Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[O:30])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1)[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][CH3:16].[OH-].[K+].C(O)C.O>C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:30])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=1)[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)O)cc1

Procedure:
A mixture of 5 g. of methyl (4-hexadecylaminophenyl)pyruvate, 5 g. of potassium hydroxide and 50 ml. of a 1:1 ethanol:water solution is heated to 50° for 3 hrs. While hot, the reaction mixture is neutralized with acetic acid and cooled. The precipitate is collected, dried and recrystallized, yielding (4-hexadecylaminophenyl)pyruvic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(C(C)=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: OCCCl
Reactant: Cc1nccn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(OCCO)cc1

Procedure:
4-(2-Methyl-1H-imidazol-1-yl)phenol (10.0g, 0.057 mole), 2-chloroethanol (13.88 g, 0.172 mole) and potassium carbonate (23.74 g, 0.172 mole) were combined in methyl ethyl ketone (200 ml) and heated at reflux temperature for four days. The solution was cooled and the solid filtered and rinsed with acetone. The filtrate was concentrated to a residue and the residue triturated with hot acetone (2×50 ml). The remaining solid (1.5 g) was dissolved in methylene chloride. Insoluble materials were removed by filtrateion, and the filtrate concentraed to obtain 0.50 g (4%), mp 125°-127° C. Proton NMR indicates that methylene chloride is present in the sample.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[F:20].BrCC1C(F)=CC2C=COC=2C=1>C(#N)C>[F:20][C:12]1[C:11]([CH:10]=[O:5])=[C:16]2[CH:17]=[CH:18][O:19][C:15]2=[CH:14][CH:13]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Fc1ccc2occc2c1CBr
Agent: Fc1cc2ccoc2cc1CBr
Solvent: CC#N
Product: O=Cc1c(F)ccc2occc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the N-methylmorpholine-N-oxide (13.6 g) in acetonitrile (135 ml) containing 3 Å molecular sieves (13.2 g) was stirred at room temperature overnight and cooled in ice. A solution of 4-bromomethyl-5-fluorobenzofuran and 6-bromomethyl-5-fluorobenzofuran (13.33 g) in acetonitrile (35 ml) was added and the mixture stirred at 5° for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase separated, dried and evaporated to give the mixture of aldehydes. The mixture was separated by chromatography on silica (600 g) using a mixture of ethyl acetate and hexane (1:9) as the eluant to give the title compound (A) (2.19 g);
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:4]1[O:6][CH2:5]1>>[NH2:2][CH2:5][CH:4]([OH:6])[CH2:3][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: CCN(CC)CC1CO1
Reactant: [NH4+]
Agent: [OH-]
Product: CCN(CC)CC(O)CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To the ice-cold solution of ammonium hydroxide (25 mL, 159 mmole) of 25% (w/w) was added glycidyldiethylamine dropwise (3.2 g, 24.8 mmol) over 10 minutes. The reaction mixture was stirred at 0–5° C. for 1 hour and then room temperature for 14 hours. The resulting reaction mixture was evaporated and distilled (84–90° C. at 500–600 mT) to yield 1-amino-3-diethylamino-propan-2-ol (3.3 g, 92%). MS m/z 147 ([M+1]+).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:10]1=[O:54])(C)(C)C>O1CCOCC1.ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:48][C@@H:44]([C:43]([N:39]1[CH2:40][CH2:41][CH2:42][CH:38]1[C:35]1[NH:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:17][C:16]([CH2:15][N:11]5[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[C:10]5=[O:54])=[N:20][CH:19]=4)=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)=[CH:37][N:36]=1)=[O:53])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCC[C@@H](NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)N[C@@H](C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride (4N, 8 mL) in dioxane was added to a solution of (R)-{1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester (175 mg, 0.24 mmol) in dichloromethane (2 mL). After 1 hour the solvent was removed under reduced pressure. The resulting residue was placed on a high vacuum for 1 hour to provide (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. The yield was assumed to be 100% percent. A sample suitable for analysis was obtained by subjection to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization. C35H42N8O4 calculated 638.3 observed [M+1]+ 639.4; rt=1.41 min. 1H (DMSO-d6): δ=8.33 (m, 1H), 8.12 (m, 1H), 7.99 (m, 1H), 7.92 (m, 6H), 7.26 (d, J=8.4 Hz, 1H), 5.13 (t, J=8.0 Hz, 1H), 4.83 (m, 2H), 4.09 (t J=8.0 Hz, 1H), 4.09-3.82 (series m, 6H), 2.36 (m, 2H), 2.14 (m, 2H), 1.96 (m, 4H), 0.76 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=O)[NH:7][C:6]=2[CH:14]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:22].C(N(CC)CC)C>C(O)C>[NH:15]([C:8]1[NH:7][C:6]2[CH:14]=[CH:2][C:3]([Cl:22])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2S(=O)(=O)N1
Reactant: Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S1(=O)N=C(Nc2ccccc2)Nc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-2,3-dihydro-3-oxo-1,2,4-benzothiadiazine 1,1-dioxide (3.0 g, 12.9 mmol) and aniline (4.8 g, 52.0 mmol) by a method analogous to the method described in example 37, except that triethylamine hydrochloride (7.1 g, 52.0 mmol) was used instead of N,N-dimethylcyclohexylamine. Yield 1.68 g (44%) of pure product; m.p. (DSC) >350° C. (ethanol); 1H-NMR (DMSO-d6): δ 7.1-7.8 (m, 8H, ArH), 9.5 (br.s, 1H, NH), 11.05 (br.s, 1H, NH,; MS: m/e 307/309 (M+); (C13H10N3Cl1O2S1) calc. C, 50.74; H, 3.28; N, 13.65; found C, 50.31; H, 3.24; N, 13.59.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.Br[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].[OH-].[C:15]([OH:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([OH:25])=[O:24])([C:19]([OH:21])=[O:20])[OH:18]>C(#N)C>[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[CH3:12][C:11]([CH3:13])=[CH:10][CH2:9][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[CH3:12][C:11]([CH3:13])=[CH:10][CH2:9][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[CH3:12][C:11]([CH3:13])=[CH:10][CH2:9][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1
Reactant: CC(C)=CCBr
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cccnc1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)=CC[n+]1cccc(C)c1
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
3-Picoline is reacted with 1-bromo-3-methyl-2-butene in acetonitrile; and the halide intermediate is converted to the hydroxide with Rexyn 201 and then reacted with citric acid to form the citrate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][CH2:21][CH2:20][CH2:19][Br:18])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: OCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCCBr)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
To a solution of 2-(phenylmethoxy)benzoic acid (1.0 g, 4.4 mmol), 3-bromopropan-1-ol (0.35 mL, 4.0 mmol), and 4-(dimethylamino)pyridine (50 mg) in 20 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (1.3 g, 6.6 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl three times followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad, and concentrated under reduced pressure. Chromatography (silica gel, 1:9 ethyl acetate/hexane) of the residue afforded 0.8 g (58%) of 3-Bromopropyl 2-(phenylmethoxy)benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][C:43]=2[NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:45]4[CH:46]=[CH:47][C:42]([N:39]5[CH2:38][CH2:37][O:36][CH2:41][CH2:40]5)=[C:43]([NH:57][S:58]([CH3:61])(=[O:59])=[O:60])[CH:44]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 45.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-14) (250 mg, 0.451 mmol) was coupled with N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (intermediate 51) (259 mg, 0.677 mmol) in sodium carbonate (143.4 mg, 1.353 mmol), Toluene/ethanol/water (3/8/1 ml). This afforded 150 mg (45.59% yield) of the titled compound. MS: m/z=728.9 (M+1).
Reaction SMILES: [Cl-].[NH4+].O.C(O)(=O)C.[C:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:14][C:13]=1[NH:43][S:44]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)(=[O:46])=[O:45])(=[O:10])[CH3:9]>C(O)(C)C>[C:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:14][C:13]=1[NH:43][S:44]([C:47]1[CH:52]=[C:51]([NH2:53])[CH:50]=[CH:49][C:48]=1[N:56]1[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1)(=[O:45])=[O:46])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(OC(C)=O)cc1C(C)(C)CC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2N2CCOCC2)c(OC(C)=O)cc1C(C)(C)CC(C)(C)C

