Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C@@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C@@H:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][OH:25])=[O:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: N[C@H](CO)Cc1ccccc1
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@H](CO)Cc3ccccc3)cnc21

Procedure:
Intermediate 44 was prepared from Intermediate 17 and (2S)-2-amino-3-phenyl-1-propanol (commercially available from Aldrich) using an analogous method to that for Intermediate 42. LCMS showed MH+=424; TRET=2.60 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]\[CH:22]=O)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]\[CH2:22][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(/C=C\C=O)ccc1OCc1ccc(F)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(/C=C\CN2CCOCC2)ccc1OCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-[(1Z)-3-oxo-1-propen-1-yl]benzoate (may be prepared as described in Description 122; 163 mg, 0.52 mmol) in 1,2-dichloroethane (10 ml) was added morpholine (0.05 ml, 0.52 mmol) and acetic acid (0.03 ml, 0.52 mmol). The solution was stirred for 3 hours then sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added and stirred for one hour. Saturated NaHCO3 solution (10 ml) was added and the mixture was stirred for 15 minutes. Dichloromethane (10 ml) was added and the organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow gum. 197 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=S(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][CH:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Fc1ccc(C2=CCC(N3CCC(Cc4ccccc4)CC3)CC2)cc1

Procedure:
4-Fluorophenyl magnesium bromide (10 mmole) and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone (7.38 mmole) were reacted by the method described in Example 13 to give the intermediate mixture of cis and trans alcohols. This crude mixture was then dehydrated using SOCl2 in CH2Cl2 by the method described in Example 35 to give the crude product which was purified by chromatography on silica gel using ethyl acetate as the eluent. The pure product was converted the HCl salt in acetone using 12N HCl (23.3% overall, mp: 214-217° C.). Calc'd for C24H28NF.HCl.0.25H2O: C, 73.83%; H, 7.62%; N, 3.59%. Found: C, 73.85%; H, 7.61%; N, 3.56%.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:6])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:17]1[N:16]2[C:11]([S:10][CH2:9][CH2:8][NH:7][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:12][CH:13]=[CH:14][C:15]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)NCCSc1cccc2nccn12
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)NCCSc1cccc2ncc(Br)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (279 mg, 1 mmole) in chloroform (5 ml) was added N-bromosuccinimide (187 ml, 1.05 mmoles) and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 296 mg of the desired product (82.7%, colorless solid).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:19]>[Pd].C(O)C>[ClH:19].[ClH:19].[N:12]1([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCN2CCCCCC2)cc1

Procedure:
Compound 71 (9.1 g, 36.65 mmol) is hydrogenated for 3 h at room temperature with palladium on carbon in 150 ml of ethanol and 18.3 ml of 4M aqueous hydrochloric acid. The mixture is filtered over celite and evaporated.
Reaction SMILES: [NH2:1][C:2]1[C:16]([C:17]([OH:19])=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.CCN(CC)CC.CN(C(O[N:35]1[N:43]=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:16]([C:17]([O:19][N:35]2[CH:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]3[N:42]=[N:43]2)=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccn2nc(N)c(C(=O)ON3N=NC4C=CC=CC43)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
To a suspension of 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 0.3016 mmol) in NMP (1 mL) was added Et3N (37.24 mg, 51.29 μL, 0.3680 mmol). To the mixture was added TBTU (Boron Tetrafluoride Ion (1)) (109.0 mg, 0.3396 mmol) portionwise over a 5 minutes. The mixture was allowed to stir at room temperature for 20 minutes before being partitioned between ethylacetate and water. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to afford the product 3a,7a-dihydro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an oil (92 mg, 80% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=[CH:17][C:18](OCC)=[O:19])[N:15]=2)=[CH:4][CH:3]=1.BrC1C=CC(NC(=O)NC2SC=C(C=O)N=2)=CC=1.C(OC(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH2:18][OH:19])[N:15]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1csc(NC(=O)Nc2ccc(Br)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1csc(NC(=O)Nc2ccc(Br)cc2)n1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)Nc1nc(/C=C/CO)cs1

Procedure:
Following a procedure similar to that described in Preparation 48, crude ethyl 3-[2-(3-p-bromophenylureido)thiazol-4-yl]acrylate was prepared from 1 g of 2-(3-p-bromophenylureido)thiazole-4-carbaldehyde, 1.2 g of ethoxycarbonylmethylenetriphenylphosphorane and 20 ml of tetrahydrofuran. Subsequently. following a procedure similar to that described in Preparation 49, the desired compound was prepared from 1.1 g of the above crude ethyl ester, 14 ml of a 1M hexane solution of diisobutyl aluminum hydride and 30 ml of tetrahydrofuran. The resulting product was a white powder having the following physical properties.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])=[CH:7][CH2:8]O.N1C=CC=CC=1>CCCCCC>[Br:2][CH2:8][CH:7]=[C:6]([CH3:5])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Temperature: 10 °C
Yield: 168.8 %

