Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[CH:21]=O)[CH:9]=2)[N:3]=1.[CH3:23][NH:24][C:25]1[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.CC(O)=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:24]([CH3:23])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N:31]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)nc(C(F)(F)F)n2)n1
Reactant: CNc1ccccc1N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the mixture of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropanecarbaldehyde (16-6, 280 mg, 0.899 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (0.11 mL, 0.989 mmol, 1.1 eq.) in anhydrous ethanol (5.0 mL) at room temperature was added glacial AcOH (0.062 mL, 1.08 mmol, 1.2 eq.) followed by anhydrous CuSO4 (158 mg, 0.989 mmol, 1.1 eq.). The resulting brownish mixture was stirred at room temperature for 4 hours under an atmosphere of nitrogen gas. The mixture was concentrated in vacuo and neutralized with 7 M NH3 in methanol (1.0 mL). Then it was filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (16-7) as a light brown solid. 1H NMR (300 MHz, CDCl3) 8.07 (s, 1H), 7.74-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 3.08-2.99 (m, 1H), 2.98-2.88 (m, 1H), 2.93 (s, 3H), 2.42 (s, 3H), 2.13-2.02 (m, 2H). LRMS m/z (M+H) 414 found, 414 required. m.p. 151-153° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:36]>C1(C)C=CC=CC=1.O>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:36])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCBr
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a stirred solution of compound 2 (1 g, 4.61 mmol) in toluene (30 mL) were added Ph3P (1.81 g, 6.91 mmol) and CBr4 (2.29 g, 6.91 mmol) at RT under inert atmosphere and stirred for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×60 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude. The crude was purified (silica gel; 20% EtOAc/hexanes) to afford compound 3 (1 g, 78%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.51 (br s, 1H), 3.40 (t, J=6.8 Hz, 2H), 3.13-3.08 (m, 2H), 1.89-1.82 (m, 2H), 1.52-1.42 (m, 13H), 1.37-1.31 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:42][C@@H:43]([CH3:60])[CH2:44][N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:57]=[C:56]([F:58])[C:53]([C:54]#[N:55])=[C:52]([Cl:59])[CH:51]=2)=[N:46]1>C(Cl)Cl>[Cl:59][C:52]1[CH:51]=[C:50]([C:47]2[CH:48]=[CH:49][N:45]([CH2:44][C@@H:43]([NH:42][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)=[O:11])[CH3:60])[N:46]=2)[CH:57]=[C:56]([F:58])[C:53]=1[C:54]#[N:55]
Reactant: O=C(O)c1ccn(C2CC2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(C2CC2)n1
Reaction time: 8 h

Procedure:
1-Cyclopropyl-1H-pyrazole-3-carboxylic acid (0.30 g, 1.29 mmol) was dissolved in DCM (20 ml). EDCI (0.692 g, 3.61 mmol), HOBt (0.487 g, 3.61 mmol) and DIPEA (0.932 g, 7.22 mmol) were added at 0° C. to the solution. The resulting mixture was stirred at 0° C. for 15 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.502 g, 1.8 mmol) dissolved in DCM (2 ml) was added and the mixture was stirred overnight. The reaction mixture was quenched by the addition of water and extracted with DCM. The organic layer was evaporated and the residue was purified by flash chromatography. Yield: 400 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.97-1.17 (m, 7H), 3.74-3.80 (m, 1H), 4.26-4.41 (m, 3H), 6.53 (d, 1H), 7.01 (d, 1H), 7.82-7.87 (m, 3H), 7.96 (s, 1H), 8.14 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2)CC1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Yield: 546.6 %

