Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5](CCl)[CH:6]=[CH:7][CH:8]=1.[OH:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CS(C)=O>[C:3]1([CH2:2][O:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: FC(F)(F)c1cccc(CCl)c1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH:9]([CH3:13])[C:10](=O)[CH3:11]>>[CH3:13][C:9]1[N:1]=[C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]2[C:10]=1[CH3:11]
Reactant: CC(=O)C(C)Br
Reactant: Nc1cnccn1
Product: Cc1nc2cnccn2c1C

Procedure:
Similarly, condensation of the 2-aminopyrazine with 3-bromo-2-butanone gives the 2,3-dimethylimidazo[1,2-a]pyrazine as shown in the following reaction Scheme IV. ##STR16##
Reaction SMILES: Cl/[C:2](/[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[CH:3]/[CH:4]=O.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[O-]CC.[Na+]>CCO.CCOC(C)=O>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:2]2[S:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=2)=[CH:7]1
Reactant: O=C/C=C(/Cl)c1c[nH]c2ncccc12
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2c[nH]c3ncccc23)s1
Yield: 74 %

Procedure:
(E)-3-chloro-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylaldehyde (0.9 g. 4.3 mmol) was dissolved in EtOH (20 mL) and ethyl 2-mercaptoacetate (0.76 g, 6.3 mmol) and sodium ethoxide (1.0 g, 14.7 mmol) were added. The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a solid, which was purified by column chromatography on silica (20 to 100% EtOAc/hexanes) to give the product, 890 mg, 3.3 mmol, 74% yield. 1H NMR 500 MHz (DMSO-d6) 12.19 (1H, br s), 8.32 (2H, m), 8.13 (1H, s), 7.78 (1H, d), 7.48 (1H, d), 7.23 (1H, dd), 4.31 (2H, q), 1.30 (3H, t).
Reaction SMILES: BrC1C(F)=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:37])[C:32]=2[Br:36])[CH:27]1[CH2:38][C:39]([O:41]C)=O)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>O.CO>[Br:36][C:32]1[C:31]([F:37])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH2:34][CH2:35][N:26]1[C:23](=[O:25])[CH2:24][NH:6][C:39](=[O:41])[CH:38]=[C:27]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1NCCc2c1ccc(F)c2Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL, 1383 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (47.6 g, 138 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (244 g) in water (500 mL). The slightly basic aqueous solution was extracted with AcOEt (3×). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (41.58 g) which was used without further purification. UPLC-MS: MS 302.1/304.1 (M+H+); UPLC rt 0.51 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH3:2][N:3]([CH2:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)[CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CNCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCN1C(=O)c2ccccc2C1=O)Cc1ccc2ccccc2n1
Reaction time: 16 h

Procedure:
To the HCl salt of 2-(2-methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added quinoline-2-carbaldehyde (1.2 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (1.2 eq) at room temperature. The solution was allowed to stir for 16 hours. After concentration, the solution was diluted with ethyl acetate, washed with NaHCO3 (sat.), NaCl (sat.). dried over MgSO4 filtered, concentrated, and pumped on. The yellow oil was then purified using flash chromatography (2% methanol/dichloromethane with 0.1% triethylamine) to yield 2-[2-(methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione as a green solid. MH+(346)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2ccc(F)cc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c3) the title compound is obtained as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c(F)c1
Yield: 95.2 %

Procedure:
A solution of (3,4-difluoro-phenyl)-acetic acid (5.0 g, 0.029 mol) in methanol (30.0 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 4 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3,4-difluoro-phenyl)-acetic acid methyl ester (5.15 g, 95.2%) as a clear oil: EI-HRMS m/e calcd for C9H8F2O2 (M+) 186.0493, found 186.0492.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1>N1C=CC=CC=1>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
4-Fluorobenzoyl chloride (0.15 mL, 1.30 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide (0.24 g, 77% yield) as a solid.
Reaction SMILES: C1C2C(CO[C:16]([N:18]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:19]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(O)(=O)/[CH:58]=[CH:59]/[C:60]1[CH:67]=[CH:66][C:64]([OH:65])=[C:62]([OH:63])[CH:61]=1>>[C:16]([N:18]([C:38]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@H:19]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])(=[O:17])/[CH:58]=[CH:59]/[C:60]1[CH:67]=[CH:66][C:64]([OH:65])=[C:62]([OH:63])[CH:61]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)/C=C/c1ccc(O)c(O)c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]-3,4-dihydroxybenzylamine (900 mg, 1.2 mmol, example 26, step A) as described for example 26 (step B) using caffeic acid (326 mg, 1.8 mmol) instead of 4-hydroxy-3-nitrobenzoic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 70% EtOAc/CH2Cl2/1% AcOH. The title compound was obtained as a yellow powder (430 mg, 52%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.C(=O)(O)[O-].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][CH:2]3[CH:7]4[CH:3]3[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]4)=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
tert-Butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 1.0 eq.) was added to a solution of sodium bicarbonate (0.84 g, 2.0 eq.) in water (5 ml) at 5° C. FMOC—Cl (1.56 g, 1.2 eq.) in 1,4-dioxane (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, transferred into iced water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 1.9 g of tert-butyl 6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (yield 90%).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:28][CH:29]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl(+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoate (325 mg, 0.803 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (0.62 mL, 8.0 mmol). The solution was stirred at room temperature for 17 hours then concentrated under reduced pressure. Toluene (3 mL) was added, and the solution was again concentrated under reduced pressure to remove excess trifluoroacetic acid to give (+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.84 (d, J=7.8 Hz, 1H), 7.80-7.75 (m, 1H), 7.75-7.69 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.55-7.48 (m, 1H), 5.50 (dd, J=5.0, 9.5 Hz, 1H), 2.56 (s, 3H), 2.24-2.14 (m, 1H), 1.92-1.75 (m, 2H), 1.08 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:12]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Temperature: 8 °C

