Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14]Br>C(#N)C>[BrH:11].[Br-:1].[Br:11][CH2:12][CH2:13][CH2:14][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: BrCCCBr
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: Br
Product: CN(CCCBr)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.88 g. (14.3 mmoles) of 1,3-dibromopropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give the product.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[C:22]1([C:28]2([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:36]([N:43]1[CH2:47][C@H:46]2[CH:48]([NH2:51])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@H:48]([NH:51][C:33]([C:28]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:35])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Hydroxybenzotriazole (33 mg, 0.24 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43 μL, 0.24 mmol) were added to a solution of 1-phenylcyclopentanecarboxylic acid (46 mg, 0.24 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature for 10 minutes, then (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (52 mg, 0.24 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water, and extracted with dichloromethane, then purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/chloroform as eluent to give the title compounds.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](O)C)(=[O:4])[CH:2]=[CH2:3].COC1C=CC(O)=CC=1.O=C=[N:21]C1CC(C)(C)CC(C)(CN=C=O)C1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:21][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC(C)O
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 50 °C

Procedure:
400 parts by weight of polycaprolactone diol having an average molecular weight of 800, 131 parts by weight of 2-hydroxypropyl acrylate, 0.5 part by weight of dibutyltin dilaurate as a catalyst and 1.0 part by weight of hydroquinone monomethyl ether as a polymerization inhibitor were mixed while heating them to 50° C. with stirring. Then, 222 parts by weight of isophorone diisocyanate was dropwise added, and further the temperature was raised to 80° C. with stirring to carry out urethanation reaction. Making sure that the NCO conversion reached 99% or more, the reaction temperature was dropped to obtain urethane acrylate B.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COc1ccc(N)c(OC)c1
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Product: COc1ccc(Nc2cc3c(-c4cnn(C)c4)cccc3cn2)c(OC)c1
Reaction time: 1.5 h
Yield: 27 %

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2,4-dimethoxyaniline at 80° C. for 1.5 hours followed by 100° C. for 1.5 hours. The reaction mixture was concentrated onto silica gel in vacuo and purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to afford the title compound (22 mg, 27%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24][N:23]([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.[C:73]1(=[O:82])[N:77]([CH2:78][CH2:79][NH2:80])[C:76](=[O:81])[CH:75]=[CH:74]1.Cl>CC#N>[O:82]=[C:73]1[CH:74]=[CH:75][C:76](=[O:81])[N:77]1[CH2:78][CH2:79][NH:80][C:59](=[O:60])[CH2:58][NH:57][C:55](=[O:56])[CH2:54][N:11]([C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:36])[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]1
Reactant: NCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)NCCN2C(=O)C=CC2=O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50-mL round bottom flask loaded with 2-(2-(2-(4-hydroxyphenyl)-N-(2-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)ethyl)acetamido)acetamido)acetic acid 3 (0.113 g, 0.131 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.038 g, 0.198 mmol, 1.5 eq.) and 2-maleimidoethylamine.HCl (0.035 g, 0.198 mmol, 1.5 eq.). The mixture was dissolved in 10 mL of CH3CN and stirred for 12 hours at room temperature. After solvent removal in vacuo, purification was achieved by preparative reverse-phase HPLC (gradient from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water/50% CH3CN) to give 4. 