Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC(N([C@@H](C2C=CC=CC=2)C)[C:11](=[O:22])[CH:12]([CH2:19][CH:20]=[CH2:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O)C=CC=CC=1.[O:31]([CH3:33])[Li]>CO>[CH2:19]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([O:31][CH3:33])=[O:22])[CH:20]=[CH2:21]
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)Oc1ccccc1)[C@H](C)c1ccccc1
Reactant: [Li]OC
Solvent: CO
Product: C=CCC(CCCCCC)C(=O)OC
Reaction time: 22 h
Yield: 57.5 %

Procedure:
A solution of 0.218 g (0.5 mmol) of N-phenyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 2 ml of methanol was cooled to 0° C., 0.38 g (1.0 mmol) of LiOMe was added, and the mixture was stirred for 22 hours. The reaction was terminated by addition of 2 ml of 1 N hydrochloric acid, and the product was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by GC. Thus was obtained 0.057 g (58%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH:23]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:24]([C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O>[C:45]([O:44][C:42]([NH:23][C@@H:24]([C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([NH:13][CH2:12][C:11]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:37])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamine from the previous step (0.14 mmol, 37 mg), EDC (0.21 mmol, 40 mg), and Boc-D-Phe-L-Pro-OH (0.14 mmol, 50 mg), in 0.5 mL dimethylformamide, was added HOAT (0.15 mmol, 21 mg). The solution was stirred overnight and purified by preparative reverse phase HPLC using an acetonitrile:water gradient containing 0.1% TFA to give N-(tert-buyloxycarbonyl)-D-phenylalanyl-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide. Mass Spec ES (M+1)=615.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)=O.[C:20]([O:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[C:20]([O:24][C:25]([NH:27][C:28]1[NH:29][CH:2]=[C:3]([C:5]2[C:13]3[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=3[C:8]([O:18][CH3:19])=[CH:7][CH:6]=2)[N:30]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(C(=O)CBr)c2sc(NC(=O)O)nc12
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CC#N
Product: COc1ccc(-c2c[nH]c(NC(=O)OC(C)(C)C)n2)c2sc(NC(=O)O)nc12
Yield: 17 %

Procedure:
0.25 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (0.0007 Mol) and 0.33 g of tert-butoxycarbonylguanidine (0.0021 Mol) were heated to reflux in acetonitril (3 ml) for 3 hrs. After evaporation of the solvent the residue was triturated with water (10 ml) and filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, ethyl-acetate/hexanes 1:1) to yield the title compound as a white solid (17%); F.p.: 255-265° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[C:35]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:28]=[CH:27][C:26]=3[N:25]=[C:24]2[CH2:36][CH2:37][CH3:38])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:12]1([C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[C:35]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:28]=[C:27]([NH2:41])[C:26]=3[N:25]=[C:24]2[CH2:36][CH2:37][CH3:38])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
mCPBA (6.56 g, 28.5 mmol) was added to a solution of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinoline (6.2 g, 16 mmol) in chloroform (100 mL); the reaction was stirred for three hours at ambient temperature. Ammonium hydroxide (50 mL) was added. p-Toluenesulfonyl chloride (6.056 g, 31.76 mmol) was added over a period of five minutes, and the reaction was stirred for one hour. The work-up procedure and chromatographic purification was carried out as described in Part D of Example 8. The resulting oil was triturated with acetone, isolated by filtration, and dried to provide 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 178-179° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][O:6][C:5]2([CH2:12][C@@H:11]([CH3:13])[C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:4][CH2:3]1.[CH3:18]/[C:19](/[C:23]#[CH:24])=[CH:20]/[CH2:21][OH:22].C([Li])CCC>C1COCC1>[OH:22][CH2:21][CH:20]=[C:19]([CH3:18])[C:23]#[C:24][C:10]1([OH:14])[CH:11]([CH3:13])[CH2:12][C:5]2([O:4][CH2:3][C:2]([CH3:1])([CH3:17])[CH2:7][O:6]2)[CH2:8][C:9]1([CH3:16])[CH3:15]
Reactant: C[C@@H]1CC2(CC(C)(C)C1=O)OCC(C)(C)CO2
Reactant: C#C/C(C)=C\CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C#CC1(O)C(C)CC2(CC1(C)C)OCC(C)(C)CO2)=CCO
Yield: 75.7 %