Procedure:
Under an atmosphere of argon, a solution of phosphorus tribromide (8.32 g, 30.7 mmol) in 27 ml of n-hexane was added in dropwise to a mixture of 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ol (40 g, 57.3 mmol) and pyridine (1.92 ml, 23.8 mmol) in 587 ml of n-hexane at the temperature below 10° C. The solution was stirred at 10° C. for an hour, allowed to warm slowly from 10° to 20° C., stirred at 20°-25° C. for an hour and poured into cracked ice with stirring. The resulting precipitate was filtered off and the filtrate was extracted with n-hexane. The organic layer was washed with 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to afford 39.5 g (90.4%) of the desired compound, as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9](=[O:26])[C@H:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:11]C(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9](=[O:26])[C@H:10]([C:22]([CH3:24])([CH3:23])[CH3:25])[NH2:11]
Reactant: COCCOCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COCCOCCNC(=O)[C@@H](N)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Cbz-L-tert-leucine-N-2-(2-methoxyethoxy)ethylamide (7.66 g, 20.9 mmol) was dissolved in ethanol (100 ml) under an argon atmosphere and 10% Palladium on charcoal (1 g) was added as a slurry in ethanol (30 ml). The mixture was placed under an atmosphere of hydrogen as and left to stir overnight at room temperature. TLC analysis revealed that no starting material remained. The flask was purged with argon and the catalyst was removed by filtration. The solvent was removed under reduced pressure to provide L-tert-leucine-N-2-(2-methoxyethoxy)ethylamide as a colourless oil (4.55 g, 94%). 1H--NMR; δ(CDCI3), 6.95 (1H, br s), 3.60-3.40 (8H, m), 3.34 (3H, s), 3.01 (1H, s), 1.61 (2H, br s) and 0.95 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)NCc2ccccn2)c1
Reaction time: 18 h
Yield: 89 %

Procedure:
To a pre-cooled (ice bath) solution of 2-(aminomethyl)-pyridine (1.05 g, 9.7 mmol) in anhydrous CH2Cl2 (15 ml) was added 3-(Chlorosulfonyl)benzoic acid (714 mg, 3.23 mmol) under N2 and the ice bath was removed after addition. Stirring was continued for 18 hours at room temperature, and the reaction mixture was diluted with 300 ml CH2Cl2, and filtered through celite. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 3:6:91 CH3COOH-MeOH—CH2Cl2, gave the title compound (840 mg, 89%) as a pure white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:34]1[NH2:42].C([O-])([O-])=O.[Na+].[Na+]>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:42][C@@H:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41][C@@H:33]3[O:32][CH3:31])[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Temperature: 180 °C
Yield: 10.6 %

Procedure:
A mixture of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloropyrimidin-4-amine (0.114 g, 2.42 mmol), (1R,2S)-2-methoxyindan-1-amine (0.170 g, 1.04 mmol) and Na2CO3 (0.10 g, 0.97 mmol) was heated to 180° C. for 2 h in a sealed tube using an oil bath. The reaction was cooled and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (50 to 60% EtOAc/hexanes) to afford the title compound as a beige foam (0.066 g, 46%). LC/MS: Rt=2.20 min, ES+ 599 (Formic Acid).
Reaction SMILES: N[C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].[CH:43]1[CH:48]=[N+:47]([C@@H:49]2[O:53][C@H:52]([CH2:54][O:55][P:56]([O:59][P:60]([O:63][CH2:64][C@H:65]3[O:69][C@@H:68]([N:70]4[C:74]5[N:75]=[CH:76][N:77]=[C:78]([NH2:79])[C:73]=5[N:72]=[CH:71]4)[C@H:67]([O:80][P:81]([OH:84])([OH:83])=[O:82])[C@@H:66]3[OH:85])([OH:62])=[O:61])([OH:58])=[O:57])[C@@H:51]([OH:86])[C@H:50]2[OH:87])[CH:46]=[C:45]([C:88]([NH2:90])=[O:89])[CH:44]=1.[Cl-].[Mg+2].[Cl-].C(OP(O)(O)=O)[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O.P(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(O)(O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH:76]1[N:77]=[C:78]([NH2:79])[C:73]2[N:72]=[CH:71][N:70]([C@@H:68]3[O:69][C@H:65]([CH2:64][O:63][P:60]([O:59][P:56]([O:55][CH2:54][C@H:52]4[O:53][C@@H:49]([N:47]5[CH:46]=[C:45]([C:88]([NH2:90])=[O:89])[CH2:44][CH:43]=[CH:48]5)[C@H:50]([OH:87])[C@@H:51]4[OH:86])([OH:58])=[O:57])([OH:62])=[O:61])[C@@H:66]([OH:85])[C@H:67]3[O:80][P:81]([OH:84])([OH:83])=[O:82])[C:74]=2[N:75]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
The enzymic activity is determined according to the following procedure: 1.72 g of glutathione, and 34.2 mg of Na2EDTA are dissolved in a 114 mM potassium phosphate buffer solution (pH 7.0) to prepare 100 ml of a solution. A mixture of 700 μl of the solution, 700 μl of a thermally dissolved 5.72% starch solution, 100 μl of a 20 mM NADP+ solution, 100 μl of a 26 mM magnesium chloride solution, 100 μl of a 1.34 mM glucose 1,6-diphosphate solution, 100 μl of a 31 unit/ml phosphoglucomutase solution, 100 μl of a 35 unit/ml glucose 6-phosphate dehydrogenase solution, and 100 μl of a sample enzyme solution is incubated at 30° C. and the quantity of produced NADPH is monitored consecutively by means of absorption spectrophotometry at 340 nm. One unit refers to the amount of enzyme which is capable of producing 1 μ mol of NADPH for 1 min. under the conditions.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)benzoate from Step 1 above (2.26 g, 6.70 mmol) in DMF (40 mL) under N2, was added NaH (400 mg, 10.1 mmol). The reaction mixture was cooled, and CH3I (0.83 mL, 13.4 mmol) was added via syringe. The reaction mixture was allowed to warm to ambient temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography, eluting with 20% ethyl acetate in hexanes. Methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)-benzoate was obtained as a colorless oil which crystallized on standing overnight.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.N[C@@H](CCN1CC([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)C1)CO>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:26][CH2:27]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:43][CH:44]=1
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Product: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1