1H-NMR (300 MHz, CDCl3) δ 9.02 (m, 1H), 8.07 (m, 1H), 7.01 (m, 2H), 6.79 (m, 2H), 6.65 (s, 1H), 4.23-2.80 (m, 34H), 1.45 (s, 27H); 13C-NMR (75 MHz, CDCl3) δ 173.67, 173.43, 171.04, 170.33, 170.26, 170.08, 169.94, 169.86, 168.64, 156.55, 156.47, 134.16, 130.33, 130.06, 125.57, 125.09, 115.95, 115.84, 81.93, 81.87, 81.81, 81.70, 56.63, 56.08, 55.90, 53.12, 52.01, 50.95, 49.79, 49.41, 49.39, 47.22, 43.44, 43.07, 39.58, 39.15, 38.25, 38.10, 37.74, 37.34, 28.17.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:48])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40]CC2C=CC=CC=2)=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.C1COCC1.[Pd]>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:48])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@@H:16]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
The product of Step J, 85 mg was dissolved in 10 mL of methanol and 10 mL of THF, and to it was added 0.10 g of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for 48 hours at room temperature, then filtered and concentrated to dryness. The residue was dissolved in 10 mL of hot ethanol and 20 mL water was added. On cooling the white solid precipitate was collected and dried under vacuum over P2O5. The yield was 72 mg (98% yield) of pure product: mp 218°-219° C. (effervesces, sinters at 215) elemental analysis, Calc'd for C33H40N2O6 : (560.696):
Reaction SMILES: CCN(CC)CC.Cl.Cl.[N:10]1([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:25]([O:29][C:30]([NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:35](O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:35](=[O:36])[N:13]1[CH2:12][CH2:11][N:10]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1nc(N2CCNCC2)c2cc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (150 μL, 1.1 mmol) was added to a stirred suspension of 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (100 mg, 0.36 mmol), (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (130 mg, 0.40 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DMF (15 mL) at RT. Stirred at RT overnight. Poured into EtOAc (100 mL), washed with water (100 mL), 1N NaOH (50 mL), dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica (100% EtOAc) to give (S)-{2-(4-Chlorobenzyl)-3-oxo-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propyl}-carbamic acid tert-butyl ester. LCMS (APCI+) m/z 499 [M+H]+; Rt: 2.70 minutes. This was taken up into DCM (50 mL) and stirred with TFA (5 mL) overnight. Poured into EtOAc (100 mL) and washed with 1N NaOH (2×100 mL), dried over Na2SO4 and concentrated in vacuo. Formed HCl salt (Et2O.HCl, 2M in diethyl ether) to give (S)-2-Aminomethyl-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (100 mg, 59%.) LCMS (APCI+) m/z 399 [M+H]+; Rt: 1.82 min. [Free base: 1H NMR (CDCl3, 400 MHz) δ 9.97 (1H, br.s), 8.32 (1H, s), 7.24 (2H, d, J 7.4 Hz), 7.13 (2H, d, J 7.4 Hz), 7.09 (1H, d, J 2.4 Hz), 6.45 (1H, d, J 2.3 Hz), 4.00-3.68 (5H, m), 3.60-3.53 (1H, m), 3.46-3.40 (1H, m), 3.33-3.27 (1H, m), 3.16-3.05 (2H, m), 2.92-2.83 (2H, m), 2.77 (1H, dd, J 13.3 and 5.5 Hz.)]
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#N)[CH:7]=[CH:6][C:5]=1[CH3:12].S(=O)(=O)(O)[OH:15].[OH2:19]>>[CH3:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]([OH:15])=[O:19])=[CH:9][C:4]=1[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1cc(C#N)ccc1C
Reactant: O=S(=O)(O)O
Reactant: O
Product: Cc1ccc(C(=O)O)cc1C(=O)O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
