Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3](N[C@@H](CC2C=C(OC)C(OC)=C(OC)C=2)C(O)=O)[CH:2]=1.[NH2:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[C:33]([OH:35])=[O:34]>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@H:32]([NH:31][C:27]2[CH:26]=[C:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:30]=[CH:29][CH:28]=2)[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)Nc1cccc(-c2ccccc2)c1

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (S)-2-Amino-3-(4-benzyloxy-phenyl)-propionic acid (O-benzyl-L-tyrosine). Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 424.3 [M+H]+; HPLC: single peak at tR=10.40 min (System 1).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]2[C:14]([OH:30])=[CH:15][C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH3:19])=[CH:17][C:4]=2[O:3]1.C(O)C>CCOCC.[Pd]>[CH3:31][C:2]1([CH3:1])[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[C:5]2[C:14]([OH:30])=[CH:15][C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH3:19])=[CH:17][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C=C2c1ccncc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)CC2c1ccncc1

Procedure:
3.0 g. (0.0072 mole) of the compound of Example 3 was hydrogenated in 100 ml. of ethanol at 3 atmospheres employing 0.7 g. of 5% Pd/C. After the reaction was completed the ethanol was stripped off, the obtained white glass dissolved in ether and a white solid isolated which, after recrystallization from acetonitrile, gave a m.p. of 162°-164° C. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([CH:7]([C:21]([O-:23])=O)[C:8]([C:18]([O-:20])=O)([OH:17])[C:9](CC)(CC)[C:10]([O-:12])=O)C>CO>[CH2:1]([NH:4][C:10](=[O:12])[CH2:9][C:8]([CH2:7][C:21]([NH:4][CH2:1][CH2:2][CH3:3])=[O:23])([C:18]([NH:4][CH2:1][CH2:2][CH3:3])=[O:20])[OH:17])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Solvent: CO
Product: CCCNC(=O)CC(O)(CC(=O)NCCC)C(=O)NCCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
N,N′,N″-tri-n-propylcitramide was prepared by the reaction of n-propylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.245 g; 1 eq), n-propylamine (19.427 g; 3.16 eq) and methanol (40 mL). The clear light yellow solution stirred for 3 days at room temperature prior to the removal of methanol via rotary evaporation at 50° C. The resulting yellow liquid was dried in vacuo at 70° C. and a tacky white solid was obtained. The crude solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with a slight odor (19.19 g; 55% yield).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([NH:28][CH2:29][C:30](O)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:31]=[C:30]([NH:17]/[N:16]=[C:7]1\[NH:8][C:9](=[O:15])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:6]\1[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:29][NH:28][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCn1/c(=N/NC(=O)CNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.8 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.50 g, 0.0021 mol), N-carbobenzyloxyglycine (0.49 g, 0.0023 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.0 g, 2.3 mmol) and triethylamine (0.59 mL, 0.0042 mol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water (4×) and brine (1×). The aqueous was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to give the desired product (1.30 g, 86%). LCMS calculated for C20H26N7O4 (M+H): 428.2. found 428.2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.[Pd].C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=C1CC(=O)C2C(=CC=CC=2)C1=O)(C)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1C=CN(c2c(C(C)C)cccc2C(C)C)C1=C1CC(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 20.0 g of 3,5-bis(trifluoromethyl)phenylboronic acid in 100 mL of tetrahydrofuran and 40 mL of water, 20.2 g of 2-bromo-3,3,3-trifluoropropene, 30.0 g of potassium carbonate and 0.023 g of 1,3-bis(2,6-diisopropylphenyl) imidazole-2-ylidene(1,4-naphthoquinone) palladium (0) dimer were added and the resultant mixture was stirred at 60° C. in a nitrogen atmosphere for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 100 mL of ice water was added to the reaction mixture, followed by extracting the resultant mixture with ethyl acetate (100 mL×2). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 21.9 g of the objective substance as an orange oily substance.
Reaction SMILES: [CH:1]1([N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:7][CH2:6][CH2:5][N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:17])[CH3:16]
Reactant: NCCN(Cc1ccccc1)C1CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCN(Cc1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
19 g (0.1 mole) of N-cyclopropyl-N-benzylethylenediamine are added at 50° C. to 15.3 g (0.15 mole) of acetic anhydride. When the exothermic phase is over, the mixture is kept for further 30 minutes at 70° C., then cooled down and poured into ice. The organic phase is extracted with toluene and, after drying and evaporation, it gives a residue of gas-chromatographically pure N-acetyl-N'-cyclopropyl-N'-benzylethylenediamine with an almost quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1cc(CN)cc(OC)c1
Solvent: CCN(CC)CC
Product: COc1cc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1

Procedure:
2-Chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,5-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[Cl:16].CI.[C:19]([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[CH3:19][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([Cl:16])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzamide (10.40 g, 30.88 mmol) in THF (200 mL) was added methyl iodide (5.77 mL, 13.15 g, 92.7 mmol) and Cs2CO3 (30.19 g, 92.7 mmol) at −5° C. After 1 h at this temperature, the mixture was heated at 40° C. and stirred over night. Water was added and the mixture was extracted three times with MTBE. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by filtration over a short plug of silica gel to give the title compound (8.25 g), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccnc(Cl)c1
Product: N#Cc1cc(-c2ccnc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light yellow solid (72 mg, 86%), MS (ISP) m/z=337.3 [(M+H)+], mp 286.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[CH3:27][C:25]1[CH:24]=[CH:23][C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[CH2:13][C:14]=2[CH:26]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
5.4 g of 1-carbethoxy-4-(10,11-dihydro-2-methyl-dibenzo-[b,f]thiepin-10-yl)-piperazine, 80 ml of ethylene glycol, 4.64 g of potassium hydroxide and 0.33 ml of water and heated for 0.75 hour at 160° C. Then the mixture is poured on to water, extracted with ether, the extracts washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There is obtained 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:51])[N:33]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])[C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28].O>O1CCCC1>[C:27]([O:31][C:32](=[O:51])[N:33]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]([C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:41])=[C:36]([F:42])[N:35]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ncnc2c1c(C(O)c1ccc(N(Cc3ccccc3Cl)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 5 °C
Yield: 92.9 %