Procedure:
This compound is prepared in a manner analogous to that used to prepare 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:26])=O>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 51 %

Procedure:
DMF (0.5 ml) was added to a mixture of 6-methoxy-7-(2-methoxyethoxy)3,4-dihydroquinazolin-4-one (5.1 g, 20 mmol) in thionyl chloride (50 ml). The mixture was stirred and heated at reflux for 3 hours, allowed to cool and the excess thionyl chloride removed by evaporation. The residue was suspended in methylene chloride and washed with aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with methylene chloride and the combined extracts dried (MgSO4). The crude product was recrystallised from methylene chloride/hexane to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.8 g, 51%) as a fine white solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[N:12]=[C:11]1[CH3:28]>CN(C)C=O>[CH3:28][C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][S:2][CH3:1])[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[N:12]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
Sodium thiomethoxide (1.5 g, 21 mmol) was added to a solution of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (7.00 g, 19 mmol) in anhydrous N,N-dimethylformamide (80 mL). The reaction mixture was stirred at ambient temperature for 1.5 hours, then it as quenched with water and extracted with ethyl acetate (250 mL). The extract was washed with water (5×50 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 6.73 g of 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-4-phenoxy-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[Si]([C:25]#[CH:26])(C)C>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:25]#[CH:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)OC)cc(C(=O)N(CCC)CCC)c1
Reaction time: 3 h
Yield: 111.3 %

Procedure:
A mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, 200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and copper (I) iodide (6 mg, 0.05 mol %) in triethylamine (1.2 mL) is heated to reflux. (Trimethylsilyl)acetylene (100 microliter, 0.7 mmol) is added, and the mixture stirred for 3 hours, cooled to 20-25 degrees, diluted with water (20 mL), and extracted with chloroform (3×15 mL). The combined organic extracts are washed with saline (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, 185.5 mg), NMR (300 MHz, CDCl3): δ 7.95, 7.75, 7.43, 3.74, 3.25, 2.95, 1.49, 1.34, 0.79, 0.56 and 0.06.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=2[C:8]=1[Cl:25])(=O)=O.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:25][C:8]1[C:9]2[N:13]=[C:18]([C:19]([F:22])([F:21])[F:20])[N:11]([CH2:12][C:14]([F:16])([F:17])[F:15])[C:10]=2[CH:23]=[CH:24][C:7]=1[C:28]#[N:29]
Reactant: O=S(=O)(Oc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl
Temperature: 140 °C

Procedure:
To 4-chloro-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl trifluoromethanesulfonate (0.053 g, 118 mmol) in DMF (3 mL) was added zinc cyanide (0.008 g, 0.071 mmol) and palladium tetrakistriphenylphosphine (0.014 g, 0.012 mmol). The resulting mixture was heated over night under N2 atm at 140° C. The cooled reaction mixture was partitioned between EtOAc and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.0045 g): MS (ESI) m/z 328 (M+1).