5-Cyano-2-methyl-benzoic acid methyl ester (1.09 g, 6.22 mmol) was suspended in a mixture of water (25 mL) and concentrated sulfuric acid (10 mL). The yellow solution was stirred at 150° C. for 4 hours to give a pale yellow slurry. The reaction mixture was cooled to room temperature and the precipitate was isolated via suction filtration, washed with water (2×10 mL) and dried in vacuo to yield 4-methyl-isophthalic acid as a tan solid. The diacid was then suspended in MeOH (25 mL) and concentrated sulfuric acid (10 mL) and the resulting mixture was stirred at 90° C. for 14 hours to give a bright yellow solution. The MeOH was removed under reduced pressure and the remaining aqueous solution was diluted with brine (60 mL) and EtOAc (50 mL) and then neutralized with 3M NaOH until pH of aqueous layer was approximately 10. The mixture was extracted with EtOAc (3×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give pure 4-methyl-isophthalic acid dimethyl ester as a pale orange solid (1.06 g, 82%, 2-steps). 1H NMR (CDCl3) δ 2.66 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 7.33 (d, 1H, J=9.0 Hz), 8.05 (dd, 1H, J=9.0, 3.0 Hz), 8.57 (d, 1H, J=3.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](/[CH:12]=[N:13]/[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:8]=[CH:7]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:14]1[N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([F:21])[CH:5]=3)[N:10]=2)[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: Fc1cc(Br)c2nc(/C=N/Nc3ccccn3)ccc2c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Fc1cc(Br)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
(E)-1-((8-Bromo-6-fluoroquinolin-2-yl)methylene)-2-(pyridin-2-yl)hydrazine (100 mg, 0.290 mmol) was weighed into a 25 mL 1 neck round bottom flask and suspended in 6.0 mL of DCM, followed by addition of iodobenzene diacetate (103 mg, 0.32 mmol). The reaction was stirred at 23° C. overnight, after which all starting materials had been consumed. The reaction was transferred to a reparatory funnel and partitioned between 30 mL DCM and 30 mL Na2SO3, and the aqueous layer was washed with DCM. The combined organics were dried over magnesium sulfate and concentrated in vacuo to afford a white/yellow powder. The powder was triturated with 10 mL of anhydrous Et2O, affording the desired product as a white solid (74 mg, 74.4% yield). MS APCI (+) m/z 343 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[K+].BrBr.C(#N)C1C=CC=CC=1>C(O)(=O)C.O>[NH2:12][C:11]1[S:10][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccc2nc(N)sc2c1
Reaction time: 16 h

Procedure:
4-Aminobenzonitrile is dissolved in acetic acid (or a weak protic acid) and the solution is cooled to about 16–30° C., preferably 16–18° C. Potassium thiocyanate is added and the flask is then equipped with an addition funnel. The addition funnel is charged with bromine and acetic acid. This dark solution is then added to the benzonitrile solution in a dropwise fashion under good agitation and allowed to stir for about 12–20 hours, preferrably about 16 hours. The slurry is then drowned into water and filtered. The presscake is washed well with water, reslurried in dilute aqueous alkali and filtered. Again the presscake is washed well with water to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[H][H].CO.C(Cl)Cl>C(O)C.[Pd]>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(S(N)(=O)=O)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCCc1cc(S(N)(=O)=O)ccc1O
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A Parr hydrogenation flask was charged with a solution of 3.04 g (14.30 mmol) of the product of Step A dissolved in 25 mL of ethanol and 0.300 g of a 10% palladium on carbon catalyst was added. The flask was mounted in the hydrogenation apparatus, freed of air, pressurized with hydrogen (40 psig) and shaken for 15 minutes. At the end of this period TLC analysis (3% MeOH-CH2Cl2, 2 elutions) indicated that the reaction was complete and the reaction mixture was filtered and evaporated. The product was dried in vacuo to afford 3.06 g (99%) of the title compound. 1H-NMR (400 MHz, CD3OD, ppm): δ 0.94 (t, J=7.20 Hz, 3H), 1.58-1.68 (m, 2H), 2.01-2.62 (m, 2H), 6.82 (d, J=8.40 Hz, 1H), 7.55 (dd, J=2.40, 8.40 Hz, 1H), 7.60 (d, J=2.40 Hz, 1H). FAB-MS m/e=216 (M+1).
