Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:29])[NH:13][C:14](=[O:28])[C:15]=1[C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:29])[NH:13][C:14](=[O:28])[C:15]=1[C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([CH:26]=[CH:27][N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(c1)CCN3CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(ccn3CCC2)c1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of 3-(5-bromo-1H-indol-3-yl)-4-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione (300 mg, 0.668 mmol) in anhydrous tetrahydrofuran (15 ml) at room temperature was treated with 2,3-dichloro-5,6-dicyano-p-benzoquinone (182 mg, 0.802 mmol) and stirred for 30 minutes. The reaction was treated with 10% aqueous sodium sulfite (40 ml) and diluted with water (50 ml) and ethyl acetate (50 ml). The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) then water (2×50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 1% methanol to 10% methanol in dichloromethane) to provide 3-(5-bromo-1H-indol-3-yl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione as an orange solid (255 mg). 400 MHz 1H NMR (DMSO-d6) δ: 11.94 (s, 1H), 10.95 (s, 1H), 7.99 (s, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.33 (m, 2H), 7.08 (dd, J=6.8 and 1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 6.34 (d, J=2.8 Hz, 1H), 6.20 (d, J=2.0 Hz, 2H), 4.17 (m, 2H), 2.75 (m, 2H), 2.12 (m, 2H); LCMS: 446 and 448 [M+H].
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[CH:5]1([CH2:4][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24](=[O:25])[N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=3[CH3:44])=[CH:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCCc1nc(C)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (bromomethyl)cyclopropane (0.17 mL), cesium carbonate (1.7 g) and 4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (0.56 g, 100%).
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].N[CH:6]1[CH:11]2[CH:7]1[CH2:8][N:9]([C:12]([C:14]1[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=1)=[O:13])[CH2:10]2.C=O.[CH3:26]C(O)=O>CC#N>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH:11]4[CH:7]([CH:6]4[N:3]([CH3:2])[CH3:26])[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC12
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Temperature: 25 °C
Yield: 16 %

Procedure:
NaBH3CN (211 mg, 3.36 mmol) was added to a solution of (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-methanone (250 mg, 0.85 mmol) and formaldehyde (1.14 mL, 17 mmol) in CH3CN at 0° C. After 30 min AcOH (0.5 mL) was added and the reaction mixture was allowed to warm to room temperature. After 1 h the reaction mixture was concentrated, and the resulting residue was dissolved in H20. The resulting aqueous layer was adjusted to pH 9 with 6N NaOH. The resulting solution was extracted with CH2Cl2 (2×) and the combined organic extracts were dried over Na2SO4, filtered, then concentrated. The resulting material was purified on silica gel by flash column chromatography CH2Cl2/MeOH (85/15) to afford the title compound as a white solid (44 mg, 16%). MS: 322.2/324.2 (MH+); HPLC Rf: 3.62 min.; HPLC purity 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C@@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH2:8].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:8][C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1cccc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-methoxyphenylalaninate (526 mg, 2.35 mmol), 2-(tert-butoxycarbonylamino)acetic acid (454 mg, 2.59 mmol, Sigma-Aldrich, St. Louis, Mo.), HATU (1.07 g, 2.82 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.819 mL, 4.71 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature for 2 h then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc in hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-methoxyphenylalaninate (822 mg).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[C:30]([N+]([O-])=O)[CH2:31][CH:32]2[O:36][CH2:35][CH2:34][O:33]2)=[CH:25][CH:24]=1>CCN(CC)CC>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][C:19]1[C:30]([CH2:31][CH:32]2[O:36][CH2:35][CH2:34][O:33]2)=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isopropylhydrazine hydrochloride (1.07 g, 9.7 mmol) and (3-oxo-propyl)-carbamic acid benzyl ester (2.0 g, 9.7 mmol) in Et3N (20 mL) was heated at 60° C. After 1 h, 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (2.2 g, 8.7 mmol) was added. After 16 h at 60° C., the mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated. Purification by FCC gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19]C2C=CC=CC=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2N=N1.[CH2:51]([NH:54][CH2:55][C:56]#[CH:57])[C:52]#[CH:53]>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:54]([CH2:55][C:56]#[CH:57])[CH2:51][C:52]#[CH:53])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCNCC#C