Procedure:
To a solution of tert-butyl 4-(4-bromophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.30 mmol) in EtOAc was added Rh/C (8 mg, 0.03 mmol). The resulting reaction mixture was stirred at rt in a hydrogen atmosphere for 17 h. The mixture was filtered through a cake of Celite and the filtrate was concentrated to give the title compound as a colourless oil (558 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 4.27-4.23 (m, 2H), 2.79 (t, J=12.9 Hz, 2H), 2.65-2.58 (m, 1H), 1.82-1.79 (m, 2H), 1.64-1.56 (m, 2H), 1.49 (s, 9H); MS ESI 361.9 [M+Na]+, calcd for [C16H22BrNO2+Na]+ 362.07.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2([CH2:13][CH2:12]2)[O:10][C:9](=[O:14])[C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:17][CH:16]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:35]1[CH:40]=[CH:39][C:38]([C:7]2[C:11]3([CH2:12][CH2:13]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1OC2(CC2)C(OS(=O)(=O)C(F)(F)F)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OC2(CC2)C(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a room temperature, stirred solution of 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (200 mg, 0.4 mmol) in 1,4-dioxane (10 mL) were added pyridin-4-ylboronic acid (74 mg, 0.6 mmol), Na2CO3 (102 mg, 1.2 mmol) and water (4 mL) under an inert atmosphere. The mixture was stirred for 30 minutes and then Pd(PPh3)4 (46 mg, 0.04 mmol) was added and the mixture refluxed for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (30 mg, 18%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64-8.61 (m, 2H), 8.40 (d, J=7.2 Hz, 1H), 8.02-7.99 (m, 2H), 7.81-7.77 (m, 1H), 7.67-7.51 (m, 3H), 7.38-7.24 (m, 5H), 5.36 (s, 2H), 1.88-1.85 (m, 2H), 1.24-1.21 (m, 2H). MS: M+H: m/z=421.2; M+Na: m/z=443.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.IN1[C:26](=[O:27])CCC1=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([O:27][CH3:26])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
4.8 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine, 8.4 g of N-iodosuccinimide, 5.2 g of potassium carbonate and 120 ml of methanol were stirred at 23° C. for 20 hours. Most of the methanol was removed by distillation and then a solution of 7 g of Na2S2O3 pentahydrate in 200 ml of water was added, after which the mixture was extracted three times with 100 ml of tert-butyl methyl ether each time. The combined organic phases were washed with 50 ml of water, dried over sodium sulfate and concentrated. Yield: 4.9 g (93%) of a colorless oil;
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:14][CH2:15][CH2:16][SH:17].Cl.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:1]2[NH:14][CH2:15][CH2:16][S:17]2)[CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[OH:8]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: NCCS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C2NCCS2)cc(OC)c1O
Yield: 44.4 %

Procedure:
In a solvent including an ethyl alcohol (2 mL) and water (2 mL), a mixture including syringaldehyde (100 mg, 0.55 mmol), cysteamine.HCl (93.2 mg, 0.82 mmol), and sodium acetate (72 mg, 0.88 mmol) was stirred at room temperature for 4 hours. The produced precipitate was filtered and washed with water and methylene chloride to obtain a solid target product Compound 80.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(C)cc(c23)C1=O
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(C)cc(c23)C1=O
Yield: 96.2 %

Procedure:
Following the procedure of Example W1, 2-allyloxy-5-methyl-7-nitro-benzo[de]isoquinoline-1,3-dione (0.52 g, 1.7 mmol, from Example 12), pyrrolidine (0.23 g, 3.2 mmol), triethyl amine (0.65 g, 6.4 mmol) in DMF (5 mL) were reacted to give 0.55 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:15])[NH:7][C:6]=2[N:5]=[C:4]([NH:16]C(=O)C(C)(C)C)[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([NH:29][CH3:30])=[CH:27][CH:26]=1.C(O)(C)C>Cl.CC(C)=O.CO>[Cl:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]1[C:2]([N:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH3:30])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[NH:7]2
Reactant: CNc1ccc(OC)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(N)nc3[nH]c4cccc(Cl)c4c23)cc1
Temperature: 115 °C
Yield: 69 %

Procedure:
To 10 (20 mg, 0.06 mmol) was added 4-methoxy-N-methyl aniline (61 mg, 0.44 mmol), 50 mL of Isopropanol, and 4 drops of conc. HCl in a 100 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 26 hours, following which the Isopropanol was evaporated and the mixture was basified with ammonia in methanol to obtain a slight precipitate. The resulting precipitate was then dissolved in acetone and methanol. To the solution was added silica, and the solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform and 1% methanol in chloroform. Fractions containing the product AAG13 (TLC) were pooled and evaporated to give a solid which was further purified by washing with hexane. The overall yield was 69%. TLC Rf 0.25 (chloroform-methanol 20:1), m.p. 163-164° C., 1H NMR: δ 3.30 (s, 3H, OCH3), 3.66 (s, 3H, N—CH3), 6.55 (s, 2H, NH2, exch), 6.76-7.25 (m, 7H, ArH), 11.65 (s, 1H, 9-NH, exch). Anal. Calculated (C18H16ClN5O. 0.2 CH3(CH2)4—CH3): C, 62.15; H, 5.10; N, 18.87; Cl, 9.55. Found: C, 61.79; H, 4.95; N, 18.72; Cl, 9.48.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:31]([O:38][C:39](=[O:51])[CH2:40][NH:41][CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:51])[CH2:40][N:41]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CNC1Cc2ccccc2C1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-valine (4.35 g) and triethylamine (2.13 g) in dry CH2Cl2 (40 ml) was added isobutyl chloroformate (2.87 g) at -20° C. After being stirred at same temperature for 30 minutes, a solution of N-(2-indanyl)glycine benzyl ester (5.37 g) in dry CH2Cl2 (20 ml) was added at -20° C. The reaction mixture was stirred at -10° C. for one hour then at room temperature for 4 hours. After the reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (100 ml×2). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure The residue was purified with silica gel (50 g) column chromatography (CHCl3 :AcOEt=10:1) to give N-(tert-butoxycarbonyl)-L-valyl-N-(2-indanyl)glycine benzyl ester (2.20 g) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[C:4](=[O:20])[NH:5][C@@H:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:7]([O:9]C)=[O:8])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:3]([CH2:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[C:4](=[O:20])[NH:5][CH:6]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCN(CCc1c[nH]cn1)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CCc1c[nH]cn1)C(=O)NC(Cc1ccc(OC)cc1)C(=O)O
Temperature: 100 °C
Yield: 69.4 %

