate was collected by filtration and rinsed with cold 1:1 Et2O:CH2Cl2 to give Example 1, (R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate 187 mg (52%). HPLC RT: 3.253 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:445.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][O:13][C:14]1[C:23]([O:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[Br:10][CH2:11][CH2:12][O:13][C:14]1[C:23]([O:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1OCCBr
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(OC(=O)c2ccccc2)c1OCCBr
Yield: 87 %

Procedure:
A solution of fuming nitric acid (55 mL) and concentrated sulfuric acid (11 mL) was cooled to −5° C. Powdered methyl 2-[(2-bromoethyl)oxy]-3-[(phenylcarbonyl)oxy]benzoate (30 g, 79.1 mmol) was slowly added over a period of 30 min. After an additional stirring time of 30 min., the reaction mixture was quickly poured over ice, which was then extracted with dichloromethane (2×400 mL). The combined organic layers were washed with water (400 mL) and aqueous saturated sodium bicarbonate (200 mL). The organic solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The crude precipitate was triturated with diethyl ether (200 mL) to give 29.1 g (87%) of methyl 2-[(2-bromoethyl)oxy]-5-nitro-3-[(phenylcarbonyl)oxy]benzoate as an off-white powder: 1H NMR (400 MHz, CDCl3): 9.06 (t, J=2.2 Hz, 1H), 8.72 (d, J=3.2 Hz, 1H), 8.57-8.53 (m, 3H), 8.32 (d, J=3.2 Hz, 1H), 7.79 (t, J=8.0 H, 1H), 4.43 (t, J=5.8 Hz, 2H), 4.00 (s, 3H), 3.57 (t, J=5.6 Hz, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Si:9]([O:16][CH2:17][CH:18]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20](=[O:34])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:47][C:48]#[C:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54]>C1COCC1>[CH3:56][O:55][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][C:49]#[C:48][CH2:47][C@@H:19]1[C@@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:20]1=[O:34]
Reactant: COc1ccc(CN2CC(CO[Si](C)(C)C(C)(C)C)CC2=O)c(OC)c1
Reactant: COC(=O)CCCC#CCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
Lithium diisopropylamide (1.5 M in cyclohexane, 9.22 mL, 13.83 mmol) was added to a solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one (2.63 g, 6.93 mmol) in THF (41 mL) at −78° C. under nitrogen. After 30 min at −78° C., hexamethylphosphoramide (3.61 mL, 20.7 mmol) was added dropwise. After 30 min at −78° C., methyl 7-iodohept-5-ynoate (5.52 g, 20.7 mmol) in THF (20 mL+3 mL) was added. The reaction mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×50 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (40% EtOAc/hexane) to afford 579 mg (16%) of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CF)(CCCC)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(CF)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 6.36 g. of 4-fluoromethyl-4-trimethylsilyloxy-1-octyne, 11.64 g. of (10.6 ml.) of tributylstannane and 40 mg. of azobisisobutyronitrile is heated and stirred at 120° C. under nitrogen for 3 hours. The mixture is cooled, filtered through Celite and washed with hexanes. The hexanes are removed in vacuo and the residual liquid is vacuum distilled through a short path. The product is obtained at b.p. 110°-135° C./0.2-0.25 mm. (The product contains a minor amount of cis isomer.)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])=[CH:8][CH:9]=1
Reactant: C=CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-nitrophenyl)-acrylamide (Step 1) (0.203 g, 1.06 mmol), Iron powder (0.354 g, 6.34 mmol), FeSO4 (0.587 g, 2.11 mmol), Celite® (0.2 g) and water (6 mL) was heated to reflux with stirring for 3 h. The reaction mixture was cooled to RT and the solution was made basic to pH 13-14 by the addition of 2 N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and solids washed with EtOAc. The aqueous layer was extracted three times with EtOAc (25 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(4-aminophenyl)-acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:94])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])[CH2:83][C@H:82]3[CH3:93])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:90])([CH3:91])[CH3:89])[CH2:83][C@H:82]5[CH3:93])=[CH:79][CH:80]=4)=[O:94])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (1 mL) was added HATU (6.4 mg, 0.017 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (12.0 mg, 0.014 mmol; Preparation 32) was added followed by DIPEA (12.3 μL, 0.07 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (9 mg, 56% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O8 939.37. found 939.8.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH:10]([N:23]1[CH2:26][CH:25](O)[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH:10]([N:23]1[CH2:26][CH:25]([F:7])[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
DAST (26.46 g, 0.164 mol) was added to a solution of Compound 19-2 (13.1 g, 0.0547 mol) in dry DCM (200 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The end of the reaction was monitored with TLC (petroleum ether/ethyl acetate=5:1). The reaction mixture was poured into ice water, extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, and the organic layer was concentrated under reduced pressure, the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=150:1) to give Compound 19-3 (4.0 g, 30% yield) as a white solid.
