Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Solvent: ClCCl
Product: C=C(C(=O)OC)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184 mmol) was dissolved in DCM (500 mL) and treated with TEA (64.0 mL, 459 mmol). The solution was cooled to 0° C. and slowly treated with MSCl (15.6 mL, 202 mmol), then allowed to stir for 30 minutes to completion by TLC analysis. The solution was partitioned with 1N HCl solution, and the aqueous layer was extracted once with DCM. The combined organic layer was washed once more with 1N HCl solution, separated, washed with diluted NaHCO3 solution, and separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford an orange oil. The residue was loaded onto a large fritted filter with a plug of silica gel and eluted with 9:1 hexanes:ethyl acetate affording the pure desired product by TLC analysis. The concentrated pure fractions yielded the methyl 2-(4-chlorophenyl)acrylate as a colorless oil (30.8 g, 85%). This methyl 2-(4-chlorophenyl)acrylate (500 mg, 2.54 mmol) was added as a solution in THF (1.35 mL) to a stirring solution of i-PrNH2 (217 uL, 2.54 mmol) in THF (5.0 mL) at 0° C. The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The Boc2O (584 uL, 2.54 mmol) was added to the stirring amine via pipet. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as a colorless oil (854 mg, 94%). LC/MS (APCI+) m/z 256.1 [M-Boc]+.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.O=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](O)=[O:16]>CO>[F:1][CH:2]([F:12])[CH2:3][N:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]1=[O:16]
Reactant: Nc1ccccc1NCC(F)F
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: CO
Product: O=c1c(-c2ccccc2)nc2ccccc2n1CC(F)F
Yield: 34.9 %

Procedure:
To a solution of 400 mg (2.32 mM) of N-(2,2-difluoroethyl)benzene-1,2-diamine in 7 ml of methanol were added 349 mg (2.32 mM) of 2-Oxo-2-phenylacetic acid. The mixture was refluxed for 3 h and the solvent was then removed under vacuum. The residue was further purified by silica gel column chromatography using dichloromethane/cyclohexane as eluant, to give 231.8 mg of 1-(2,2-difluoroethyl)-3-phenyl-quinoxalin-2(1H)-one as a pale beige solid. Yield: 35%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:22])[C:16]#[C:17][Si](C)(C)C)=[O:8].C([O-])([O-])=O.[K+].[K+].CCCCCC>CO.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:22])[C:16]#[CH:17])=[O:8]
Reactant: Cc1ncoc1C(=O)c1ccccc1C(C)C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(C)c1ccccc1C(=O)c1ocnc1C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 1.16 grams (3.72 mmol, 1.0 eq) of oxazole 11a in 19 mL of MeOH was stirred in a 50 mL round bottom flask at room temperature under argon. To this solution was added 1.54 grams (11.16 mmol, 3.0 eq) of K2CO3 forming a heterogenous mixture. This suspension was vigorously stirred at room temperature until the reaction was complete by TLC (1:1 hexane:EtOAc, Rf=0.50). Upon completion (˜1 hour), the mixture was diluted with EtOAc and washed with 1.0 M HCl. The aqueous layer was then extracted twice more with EtOAc and the combined organic fractions were washed with brine and dried over MgSO4. Concentration yielded 860 mg (97%) of 11b as a light brown oil. This material could be purified via silica gel chromatography (hexane/EtOAc), though often the material was used directly for subsequent transformations. 1H-NMR (500 MHz, CDCl3): 7.91 (s, 1H), 7.78 (1H, d, J=7.8 Hz), 7.54 (1H, t, J=7.6 Hz), 7.40 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz), 4.12 (1H, dq, J=7.0 Hz, 2.5 Hz), 2.38 (3H, s), 2.18 (1H, d, J=2.4 Hz), 1.51 (3H, d, J=6.8 Hz). 13C-NMR (500 MHz, CDCl3): 185.43, 152.17, 147.06, 145.38, 142.10, 136.17, 131.80, 128.50, 128.32, 126.68, 87.10, 70.17, 28.31, 24.65, 14.16. IR (cm−1): 3293 (w), 1653 (vs), 1579 (s), 1485 (m), 1443 (w), 1384 (m), 1356 (s), 907 (s). HRMS (EI) calcd. for C15H13NO2: 239.0946. found: 239.0936.
Reaction SMILES: C(NC1C=C([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=2[CH3:26])C=CC=1Cl)(=O)C1C=CC=CC=1.C[C@H]1CNC[C@@H](C)N1>>[CH3:26][C:20]1[N:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH2:17])=[O:27]
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: Cc1ncccc1C(N)=O