Procedure:
(-)-(10R)-3,3,8,8,10-Pentamethyl-1,5-dioxaspiro[5,5]undecan-9-one (1.31 g, 5.5 mmol) was reacted with Z-3-methylpent-2-en-4-yn-1-ol (0.65 g, 6.7 mmol) and n-butyllithium (1.6M in hexane, 8 mL, 12.8 mmol) in dry THF. The crude product obtained (yellow oil, 2.6 g) was purified by flash column chromatography (75% ether+25% hexane) followed by distillation using the Kugel-rohr apparatus (about 250° C., 0.06 mm Hg) to give the product as a colorless oil (1.40 g, 77%), [a]D +30.0° C. (c 1.05, CH3OH); ir and 1H nmr identical to those reported above for its antipode.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol) with boron tribromide (0.9 mL of 1N solution, 0.9 mmol) according to method D to yield 0.080 g (85%) of product which was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 204–206° C.; 1H NMR (DMSO-d6): δ 6.87 (2H, d, J=8.61 Hz), 7.17 (1H, dd, J=2.34 Hz, J=8.83 Hz), 7.38 (1H, d, J=2.26 Hz), 7.62 (2H, d, J=8.59 Hz), 7.85 (1H, d, J=1.64 Hz), 7.90 (1H, d, J=8.92 Hz), 8.01 (1H, bs), 9.62 (1H, s), 10.14 (1H, s); MS (ESI) m/z 269/(M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:22].S(=O)(=O)(O)O.Cl([O-])=O.[Na+]>O.C(#N)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([C:13]([OH:22])=[O:14])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)c(I)cc1OCc1ccccc1
Reactant: CS(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde (reference example 1-1) (20 g), dimethylsulfoxide (19 mL), concentrated sulfuric acid (3 mL), water (30 mL) and acetonitrile (181 mL) was added a mixture of sodium chlorite (9.8 g) and water (30 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (20.3 g).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:19][C:20]([CH:1]2[CH:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][NH:2]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCC2CNCCC2C1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)C1NCCC2CCCCC21

Procedure:
To 5.0 g of decahydroisoquinoline (mixture of cis and trans isomers), 20 mL of methylene chloride and 50 mL of 15% aqueous sodium hydroxide solution was added at 10°-15° a solution of 7 mL of phenylacetyl chloride in 20 mL of methylene chloride. Removal of the solvent from the dried organic layer and crystallizaiton of the residue from hexanes gave 3.12 g of 2-phenylacetyldecahydroisoquinoline.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([N:27]1[CH2:32][CH2:31][CH:30](Br)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(OCC)(=O)C>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[O:1][CH:30]1[CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: COc1ccc2c(c1O)OCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 3.1 %