Reaction SMILES: [C:1]([N:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].[CH2:18]([C:20]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:19]>>[C:1]([N:4]([CH2:13][CH2:14][C:15]([N:22]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:18][CH3:19])=[O:17])[C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCC(=O)O)c1c(C)cccc1C
Reactant: CCOC(=O)CCCNc1c(C)cccc1CC
Product: CCOC(=O)CCCN(C(=O)CCN(C(C)=O)c1c(C)cccc1C)c1c(C)cccc1CC

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-3-(2,6-dimethylanilino)propionic acid and ethyl 4-(2-ethyl-6-methylanilino)butyrate and suitable processing produces ethyl N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2-ethyl-6-methylanilino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2-ethyl-6-methylanilino)butyric acid (M.P. 139° to 141°).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: Nc1cnc(F)cc1I
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(F)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.43 g, 0.53 mmol) in acetonitrile (25 mL) and 1N aqueous potassium fluoride solution (25 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford the title compound as an brown solid (0.54 g, 29%). 1H NMR (CDCl3, 300 MHz): 8.37 (dd, J=2.5, 1.4 Hz, 1H), 7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 3.62 (s, 2H). LCMS (Method B): RT=3.01 min, M+H+=286/288.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[K+]>C(O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:22]=[CH:12][C:11]=1[CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: CC(=O)CCCNC(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-4 (5.0 g, 24.8 mmol), 2-amino-3-formylpyridine 1-5 [3.6 g, 29.8 mmol; for preparation see J. Org. Chem., 48: 3401 (1983)] and 20% KOH (1 ml) in absolute ethanol (100 mL) was heated at reflux for 8 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 1-6 as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][N:8]2[CH2:12][CH2:11][C@@H:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: O=CCCCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20 +10.15° (c=0.56, chloroform) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid salt and 4-phenyl-butyraldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].ClC([O-])=O>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[NH:15][C:13]1[S:14][C:10]2[CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:17][CH2:16][C:11]=2[N:12]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Dissolved ((S)-2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (32.6 g, 121.02 mmol) in 300 mL of CH2Cl2. To this was added DIPEA (41.8 mL, 240 mmol). The mixture was cooled to 4° C. To this was added the benzyl chloroformate (17.8 mL, 125 mmol). The mixture stirred overnight. TLC analysis indicated some starting material remaining. Added 0.3 eq more of chloroformate and 0.3 eq. more of DIPEA. Stirred for 4 h. TLC indicated remaining starting material Quenched with 200 mL of saturated NH4Cl. Washed with 2×200 mL of H2O, 200 mL of Na2CO3 and 1×200 mL of brine. Dried organic phase with MgSO4, filtered and concentrated. Applied to a SiO2 column and purified (5:5 CH2Cl2/hexanes to 9:1 CH2Cl2/MeOH) to give two main fractions. 1H NMR analysis indicated that both fractions were acceptable and they were combined to give 44.5 g of ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester. 3.06 g of S.M recovered 9%.