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#CCN(CC#C)C(=O)c1cc(C(=C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (Example 1 Step 6) (1 equivalent) in dichloromethane (10 ml) was treated successively with N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 equivalents), 1-hydroxybenzotriazole (1.2 equivalents) and dipropargylamine (1.5 equivalents) and the mixture was stirred at room temperature overnight. The mixture was washed successively with 2M hydrochloric acid and 2M sodium hydroxide, the organic layer was separated and the solvent removed in vacuo to afford the product which was either obtained pure or was purified by column chromatography on silica (eluting with mixtures of ethyl acetate in petroleum ether or methanol in ethyl acetate as appropriate). MS: [M+H]+ 450
Reaction SMILES: [C:1]([OH:9])(=[O:8])C1C=CC=CC=1.Br[C:11]1[CH:12]=[CH:13][C:14]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:16]=1>>[C:25]([C:14]1[CH:13]=[CH:12][C:11]([C:1]([OH:9])=[O:8])=[CH:16][C:15]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Product: Cc1ccc(Oc2cc(C(=O)O)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 4-tert-butyl-3-(4'-trifluoromethyl)phenoxy]benzoic acid (Compound P), 1.02 g (3.2 mmol) of 5-bromo-2-tert-butyl-1-[(4'-methyl)phenoxy]benzene (Compound J) was converted into the title compound using 4.7 mL (8.0 mmol) of tert-butyllithium solution (1.7M in pentane) and 10 mL of tetrahydrofuran. Purification by flash chromatography (silica, 3% methanol in chloroform) gave the title compound as a creme solid.
Reaction SMILES: ClC1C=[CH:6][C:5]([C:8]2[N:9]=C3C=CC=CN3C=2CC2NC(C3C=CC=CN=3)=NN=2)=[CH:4]C=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:36]([CH2:45][C:46]([NH:48][NH2:49])=O)=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:38]=2)[CH:35]=1.Cl.C(=N)(N)C(C)C>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:36]([CH2:45][C:46]3[NH:9][C:8]([CH:5]([CH3:6])[CH3:4])=[N:49][N:48]=3)=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:38]=2)[CH:35]=1
Reactant: NNC(=O)Cc1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Agent: CC(C)C(=N)N
Agent: Cl
Product: CC(C)c1nnc(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)[nH]1

Procedure:
The title compound was prepared according to the experimental described for compound 230 from 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetohydrazide and isobutyrimidamide hydrochloride. M/e+ 352 for C19H19ClN5 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.29 (m, 5H), 7.00 (dd, J=9.5, 1.8 Hz, 1H), 4.40 (s, 2H), 3.03 (m, 1H), 1.29 (s, 3H), 1.28 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C1Cc2cc(F)cc(Br)c2N1
Yield: 86.9 %

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one 4a (1.5 g, 0.01 mol) was dissolved in 15 ml of acetonitrile under stirring, and added dropwise with N-bromosuccinimide (1.8 g, 0.01 mol) at room temperature. Upon completion of the addition, the mixture was stirred overnight and lots of precipitate was formed. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered to obtain 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b (2 g, yield 87%) as a gray solid.