Procedure:
26 g of reduced iron, 0.5 g of ammonium chloride, 7.2 ml of water and 7.2 ml of acetic acid were added to 100 ml of isopropyl alcohol and the mixture was refluxed with stirring. To the mixture was gradually added 17.5 g (0.0226 mol) of the compound obtained in Step (d) above and further refluxed with stirring for 20 minutes. After the reaction, the reaction solution was filtered with celite while hot. The filtrate was cooled and the crystals thus-precipitated were collected by filtration. Yield: 13.3 g (78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:18]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]2[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=2[N:23]([CH3:38])[C:22]1=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:18]([NH:20][CH:21]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[N:23]([CH3:38])[C:22]2=[O:39])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-valinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title compound was prepared as a solid (mp.=228-229° C.). The product was purified by slurrying in ether/hexanes (80:20).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:34][C:35]([NH2:37])=[O:36].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([O:26][CH2:34][C:35]([NH2:37])=[O:36])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(O)ccc2c1=O
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(OCC(N)=O)ccc2c1=O
Yield: 60.3 %

Procedure:
A solution of tert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 mL, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.30 g, 61.2%) as crystals.
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O-:20])=[O:19].[Na+].[Cl-].[Ca+2:23].[Cl-]>O>[OH2:16].[OH2:1].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].[Ca:23]
Reactant: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccccc1
Reactant: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Product: [Ca]
Reaction time: 0.25 h