Reaction SMILES: ICI.[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH3:28])=[O:26])=[CH2:18])[CH:8]=[CH:7][C:6]1=2.[CH2:30]([Zn]CC)C.CCCCCCC>ClCCl>[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]2[CH:10]=[C:9]([C:17]3([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([O:27][CH3:28])=[O:26])[CH2:30][CH2:18]3)[CH:8]=[CH:7][C:6]1=2
Reactant: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Solvent: CCCCCCC
Product: COC(=O)c1ccccc1C1(c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1
Reaction time: 4 h

Procedure:
Diiodomethane (230 μl, 2.85 mmol) is added dropwise, at 60° C., to a mixture of methyl 2-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (500 mg, 1.44 mmol) and a 1M solution of diethylzinc in heptane (2.9 ml, 2.9 mmol) in dichloromethane (10 ml). The heating is continued for 4 h. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed with 1N HCl solution and then with water, dried over anhydrous magnesium sulfate and concentrated. The same process is repeated once.
Reaction SMILES: [Br:1][CH:2]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:16][N:17]1[CH2:22][NH:21][C:20](=[S:23])[NH:19][CH2:18]1>CO>[BrH:1].[C:4]([CH2:3][CH:2]1[S:23][C:20]2=[N:19][CH2:18][N:17]([CH3:16])[CH2:22][N:21]2[C:7]1([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[OH:15])([OH:6])=[O:5]
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: CN1CNC(=S)NC1
Solvent: CO
Product: Br
Product: CN1CN=C2SC(CC(=O)O)C(O)(c3ccc(Cl)cc3)N2C1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid (7.29 g, 0.025 moles) in methanol (40 ml) was mixed with a solution of 5-methyl-3,4,5,6-tetrahydro-s-triazin-2(1H)-thione (3.27 g, 0.025 moles) in the same solvent (150 ml) and left for one hour. Evaporation of the solvent gave 7-carboxymethyl-6-(p-chlorophenyl)-6-hydroxy-3-methyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide as a pale yellow solid (9.6 g), m.p. 111°-113° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Yield: 9.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (151 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (25.0 mg, 9.6%) as a solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:32][O:33][CH3:34].Cl>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([CH2:32][O:33][CH3:34])[CH2:16][CH2:17][CH2:18][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](CCCBr)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -10 °C
Reaction time: 48 h
Yield: 23.5 %

Procedure:
To a solution (S)-4-benzyl-3-(5-bromopentanoyl)oxazolidin-2-one (4.00 g, 1 eq.) and THF (100 ml) was added NaHMDS (1 M in THF, 53 ml, 4.5 eq.) at −78° C. After 30 min chloro(methoxy)methane (12.3 g, 13 eq.) was added dropwise. The reaction mixture was stirred at −10° C. for 2 days. Concentrated aqueous HCl solution was carefully added. The resulting mixture was concentrated and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Silica gel chromatography using 60-80% DCM-heptane yields the title compound (1.06 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH2:51]([O:53][CH2:54][CH2:55][NH2:56])[CH3:52]>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:56][CH2:55][CH2:54][O:53][CH2:51][CH3:52])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOCCN
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Yield: 32 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (100 mg, 0.28 mmol) was dissolved in a mixture solution of dimethylsulfoxide (2 mL) and N,N-diisopropylethylamine (1 mL), 2-ethoxyethylamine (0.051 mL, 0.49 mmol) was added thereto, followed by heating in a sealed tube for 32 hours 40 minutes (oil bath temperature: 130° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (37 mg, 0.09 mmol, 32%) was obtained.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19](Br)[CH:18]=1>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:18]=1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reaction time: 0.25 h

Procedure:
Triisopropylsilane-thiol (97%, 1.29 mL, 6.0 mmol) in THF (15 mL) was cooled to 0° C. and then sodium hydride (60% in mineral oil, 0.240 g, 6.0 mmol) was added. After 15 minutes, 2-bromo-isonicotinic acid methyl ester (1 g, 4.6 mmol) in toluene was added and the mixture was purged with N2 (g). Tetrakis(triphenylphosphine)palladium(0) (0.531 g, 4.6 mmol) was added and the reaction was heated to reflux. After cooling the reaction was diluted with EtOAc then washed with H2O and brine. The organic portion was dried and concentrated to afford the title compound, which was used in the next step without further purification.