Procedure:
A solution of 7-hydroxy-6-methoxybenzofuran-3(2H)-one (0.30 g, 1.7 mmol) in DMF (5.0 mL) was added with potassium carbonate (1.0 g, 7.2 mmol), and N-Boc-4-bromopiperidine (0.50 g, 1.9 mmol), and the mixture was stirred at 80° C. for 12 hours. The reaction mixture was added with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (1:1)) to obtain tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy)piperidine-1-carboxylate (0.019 g, 3%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[C:5]([CH3:12])[N+:4]=1[O-])[CH3:2].C([Br:17])(=O)C>C(O)(=O)C>[Br:17][C:7]1[CH:6]=[C:5]([CH3:12])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CC(=O)Br
Reactant: CCc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Solvent: CC(=O)O
Product: CCc1cc(Br)cc(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Ethyl-6-methyl-4-nitropyridine N-oxide (36.4 g) was added to 60 g of acetic acid and the mixture was warmed to give a clear solution which was cooled to 15°-20° C. and treated dropwise, keeping the temperature below 25° C., with 49.2 g of acetyl bromide. After addition was complete, the mixture was stirred at room temperature for 11/2 hours and then slowly warmed to 65°-70° C. and kept in this temperature range for 24 hours. The acetic acid and volatile components were removed in vacuo and 200 ml of chloroform were added to the residue. To the chilled mixture there was added dropwise 58 g of phosphorus tribromide at 10° C. and the mixture was warmed to room temperature and then heated at reflux for 3 hours. An additional 10 g of phosphorus tribromide were added and the mixture was heated for 1 hour, poured onto ice, neutralized with cold 35% sodium hydroxide and extracted three times with 200 ml of methylene chloride. The organic extract was concentrated, 300 ml of diethyl ether were added and the ether solution was dried over magnesium sulfate and concentrated. The crude product was fractionated in vacuo to give 30 g of the title product as a yellow oil; bp13 120°-130° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([OH:10])[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:10][C:8]1[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CNC(=O)n1nc(C(C)(C)C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNC(=O)n1nc(C(C)(C)C)nc1OCc1ccccc1
Yield: 3.5 %

Procedure:
To a mixture of 3-tert-butyl-1-N-methylcarbamoyl-5-hydroxy-1,2,4-triazole 5.94 g (0.03 mole) and potassium carbonate 6.21 g (0.045 mole) was added 100 ml of methyl-ethyl ketone. Then to the mixture was added, while stirring, 4.17 g (0.033 mole) of benzyl chloride, and the mixture was heated under reflux for 2 hours. After the reaction mixture was concentrated under a reduced pressure, the residue obtained was diluted with water and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure, and the pale yellow oily substance obtained was subjected to silica gel column chromatography and eluted with a solvent mixture of 1:2 of ethyl acetate and n-hexane, to give 0.3 g of 5-benzyloxy-3-tert-butyl-1-N-methylcarbamoyl- 1,2,4-triazole as a white solid (yield 3.5%).
Reaction SMILES: [Br:1]Br.[Br-:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH2:13][P+:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[Br-:1].[Br:3][C:10]1[C:5]([OH:4])=[C:6]([CH2:13][P+:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: BrBr
Agent: [Br-]
Solvent: CO
Product: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
In the course of 1.5 hours, at 5°, 16 g of bromine are added dropwise to a solution of 50 g of [(2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium bromide in 11 of methanol. The solution is then concentrated in vacuo at 20° to 130 ml, 250 ml of ethyl acetate are added thereto in the course of 2 hours, the resulting yellow suspension is stirred for 2 hours at 0°, and the slightly yellow crystals are filtered off with suction and recrystallised from methanol. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)-methyl]-triphenyl-phosphonium bromide is thus obtained in the form of colourless crystals [m.p.: 259°; IR (KBr): 2875, 1585, 1565, 1415, 1325, 1200, 1165, 1150 cm-1 ; 1H-NMR (360 MHz), DMSO-d6); 3.43 (s, 3H, OCH3), 5.03 (d, 2H, CH2P+), 6.42 (dd, 1H), 7.08 (dd, 1H, 7.61 to 7.80 (m, 12H), 7.92 (m, 3H), 9.00 (br, s, 1H, OH) ppm]; yield 76% of the theoretical yield
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH2:36]([O:38][C:39]([C:41]1([C:44]2[CH:49]=[C:48](Br)[CH:47]=[CH:46][N:45]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1([C:44]2[CH:49]=[C:48]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[CH:47]=[CH:46][N:45]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(c2cc(Br)ccn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCOC(=O)C1(c2cc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)ccn2)CC1
Yield: 81 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(4-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described in Example 1. Yield: 81% of theory; LC (method 3): tR=2.99 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44](O)=O>CO.O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[C:36]([CH3:42])=[N:35][CH:34]=[C:33]2[CH2:43][C:44]1[NH:13][C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=2[N:20]=1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cc2c(CC(=O)O)cnc(C)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.30 mmol) is added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.223 g, 1.05 mmol)) and (6,7-dimethoxy-1-methyl-isoquinolin4-yl)-acetic acid (0.25 g, 0.96 mmol) in methanol (5 ml) and water (1 ml) and the mixture is stirred at ambient temperature for 16 hours. The methanol is evaporated and the resultant solid collected by filtration, taken into methanol (5 ml) and 5M aqueous sodium hydroxide (0.5 ml) is added. The reaction is heated to reflux for 1 hour, cooled to ambient temperature and evaporated. The residue is dissolved in water and extracted with dichloromethane, the combined organic extracts are dried over sodium sulfate and evaporated to afford 8-(6,7-dimethoxy-1-methyl-isoquinolin4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, M+ 437.
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1[N:9]=[C:10]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][N:11]2[CH:25]=1)=O)C.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:6]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:25]=2)=[N:5][CH:4]=[N:35]1
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C(=O)N=CN(C)C)cn1CCO2
Reactant: NNc1ccccc1Cl
Agent: Cl
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Yield: 59 %