Procedure:
A stirred solution of 5 g. of sodium 2-amino-3-benzoylphenylacetate hydrate (0.02 mole) in 50 ml. of water was treated with 1.2 g. of calcium chloride (0.01 mole) in 10 ml. of water. An immediate precipitate developed. After an additional 15 min. stirring the precipitate was collected. Recrystallization from ethanol-water gave bright yellow needles which melted over the broad range of 160°-240° C. (dec.).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C(O)C>[Cl:16][C:13]1[CH:12]=[C:8]2[C:7](=[CH:15][CH:14]=1)[N:6]=[C:1]([CH2:2][CH2:3][CH3:4])[N:11]=[C:9]2[OH:10]
Reactant: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc(O)c2cc(Cl)ccc2n1
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Preparation D10, Step 2: 2-butyramido-5-chlorobenzamide (1.08 g, 4.49 mmol, 1 eq) was dissolved in ethanol (10 mL) at room temperature then 1N NaOH (13.46 mL, 13.5 mmol, 3 eq) added. Worked up after 15 minutes by adding 1N HCl to pH=2. Solids precipitated and were filtered and pumped under high vacuum to give 6-chloro-2-propylquinazolin-4-ol (810 mg) as a white solid. Yield=81%. Mass Spec (ESI) (M+H)+=223.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CC(C)=O>[C:7]([CH:9]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 42.5 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→1:1) to give the title compound as a pale-yellow oil (yield 10.41 g, 90%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH2:17]([O:16][C@@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.5 g of 10% w/w palladium on activated carbon was added to a solution of 3.757 g of dl-trans-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 43) in 150 ml of methanol, and the whole was mixed with hydrogen by shaking in a Paar's apparatus at room temperature under a pressure of 4 atmospheres (about 4 bars). After 20 hours, the catalyst was removed by filtration, and the solvent was then removed by distillation to give 2.749 g of the title compound as a solid, melting at 41°-42° C. (after recrystallization from cold hexane).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([N:10]([CH2:14][CH2:15][CH2:16][CH3:17])CC#C)[CH2:7][CH2:8][CH3:9].C1(OC#[N:26])C=CC=CC=1>CCOCC>[CH2:2]([N:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]#[C:8][C:9]#[N:26])[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: C#CCN(CCCC)CCCC
Reactant: N#COc1ccccc1
Solvent: CCOCC
Product: CCCCN(CC#CC#N)CCCC
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 94.2 %

Procedure:
n-BuLi (2.2 M, 69.5 mL, 0.153 mol) was added dropwise to a cooled (-78° C.) solution of 3-dibutylaminopropyne (24.9 g, 0.149 mol) in anhydrous ether (175 mL) at a rate not allowing the temperature to rise above -50° C. The resulting solution was stirred (5minutes, -70° C.), then phenyl cyanate (19.6 g, 0.164 mol) was added dropwise at a rate not allowing the temperature to rise above -60° C. The resulting solution was stirred (45 minutes, -78° C.), then warmed (25° C.). The resulting dark brown solution was diluted with ether (250 mL), washed with 3.0 N NaOH (3×170 mL), washed with brine (1×170 mL), then dried (MgSO4), and concentrated in vacuo. The resulting oil was chromatographed on silica (chloroform) to yield 27.0 g (94.4%) of 4-dibutylamino-2-butynenitrile as a brown liquid. 1H NMR (250 MHz, CDCl3): δ 3.53 (s, 2H), 2.46 (t, 4H), 1.36 (m, 8H), 0.92 (t, 6H).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=S)[NH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1.[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH2:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]1)#[N:24].C(N(CC)C(C)C)(C)C>C1COCC1>[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH:44][C:15]2[C:14]3[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=3[O:18][C:17](=[O:19])[N:16]=2)[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH3:33])[CH2:29][CH2:30]1)#[N:24]
Reactant: O=c1[nH]c(=S)c2ccc(F)cc2o1
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-1-methyl pyridinium iodide (365 mg, 1.43 mmol, 1.00 eq) was added to a suspension of 7-fluoro-4-thioxo-3,4-dihydro-benzo[e][1,3]oxazin-2-one (280 mg, 1.42 mmol, 1.00 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (627 mg, 1.42 mmol, 1.00 eq), and N,N-diisopropyl ethylamine (1.00 mL, 5.74 mmol, 4.04 eq) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight, then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 324 mg (47% yield) of the title compound; m/z calculated for C26H36F N5O3 485.6, found 486.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.OC1C=CC=CC=1C(CCC(O)=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:20]1[O:22][CH2:21]1)[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Agent: O=C(O)CCC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Yield: 47 %

Procedure:
A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanol-ether gave 6[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30g, 47%, m.p. 92.5°-95° C) which was recrystallised from aqueous ethanol to give the pure pyridazinone (m.p. 93.5°-95° C).