Procedure:
To a solution of 7-benzenesulfonyl-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (42, 0.408 g, 0.983 mmol) in 4.0 mL of tetrahydrofuran at −50° C. under an atmosphere of nitrogen, isopropylmagnesium chloride (0.500 mL, 2.00 M in tetrahydrofuran, 1.00 mmol) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, cooled to −45° C. and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (19, 0.240 g, 0.658 mmol) in 2.0 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over an hour, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (44, 0.400 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[C:34]1[CH:44]=[CH:43][C:37]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:34]2[N:35]=[CH:36][C:37]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[CH:43][CH:44]=2)=[N:6][CH:7]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: CCNC(=O)c1ccc(Br)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)nc1
Reaction time: 0.17 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.03 g, 0.09 mmol) in 0.6 ml of THF was added 1M NaHMDS in THF (0.11 ml, 0.11 mmol). After 10 min at rt, 6-bromo-N-ethylnicotinamide (0.02 g, 0.08 mmol) was added. After 3 h, a drop of water was added to the reaction and purified by reverse phase HPLC to give 6-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)-N-ethylpyridine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.4 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.08 (m, 2H), 7.96 (dd, J=8.6, 2.6 Hz, 1H), 7.48 (dd, J=8.4, 2.6 Hz, 1H), 7.13 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.8 (d, J=8.8 Hz, 1H), 5.94 (s, 1H), 5.48 (s, 2H), 3.46 (m, 2H), 1.24 (t, J=7.3 Hz, 3H); HRMS exact mass calc for C23H18ClFN4O3S [M+H]+: 485.0845; observed: 485.0854.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1- oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesuihfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:11]([CH:10]=1)[C:12]#[N:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C#N)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C#N)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 3-benzyloxy-4-methoxybenzonitrile (43.8 g, 0.18 mol) in glacial acetic acid (87 ml) was added dropwise to concentrated nitric acid (70% w/w, 244 ml) with periodic cooling to maintain the reaction temperature below 30° C. Once the addition was complete, the reaction was stirred for a further 30 minutes, after which time the mixture was poured into water (11) and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water and dried under reduced pressure at 50° C. to afford the subtitle compound as a white solid (35.1 g, 68%). Rf 0.70 (EtOAc:hexane 1:1, v/v).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([NH2:27])(C)C.[OH-].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C1(C)C=CC=CC=1.C(O)(C)C.C(OCC)C.O>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH:31]([CH:2]([NH2:27])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:32])[CH3:30]
Reactant: O=C1c2ccccc2C(OCCCCCCl)N1c1ccccc1
Reactant: CC(C)N
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)C(N)CCCCOC1c2ccccc2C(=O)N1c1ccccc1

Procedure:
A solution of 3-(5-chloropentyloxy)-2-phenyl-isoindolin-1-one (31.6 g.) and isopropylamine (83 cc.) in toluene (50 cc.) is heated in an autoclave at 140°C. for 48 hours. After cooling, the reaction mixture is poured into water (200 cc.) and diethyl ether (200 cc.). The organic phase is separated. The aqueous solution is washed with diethyl ether (2 × 55 cc.). The organic solutions obtained are combined and washed with water (5 × 25 cc.) and are then extracted with 4N hydrochloric acid (3 × 35 cc.). The acid solutions obtained are combined and rendered alkaline by adding 10N sodium hydroxide solution (45 cc.). The resulting insoluble oil is extracted with methylene chloride (3 × 80 cc.) and the organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. An oil (30 g.) is obtained and is dissolved in isopropanol (250 cc.). Fumaric acid (9.3 g.) is added to the solution and the mixture is then heated to the boiling point. A slight amount of insoluble matter is removed by carrying out a hot filtration. The product which crystallises on cooling is filtered off and then washed with isopropanol (50 cc.) and acetone (50 cc.). After drying, 3-(5-isopropyl-aminopentyloxy)-2-phenyl-isoindolin-1-one hydrogen fumarate (30.6 g.), which melts at 150°C., is obtained.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=1)([O-:7])=[O:6].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:17]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:16]=2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: N=C(N)Nc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Yield: 53.3 %

Procedure:
4-Nitrophenyl-guanidine nitrate (20 g, 0.08 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (11.75 g, 0.06 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(4-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (9.38 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)s1
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)s1

Procedure:
In a manner similar to Example 1(d), by reaction of 1.6 g (7 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 1.4 g (7 mmol) of allyl 5-hydroxymethyl -2-thiophenecarboxylate, 1.5 g (55%) of allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3]1.C([O:30][C:31](=O)[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])C>>[Cl:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:31]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:30])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)NS(C)(=O)=O
Reactant: N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Product: CS(=O)(=O)NC(=O)N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 8.1 %

Procedure:
N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 31) (0.15 g) and (methylsulfonyl)-carbamic acid ethyl ester (0.065 g) were heated with a single mode microwave in a sealed 10 mL vial for 30 minutes at 130° C. The residue was purified on a Varian® NH2 cartridge washed with methanol (50 mL) and eluted with acetic acid:methanol (10:90) to afford the title product (0.016 g).