Procedure:
150 mg (0.4 mmol) of methyl(S)-2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionate are diluted in 4 mL of THF and 1 mL of water, and 150 mg (6 mmol) of lithium hydroxide are added. The mixture is heated for 10 minutes at 100° C. in a microwave reactor. The solvents are evaporated off and the residue is then purified on a pad of silica (eluent: 1/1 dichloromethane/methanol). 100 mg of 2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionic acid in the form of a pale yellow powder are obtained in a yield of 69%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:29])=[CH:7][C:8]([CH3:28])=[C:9]([C:11]2[NH:27][C:14]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:4].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH:12]1[C:13]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][C:14]=2[N:27]=[C:11]1[C:9]1[C:8]([CH3:28])=[CH:7][C:6]([CH3:29])=[C:5]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(=O)OC(C)(C)C)CC3)c(C)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate (compound 83.3, 800 mg, 2.00 mmol) in dichloromethane (16 mL). Trifluoroacetic acid (4 mL) was added drop-wise and the resulting solution was stirred for 5 h at room temperature. The pH of the solution was carefully adjusted to 8-9 with NaHCO3 (sat.) and the aqueous phase was extracted with DCM (3×30 mL), and the combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.60 mg (crude) of the title compound as brown oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:10]>>[NH:10]=[C:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: N
Product: CCOC(=O)CC(C)=N
Yield: 85 %

Procedure:
A solution of ethyl acetoacetate (50 g, 385 mmol, 1.0 eq) in 25% aqueous ammonia (300 mL) was stirred at room temperature for 1 h then extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to give ethyl 3-iminobutanoate (42 g, 85%) as a yellow oil, which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26]CCC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].C(O)(=O)C(O)=O>C(O)(=O)C>[CH3:26][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CN(C(=O)c1cnc(N2CCNC2=O)nc1N)c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 2.66 g (7 mmol) of a compound II (R1, R2, R3, R5, R6 =H; R4 =CH3), 0.72 g (8 mmol) of anhydrous oxalic acid and 4.5 ml of glacial acetic acid was stirred at 85° for 1 hour and subsequently worked up as in Example 5. 1.58 g (=59.4% yield) of TLC-pure 4-amino-2-(2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 249°-250°.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccc(F)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-fluorophenyl magnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-fluoro-phenyl)-methanone. MS (M+H)+, 278.
Reaction SMILES: [CH:1]1([C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](O)[CH2:12][OH:13].Cl[Si](C)(C)C>>[CH:1]1([C:6]2([CH2:7][C:8]#[N:9])[O:13][CH2:12][CH2:11][O:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Product: N#CCC1(C2CCCC2)OCCO1
Yield: 59.1 %

Procedure:
According to the procedure described in Example 133A Step 2, 3-cyclopentyl-3-oxopropanenitrile (2 g, 14 mmol) was added to a mixture of ethylene glycol (2.4 mL, 44 mmol) and chlorotrimethylsilane (5.5 mL, 44 mmol) to give 2-(2-cyclopentyl-1,3-dioxolan-2-yl)acetonitrile (1.5 g, 60%). 1H NMR (300 MHz, CDCl3) δ 4.23-4.15 (m, 2H), 4.12-4.01 (m, 2H), 2.72 (s, 2H), 2.42-2.30 (m, 1H), 1.81-1.45 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>C1COCC1>[OH:9][CH2:8][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Solvent: C1CCOC1
Product: CN1C[C@H](CO)C[C@H]1COc1cccnc1

Procedure:
A 1.0 g (4.2 mmol) sample of 3-((-1-methyl-4-hydroxymethyl-5-oxo-2(S)-pyrrolidinyl)methoxy)pyridine, from step 48a above, was dissolved in 15 mL of anhydrous THF, 12.7 mL of BH3 was added, and the mixture was heated at reflux for 2.5 hours. The reaction was quenched with methanol, the solvent was evaporated, and the residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent and purification of the residue on a silica gel column, eluting with 100:8 to 10: 1 chloroform:methanol gave 600 mg of the title compound as a mixture of cis and trans product.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH:35][CH:36]1[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]([O:35][CH:36]4[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min).