Procedure:
Following the procedure in Example 22, methyl 2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate was coupled with 2-chlorophenylhydrazine hydrochloride to give methyl 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 59%. MS(ESI+): 422.1
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32]>>[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(-c2ccc(Cc3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared from the product of Example 161 (0.1 g, 0.26 mmol) and methyl 4-bromobutyrate (56 mg, 0.31 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CDCl3) δ 7.50 (d, J=8.8 Hz, 2H), 7.32 (t J=6 Hz, 2H), 7.24 (m, 3H), 7.18 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 4.36 (dd, J=7.2, 3.6 Hz, 1H), 4.20 (br, 1H), 4.10 (s, 2H), 3.71 (br, 1H), 3.05 (br, 2H), 2.44 (br, 2H), 2.19-1.98 (m, 9H); LC/MS (ESI+) m/z: 95%; 437 (M+1, 100).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 3,4-dichlorobenzyl bromide (480 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (154 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.12 (br. s., 1 H), 7.58 (dd, J=5.05, 3.03 Hz, 2 H), 7.29 (dd, J=8.34, 2.02 Hz, 1 H), 4.97 (s, 2 H), 4.62 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.63 (s, 3 H), 1.27 (q, J=12.88 Hz, 2 H), 1.11 (q, 1 H)
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44](O)=O.C=O>ClC(Cl)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:44])[C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CCC1(NCc2ccccc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: O=CO
Agent: C=O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a solution of the product of Example 74G (10 mg, 0.016 mmol) in dichloroethane (0.1 mL) was added formic acid (1.2 μL, 0.032 mmol) followed by addition of aqueous 37% formaldehyde solution (1.3 μL, 0.018 mmol). The mixture was heated at 50° C. for 2 h. After cooling to room temperature, the solution was diluted with ethyl acetate (1 mL), washed with water (0.5 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (2% methanol/dichloromethane) afforded a greenish brown solid (6 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.31-0.50 (m, 1H), 0.73 (s, 9H), 0.90-1.07 (m, 1H), 2.11-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.71 (s, 3H), 3.00-3.10 (m, 3H), 3.45-3.62 (m, 1H), 4.07 (d, J=12.87 Hz, 1H), 7.26-7.40 (m, 5H), 7.42-7.60 (m, 3H), 7.64 (t, J=7.54 Hz, 1H), 7.71-7.80 (m, 1H), 7.93 (d, J=8.09 Hz, 1H), 8.22 (d, J=6.62 Hz, 1H), 10.06 (s, 1H), 13.53 (s, 1H); MS m/z 637.2 (M+H)+.