Procedure:
To 82.5 g. of p-nitroacetophenone in 200 ml. of glacial acetic acid at 20°-25° C. is added 80 g. of bromine dropwise over 30 minutes. The resulting solution is cooled to 8° C. A precipitate forms during cooling which is filtered, washed and partially dried. 109 g. of wet alpha-bromo-p-nitroacetophenone is obtained. It is added to 109 g. of Na2S2O3.5H2O in 400 ml. of 70% methanol. The mixture is stirred, warmed to 60° C. and allowed to stand overnight. The mixture is cooled and a solid precipitates which is filtered and dried. The resulting cake is added to 600 ml. water, 600 ml. acetic acid and 300 ml. concentrated aqueous HCl. This mixture is stirred at refluxing temperature for 6 hours. An orange-red precipitate forms which is recovered and dried. NMR analysis indicates that the product is 2,5-di(p-nitrophenyl)dithiin having the structure: ##STR9##
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]2[CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCc3c([nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 175 mg of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 5 ml of dimethylformamide, 0.2 g of 4-cyano-benzoic acid, 0.35 g of diphenylphosphoryl azide and 0.4 ml of diisopropylethylamine was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase was washed with 1 N hydrochloric acid, dried over magnesium sulfate and evaporated. Crystallization of the residue from methylene chloride/ether yielded 245 mg of 2-(4-cyano-benzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole with m.p. 228-232° C.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:18][C:19](=[O:43])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:20]=2[C:19]([NH:18][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[C:3]([OH:44])=[O:2])=[O:43])=[CH:34][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (60 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 2.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to general procedure C to give (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid (35 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:27]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:27][N:11]1[C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:14](=[O:15])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]1=[O:20]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A solution of 2.10 grams (0.0073 mole) of 3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (recovered from previous reactions) and 1.21 grams (0.0088 mole) of potassium carbonate in 30 mL of tetrahydrofuran was stirred for five minutes at ambient temperature and then 1.58 grams (0.0073 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene (prepared in a manner known by one skilled in the art) was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, the reaction mixture was diluted with water, and the resulting mixture was extracted with two 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.9 gram of crude product. This 0.90 grams of crude product was combined with 0.92 grams of crude product prepared by a similar route to yield a total of 1.82 grams of crude product. The 1.82 grams of crude product was purified by flash chromatography, yielding 1.5 grams of 1-amino-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 176°-178° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:21]=[C:22]=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH3:24]>C1(C)C=CC=CC=1>[CH2:1]([NH:21][C:22]([NH2:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCN=C=O
Reactant: N
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCNC(N)=O
Reaction time: 0.5 h

Procedure:
80.75 g (0.25 mole) of eicosylisocyanate are dissolved in 350 ml of technical-grade toluene and, at a temperature of 50°-60° C., 4.25 g (0.25 mole) of liquid NH3 are slowly added, in a pressure vessel, with stirring. After an after-stirring period of 30 minutes, the N-eicosyl-urea is isolated.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][N:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26]([SH:28])=[N:27][C:23]=2[CH:22]=1>C(O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:28][C:26]3[NH:25][C:24]4[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][C:23]=4[N:27]=3)[C:11]=2[F:12])[CH2:14][CH2:15]1
Reactant: COc1ccc2[nH]c(S)nc2c1
Reactant: Fc1c(N2CCOCC2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3F)nc2c1
Yield: 74.8 %

Procedure:
5N NaOH (3.39 ml) was added dropwise to a stirred solution of 2-chloromethyl-3-fluoro-4-morpholinopyridine hydrochloride (2.06 g) and 5-methoxy-(1H)-benzimidazole-2-thiol (1.39 g) in ethanol (35 ml). After 3 hours excess solvent was removed and the residue treated with water (80 ml) and extracted with dichloromethane. The extracts were washed with water, dried (K2CO3), excess solvent removed and the residue crystallised from ethyl acetate to yield 2-(4-morpholino-3-fluoro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (2.16 g) m.p. 121°-123°.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[N:26]=[C:25](Br)[CH:24]=[N:23][C:22]=3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH:37]1([CH2:40][N:41]2[CH:45]=[C:44]([Sn](CCCC)(CCCC)CCCC)[N:43]=[CH:42]2)[CH2:39][CH2:38]1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:44]4[N:43]=[CH:42][N:41]([CH2:40][CH:37]5[CH2:39][CH2:38]5)[CH:45]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CC2CC2)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(CC4CC4)cn3)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 80 °C
Yield: 100.7 %

Procedure:
In a round bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (150 mg, 0.26 mmol) and 1-cyclopropylmethyl-4-tributylstannanyl-1H-imidazole (160 mg, 0.39 mmol) were dissolved in DMF (2 mL). Pd(PPh3)4 (15 mg, 0.013 mmol) and CuI (10 mg, 0.052 mmol) were added. The reaction mixture was heated at 80° C. for 1 h then cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with saturated aqueous LiCl and brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (0-5% MeOH/EtOAc) to afford 162 mg (99%) of 2-(1-cyclopropylmethyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a viscous colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)N1CCOCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and N-morpholinecarbonyl chloride, there is obtained ethyl N-(morpholinecarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 379 (12), 350 (22), 293 (77), 194 (100), 167 (98), 114 (5);