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloro-2-methylnicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)-2-methyl-nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:51])=[C:32]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:51][C:31]1[C:32]([CH:38]2[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]2)=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=1[NH:29][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:10]2=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]2[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C#N)cc(N)c2Cl)CC1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Temperature: 70 °C

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (142 mg, 0.357 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (100 mg, 0.298 mmol) and Cs2CO3 (194 mg, 0.596 mmol) in DMF (3 mL) was heated at 70° C. for 2 h. This was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The crude mixture containing 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was carried forward to next step.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)=[CH:28][CH:27]=2)[CH3:25])C(=O)OC(C)(C)C)[N:11]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)=[CH:28][CH:27]=2)[CH3:25])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl 4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (45 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was washed with saturated NaHCO3 solution and brine. After separation, the aqueous phase was extracted with DCM (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give (S)-4-isopropyl-3-(2-(((S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid (35 mg, 97% yield).
Reaction SMILES: CSC1C=CC(CCC(C2C=CC=CC=2)=O)=CC=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1>>[CH3:19][S:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:26]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(SC)cc1)c1ccccc1
Agent: CSc1ccc(CCC(=O)c2ccccc2)cc1
Product: CCOC(=O)/C=C(\CCc1ccc(SC)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-[4-(methylthio)phenyl]-1-phenylpropan-1-one, (Z)-ethyl 5-[4-(methylthio)phenyl]-3-phenylpent-2-enoate and (E)-ethyl 5-[4-(methylthio)phenyl]-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [CH:1]([C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:2].[OH-].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:1]([C:4]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)=[O:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=1
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Yield: 56.9 %

Procedure:
85 g (0.466 mol) of 4-chlorophenyl isopropyl ketone, 31.3 g (0.56 mol) of potassium hydroxide and 5 g of tetrabutylammonium bromide in 120 ml of toluene are heated to the reflux temperature, and a solution of 75 g (0.466 mol) of 4-chlorobenzyl chloride in 60 ml of toluene is added dropwise. The reaction mixture is subsequently stirred under reflux for 12 hours, cooled and washed with water and the organic phase is dried over sodium sulphate and concentrated in vacuo. 81.5 g (60% of theory) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone of refractive index nD20 1.5711 are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[NH:15]1[C:19]2[CH:20]=[C:21]([CH:24]=O)[CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1>>[NH:17]1[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=4)=[CH:20][C:19]=2[N:15]=[N:16]1
Reactant: O=Cc1ccc2nn[nH]c2c1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: CC(=O)Nc1ccc2c(c1)NC(=O)/C2=C/c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting N-(2-oxoindolin-6-yl)acetamide (30 mg, 0.158 mmol) and 1H-benzo[d][1,2,3]triazole-6-carbaldehyde (26 mg, 0.174 mmol) to obtain 22 mg, 44%. 1H NMR (400 MHz, d6-DMSO) δ ˜16 (s, 1H), 10.60 (s, 1H), 10.10 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 2.02 (s, 3H); MS ESI 320.1 [M+H]+, calcd for [C17H13N5O2+H]+ 320.11.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:18])CC)C>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:18])([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1cccnc1Cl
Solvent: ClCCl
Product: CC(C)(F)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-chloro-3-pyridinyl)propan-2-ol (1 g; 5.83 mmol) in dichloromethane (10 mL) cooled to −70° C. was added diethylaminosulphur trifluoride (1.1272 g; 0.857 mL; 6.993 mmol) dropwise. On completion of the addition the reaction mixture was allowed to warm to room temperature and stir for 30 min. TLC showed starting material consumed. The reaction mixture was poured onto sodium carbonate solution and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, dried over magnesium sulphate filtered and evaporated under reduced pressure to give an oil. Yield=0.9 g. 1H NMR (360 MHz) DMSO-d6 δ: 1.83 (3H, s), 1.89 (3H, s), 7.30 (1H, dd, J 4.6 and 7.7 Hz), 8.00 (1H, dd, J 1.9 and 7.9 Hz), 8.34 (1 H, dd, J 1.9 and 4.7 Hz).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCCN1CCOCC1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCCN1CCOCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 4-(2-hydroxyethyl)-morpholine, there is obtained 2-morpholino-ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 351 (1), 238 (10), 113 (100);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(benzofuran-2-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12u, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.46 (m, 1H), 7.28-7.03 (m, 9H), 6.42 (s, 1H), 4,45 (s, 2H), 4.38 (s, 2H), 3.67 (s, 3H), 2.90 (t, 2H), 2.58 (t, 2H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([OH:30])[CH:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][CH3:29])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.CC([N:35](C)C)=O>N>[NH2:35][CH2:11][CH:12]([OH:30])[CH:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)N(C)C
Agent: N
Product: CCOc1ccccc1OC(c1ccccc1)C(O)CN
Reaction time: 12 h