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][C:8]([S:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>ClCCl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:3][C:2]([CH3:5])([CH3:4])/[CH:1]=[N:13]/[S:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)C=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Product: CC(C)(C)/C=N/S(=O)C(C)(C)C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of pivalaldehyde (2 g, 2.56 ml, 23.2 mmol) in dry dichloromethane (150 mL) under argon atmosphere was added 2-methylpropane-2-sulfinamide (3.38 g, 27.9 mmol) and titanium (IV) ethoxide (6.36 g, 5.84 ml, 27.9 mmol) to give a colorless solution. The reaction mixture was stirred at r.t overnight and quenched by slow addition of water while the reaction still stirring until a precipitate formed. The reaction mixture was then filtered through a pad of celite. The filtrate was extracted with water, the organic phase was collected, dried over Na2SO4 and evaporated down in vacuo to give the title compound (3.6 gr, 82%) as crude oil. The crude was used without any further purification for the next step, MS (EI): m/e=190.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:24][C:25]1([CH3:38])[S:30][CH2:29][CH2:28][NH:27][C@H:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN1CCOCC1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:27]2[CH2:28][CH2:29][S:30][C:25]([CH3:24])([CH3:38])[C@@H:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1NCCSC1(C)C
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a suspension of 20.0 g (0.104 mol) of 4-hydroxybenzenesulfonyl chloride in 200 mL of chloroform was added 28.25 mL (0.114 mol) of bis(trimethylsilyl)acetamide and the reaction was stirred at room temperature for 1 h, after which all of the solids have dissolved. To this mixture was added 20.0 g (0.087 mol) of tert-butyl (3S)-2,2-dimethyl-3-thiomorpholine carboxylate followed by 19.2 mL of 4-methylmorpholine and the reaction was stirred overnight at room temperature. After the addition of 400 mL of methanol to the reaction, the resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with water and 5% HCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting white solid was washed with ether/hexanes (1:2) and dried in vacuo to give 28.4 g (85%) of tert-butyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a white solid. Electrospray Mass Spec 386.5 (M−H)−.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[CH:10]([NH2:17])(N)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([N:20](CC)CC)C>CO>[C:5]([C:4]([NH:20][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH2:17])=[O:9])([F:6])([F:7])[F:8]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCCCCC(N)N
Solvent: CO
Product: NCCCCCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
N -1-trifluoroacetylhexanediamine, (CF3CONH(CH2)6NH2) is prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of hexanediamine (1.16 g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution is stirred overnight. After removal of solvents, the reaction mixture is flash chromatographed on silica using 0-25% methanol in dichloromethane. The fractions containing the desired product are pooled and concentrated to give a colorless powder (1.1 gm, yield--42.6%); melting point 52C°; 1H NMR (CDCl3, d, TMS=) 0.00) 7.1-7.2 (m, 3H, NH2, NH) 3.2-3.3 (m, 2H, CO--NH--CH2), 2.8-2.9 (m 2H, CH2 --NH2) 1.2-1.6 (m, 8H, --CH--(CH2)2 --CH2 --).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.ClC(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]#[N:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(N)=O)cc1
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(C(C)C#N)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
4-isobutyl-α-methylphenylacetamide (2 g; 9.7 mmol), prepared according the procedure described in WO 00/24710, is dissolved in a solution (2:1) toluene/trichloromethane (30 mL). 20% in toluene phosgene (15.5 mL, 30 mmol) is added and the resulting mixture is left stirring 12 h under inert atmosphere until the complete disappearance of the starting reagent. After solvents evaporation under reduced pressure, the crude is dissolved in ethyl acetate (20 mL), the organic phase is washed with a saturated solution of NaHCO3 (2×20 mL) and with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4-isobutylphenyl)propionitrile as colourless oil (1.45 g; 7.76 mmol). Yield 80%. 