Reaction SMILES: ClCCl.[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([NH:8][CH3:9])=[O:7].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)(Cl)Cl>[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([N:8]([CH3:9])[C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])=[O:7]
Reactant: CCCN(C)C(=O)NC
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 74.6 %

Procedure:
Into 300 ml of anhydrous dichloromethane, 13.0 g (0.1 mol) of 1,3-dimethyl-1-propylurea and 12.0 g (0.1 mol) of phenylisocyanate were added and dissolved. The mixture was ice-cooled under stirring and 26.0 g (0.1 mol) of stannic chloride was added drop-wise. The reaction was then continued at a room temperature for 15 hours and the precipitate formed was separated by filtration. The precipitate thus obtained was added into a mixture of 60 ml of 20% hydrochloric acid/120 ml of chloroform and the stirring was continued until the mixture became transparent. Then the chloroform layer was separated and was washed with water and the chloroform layer was dried with anhydrous sodium sulfate. The chloroform was removed by distillation under reduced pressure and the residue thus obtained was recrystallized from ligroin to obtain 18.6 g (yield: 75%) of 1,3-dimethyl-1-propyl-5-phenylbiuret having a melting point of 63° to 64° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:24][C:25]1[C:30]([C:31]2[NH:32][C:33](=[O:46])[C:34]3[C:35](=[C:37]([CH2:44][CH3:45])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[N:39]=3)[N:36]=2)=[CH:29][C:28]([C:47](=[O:50])[CH2:48]O)=[CH:27][N:26]=1)[CH2:21][CH2:22][CH3:23].C(Br)(Br)(Br)[Br:52]>ClCCl>[CH2:20]([O:24][C:25]1[C:30]([C:31]2[NH:32][C:33](=[O:46])[C:34]3[C:35](=[C:37]([CH2:44][CH3:45])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[N:39]=3)[N:36]=2)=[CH:29][C:28]([C:47](=[O:50])[CH2:48][Br:52])=[CH:27][N:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ncc(C(=O)CO)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOc1ncc(C(=O)CBr)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (110 mg, 0.42 mmol) in dichloromethane (1 mL) was added slowly to an ice cooled solution of 5-(2-butoxy-5-glycoloyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 33) (150 mg, 0.35 mmol) and carbon tetrabromide (140 mg, 0.42 mmol) in dichloromethane (3 mL). The solution was allowed to warm to room temperature. After 2 h further carbon tetrabromide (25 mg, 0.075 mmol) and triphenylphosphine were added and stirring continued for 2 h. Concentration and purification of the product by flash column chromatography (gradient elution with ethyl acetate/pentane (10:90-70:30) gave 5-[2-butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one which was used without any further purification (slight contamination with triphenylphosphine oxide). 5-[2-Butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (205 mg, 0.42 mmol) was dissolved in dichloromethane and the solution cooled to 0° C. Morpholine (54 mg, 0.62 mmol) and triethylamine (84 mg, 0.83 mmol) were added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution 20% ethyl acetate/pentane:100% ethyl acetate:3% methanol/methyl acetate) gave 70 mg product.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:18]1>>[CH3:30][C:28]1[CH:27]=[CH:26][C:25]([C:31]([F:34])([F:32])[F:33])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][C@@H:17]([NH:16][C:2]3[CH:11]=[N:10][C:9]4[C:4](=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:8]=4)[N:3]=3)[CH2:18]2)=[O:23])[CH:29]=1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Reactant: FC(F)(F)c1ccc2ncc(Cl)nc2c1
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3cnc4ccc(C(F)(F)F)cc4n3)C2)c1

Procedure:
In analogy to the procedure described for example 200, the title compound was prepared from 2-chloro-7-trifluoromethyl-quinoxaline and ((R)-3-amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13). (M+H+) 469.2.