Procedure:
To a solution of (RS,SR)-1-(p-toluenesulfonyloxy)-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane (4.3 g) in dimethylacetamide (125 ml), 30% aqueous ammonia (125 ml) was added and the reaction mixture was kept for 12 hours at room temperature in an hermetically sealed vessel. The mixture was then concentrated under vacuum to a small volume, poured into water, saturated with NaCl, and extracted with ethylacetate. The organic phase was washed with water, dried over Na2SO4, filtered, and the solvent evaporated under vacuum. The obtained oily residue was purified on chromatographic column (CHCl3 :CH3OH:NH4OH 180:20:2 as eluant), to give 1,1 g of 1-amino-2-hydroxy-3-(2-ethoxy-phenoxy)-3-phenyl-propane as single RS,SR diastereoisomer, m.p. 115°-117° C. In analogous fashion, using appropriate starting compounds prepared according to the procedure described in the example 1, 2 and 7, the compound 1-amino-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-3-phenyl-propane was obtained as single RS,SR diastereoisomer, m.p. 120°-122° C.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:17]2[N:16]=[C:15]([C:13]3[CH:12]=[N:11][N:10]([CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:14]=3)[CH:20]=[CH:19][N:18]=2)=[CH:23][CH:24]=1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc([N+](=O)[O-])cc3)n2)cn1
Agent: [Pd]
Solvent: CO
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(N)cc3)n2)cn1