1H-NMR (CDCl3): δ 7.42 (d, 2H, J=7 Hz); 7.28 (d, 2H, J=7 Hz); 4.05 (q, 1H, J=8 Hz); 2.65 (d, 2H, J=8 Hz); 1.95 (m, 1H); 1.80 (d, 3H, J=8 Hz); 1.05 (d, 6H, J=8 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:43]=[C:44](C(OC)=O)[CH:45]=1)[C:5]([NH:7][C@@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)[C@@H:9]([C@H:18]1[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][CH3:26])[CH2:20][N:19]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[O:6].NC1C=C(C=C([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])C=1)C(O)=O.C([O:69][C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1)C=C>[Pd].CO>[Si:11]([O:10][C@H:9]([C@H:18]1[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][CH3:26])[CH2:20][N:19]1[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C@@H:8]([NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:45]=[C:44]([OH:69])[CH:43]=1)[CH2:34][C:35]1[CH:36]=[C:37]([F:42])[CH:38]=[C:39]([F:41])[CH:40]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:12])[CH3:13]
Reactant: C=CCO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(Br)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(O)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
Step I (3): 3-Amino-5-(2-oxopyrrolidin-1-yl)benzoic acid. A suspension of 3-nitro-5-(2-oxopyrrolidin-1-yl)benzoic acid (Step I (2), 180 mg) and palladium on carbon (10 wt %, 50 mg) in MeOH (15 mL) was shaken in hydrogenator under hydrogen at 50 psi for 3 h. The mixture was filtered and concentrated in vacuo to give 140 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 2.16 (2H, m), 2.59 (2H, m), 3.89 (2H, t, J=5 Hz), 7.21 (1H, m), 7.26 (1H, m), 7.49 (1H, m). MS (ESI) (M+H)+ 221.14.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ncccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 388 as an off-white solid (120 mg, 74% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.42 (s, 1H), 7.85 (t, J=9.8 Hz, 1H), 7.64 (s, 1H), 7.50-7.44 (m, 1H), 4.85 (d, J=47.3 Hz, 1H), 3.64 (s, 3H), 3.40-3.22 (m, 3H), 3.23-2.83 (m, 2H), 2.31-2.01 (m, 1H), 2.04-1.66 (m, 2H), 1.92-1.48 (m, 1H). Exchangeable NH2 (×2) and NH not observed. LCMS (ES+) m/z 449 (M+1)
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:52]1[S:53][CH:54]=[CH:55][N:56]=1)CCC>CN(C)C=O.C(Cl)(Cl)Cl.[Ag-]=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>[NH2:20][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[CH:17][CH:18]=1)[CH2:10][C@H:9]([O:31][Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:34])[CH3:33])[C@@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](N)Cc1ccc(-c2nccs2)cc1)O[Si](C)(C)C(C)(C)C
Yield: 130.1 %

Procedure:
To a solution containing the product from Example 92D (0.050 g, 0.070 mmol) in N,N-dimethylformamide (1.8 mL) were added silver(I) oxide (0.016 g, 0.070 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.003 mmol), and 2-tributylstannylthiazole (0.126 g, 0.337 mmol), and the mixture was irradiated at 60 W in a microwave (internal temperature reached 100° C.) for 2 minutes. The mixture was then irradiated at 200 W in a microwave (internal temperature reached 100° C.) for 4 minutes The reaction was cooled, diluted with chloroform and washed with dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 30% methanol in chloroform containing 0.2% ammonium hydroxide to give the title compound (0.053 g).
Reaction SMILES: O.[OH-].[Li+].[NH:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:27])[NH:12][C@@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:14]([O:16]C)=[O:15])[N:6]=[CH:5]1.C(O)(=O)C>O1CCCC1.O>[NH:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:27])[NH:12][CH:13]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:14]([OH:16])=[O:15])[N:6]=[CH:5]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCc1c[nH]cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CC(NC(=O)NCc2c[nH]cn2)C(=O)O)cc1
Temperature: 100 °C
Yield: 9.8 %

Procedure:
351 mg (84 mmol) of lithium hydroxide monohydrate are added to a solution of 278 mg (8.4 mmol) of methyl(S)-2-[3-(1H-imidazol-4-ylmethyl)ureido]-3-(4-methoxy-phenyl)propanoate in 5 mL of tetrahydrofuran and 1 mL of water. The reaction mixture is heated for 10 minutes at 100° C. in a microwave reactor. The reaction is stopped by adding 2 mL of water and 0.5 mL of acetic acid and is then extracted with ethyl acetate. The aqueous phase is concentrated to dryness and the residue is then chromatographed on silica gel (eluent: 7/3 dichloromethane/methanol). 261 mg of 2-[3-(1H-imidazol-4-ylmethyl)ureido]-3-(4-methoxyphenyl)propionic acid in the form of a white foam are obtained in a yield of 98%.