Procedure:
A mixture of 3-cyclopentyl-3-(4-(2-(4-nitrophenylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (1.00 g, 0.00248 mol) in 20 mL of methanol was hydrogenated in the presence of catalytic amount of 10% Pd/C, under balloon pressure, overnight. The catalyst was filtered off and the filtrate was evaporated to dryness. The crude product was used directly in next step (900 mg, 97.2%). An analytically pure sample was obtained by RP-HPLC as a racemic mixture. LCMS (M+H) 374.4.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH3:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13])=[C:2]([NH:21][C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[N:10]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(F)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-chloro-2-fluoro-9-isopropyl-9H-purine (200 mg, 0.932 mmol), as prepared in step 1 of the alternate method of Example 2, in nBuOH, (4.66 mL) was added 1-methyl-1H-pyrazol-4-amine (109 mg, 1.12 mmol) and DIPEA (482 mg, 3.73 mmol) and the mixture stirred at ambient temperature for 6 hr to yield crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine. (S)-3-(methylsulfonyl)-N-(pyrrolidin-3-yl)propanamide hydrochloride (289 mg, 1.12 mmol) was then added to the reaction mixture and heated at 100° C. for 16 hr. LCMS showed unreacted intermediate so the reaction was heated at 110° C. for another 24 hr. The reaction was then cooled to ambient temperature and potassium tert-butoxide (3.73 mL, 3.73 mmol) was added and the resulting mixture stirred at ambient temperature for 30 min. Water was added and the reaction was extracted with DCM (3×50 mL), then the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with Na2SO4, concentrated, loaded onto silica and purified via flash chromatography using 0-20% EtOH/EtOAc to give the title compound (290 mg, 78% yield) as a pink solid, 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (s, 1 H) 8.38 (d, J=6.72 Hz, 1 H) 7.97 (s, 1 H) 7.89 (s, 1 H) 7.75 (s, 1 H) 6.20-6.34 (m, 1 H) 6.05-6.18 (m, 1 H) 5.60 (dd, J=10.03, 2.32 Hz, 1 H) 4.56-4.73 (m, 1 H) 4.43 (br. s., 1 H) 3.76-3.92 (m, 4 H) 3.68 (d, J=5.14 Hz, 2 H) 3.43-3.51 (m, 1 H) 2.15-2.28 (m, 1 H) 1.87-1.99 (m, 1 H) 1.51 (d, J=6.85 Hz, 6 H). m/z for C19H25N9O 397.25 and 396.30 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])(O)=O.[Na+].[Cl:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[Cl:45][CH2:46][C:47]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 2.21 mmol) in EtOAc:THF:sat'd NaHCO3 (110 mL: 30 mL: 50 mL) was added 2-chloroacetyl chloride (1 mL, 12.6 mmol) and stirred at RT for 2.5 hr. The reaction mixture was stirred at RT for 1.5 h. Another addition of 2-chloroacetyl chloride (0.5 mL) was added and continued to stir for 2 h. Concentrated in vacuo to remove volatiles and residue was washed with 5% citric acid (2×50 mL), water (2×100 mL), and sat'd NaCl (1×50 mL). The organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (1.02 g, 87%)
Reaction SMILES: [N:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:8][CH:7]=1)=[N+]=[N-]>CO.O=[Pt]=O>[NH2:1][CH:4]([CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: CC(Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]
Agent: O=[Pt]=O
Solvent: CO
Product: CC(N)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from {4-[4-(2-azido-propyl)-phenyl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine by hydrogenation using PtO2 in MeOH. Yield: 38 mg (81%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]([OH:15])[CH:13]=[CH:12][C:11]1=O)([OH:3])=[O:2].[OH-:17].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:14](=[O:15])[CH2:13][CH:12]([OH:17])[CH:11]=1)([OH:3])=[O:2]
Reactant: [OH-]
Reactant: O=C(O)CCCC/C=C\C1C(=O)C=CC1O
Agent: [Na+]
Product: O=C(O)CCCC/C=C\C1=CC(O)CC1=O

Procedure:
A solution of 1.0 mmole of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 39) and 3.0 mmoles of sodium carbonate in 15 ml. of water is allowed to stand at room temperature for 3 hours. The solution is acidified with HCl, saturated with sodium chloride, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxycyclopent-4-en-1-one. Further treatment of this mixture with N/10 sodium hydroxide at room temperature for 30 minutes causes the rearrangement of the latter isomer to the title compound, which is isolated from basic solution as above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1Cl)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-4-fluorophenol (0.65 g) and sodium hydride (210 mg) in dry 1,2-dimethoxyethane (15 ml) was stirred at room temperature for 30 minutes. A solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (1 g, prepared in a similar manner to that described in Example 6) in 1,2-dimethoxyethane (35 ml) was added dropwise to the stirred mixture. The mixture was stirred at room temperature for 21 hours, then was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in dichloromethane, washed with a 5% aqueous solution of sodium hydroxide followed by water, dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The solid residue was purified by flash chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 1:1), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.99 g, (m.p. 89°-91° C.).