Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:15])[C:3]([C:5]1[S:9][C:8]2[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:10]1[C:8]2[S:9][C:5]([C:3]3[N:18]4[CH2:19][CH2:20][N:16]=[C:17]4[S:21][C:2]=3[CH3:15])=[CH:6][C:7]=2[CH:13]=[CH:12][CH:11]=1
Reactant: S=C1NCCN1
Reactant: CC(Br)C(=O)c1cc2cccc(Cl)c2s1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC1=C(c2cc3cccc(Cl)c3s2)N2CCN=C2S1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A mixture of 2-bromo-1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one (2.32 g), 2-imidazolidinethione (0.53 g), ethanol (25 ml) and acetic acid (12.5 ml) was heated under reflux for 3 hours and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and dried in vacuo to give 3-(7-chlorobenzo[b]thiophen-2-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.12 g) as a white solid, m.p. 294-295° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[CH:16][N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1.[H][H].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[C:16]([S:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: ClSc1ccc(Cl)cc1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])C(Sc1ccc(Cl)cc1)=C1NCCN1Cc1ccc(Cl)nc1
Temperature: 0 °C

Procedure:
0.2 g of sodium hydride 60% in oil was added to a solution of 1.3 g of 1-(2-chloro-5-pyridylmethyl)-2-nitromethyleneimidazolidine in 15 ml of dry dimethylformamide, and the mixture was stirred at room temperature until the generation of hydrogen gas ceased. 0.9 g of 4-chlorobenzenesulfenylchloride was then drop into the solution at 0° C. with stirring. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water. The precipitated crystal was filtered and recrystalized from ethyl acetate to give 1-(2-chloro-5-pyridylmethyl)-2-{(4-chlorophenylthio)nitromethylene}imidazolidine. The yield was 1.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14]Br)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[I-:18].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][I:18])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CC2CCC(CBr)CC2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CC2CCC(CI)CC2)cc1

Procedure:
A mixture of 17.5 g. (0.065 m) of 4-(4-methoxybenzyl)-cyclohexylmethyl bromide, 11 g. (0.073 m) of sodium iodide and 100 ml. of acetone was heated under reflux for two hours. The solvent was removed, the residue partitioned between water and ether, and the ether layer dried and concentrated to give 19.8 g. of oil, used directly in the next reaction.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32](S(O)(=O)=O)=[CH:31][CH:30]=1.[CH2:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([O:23][CH2:39][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCCCC[C@@H](CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCC[C@@H](CC[C@H]1CCC(OCc2ccccc2)(OCc2ccccc2)[C@@H]1CCCCCCC(=O)OC)OC(C)=O

Procedure:
A solution of 2 g. of l-methyl 15(S)-acetoxy-9-oxo prostanoate (Example 52) and 25 mg. of p-toluene sulfonic acid in 65 ml. of benzylalcohol is stirred at 100° C. for 6 hours. The solution is concentrated to near dryness under reduced pressure. The residue is diluted with ether and the resulting solution is washed with 5% sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to afford 2.5 g. of product.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31])=[CH:24][CH:23]=[CH:22][CH:21]=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:28]([CH2:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH3:17])[C:29](=[O:32])/[CH:30]=[CH:31]/[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Reactant: COCCN1Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COCCN1Cc2cc(/C=C/C(=O)N(C)Cc3c(C)[nH]c4ccccc34)cnc2NC1=O
Yield: 35.4 %

Procedure:
A solution of 6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (0.86 g, 3.00 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (see Example 1 (a), 0.68 g, 3.00 mmole), Pd(OAc)2 (0.07 g, 0.30 mmole), tri-ortho-tolylphosphine (0.18 g, 0.60 mmole) and diisopropylethylamine (1.31 mL, 7.50 mmole) in propionitrile (50 mL) was deoxygenated, then was heated at reflux under N2 overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% EtOAc/EtOH). The title compound (0.46 g, 36%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 434 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([OH:12])=O)[N:8]=1)=[O:2].C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:37][CH:38]1[C:59](=[O:60])[N:40]2[C:41]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=3)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]12>C(OCC)(=O)C.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH3:16])[C:10]([NH:37][CH:38]2[C:59](=[O:60])[N:40]3[C:41]([C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=4)=[O:47])=[C:42]([OH:45])[CH2:43][S:44][C@H:39]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
N,N-Dimethylformamide (0.114 g.), phosphoryl chloride (0.240 g.) and ethyl acetate (0.5 ml.) were reacted in a conventional manner to give a Vilsmeier reagent. Ethyl acetate (5 ml.) and 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 0.35 g.) were added at the same temperature for 30 minutes to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.31 g.) and bis(trimethylsilyl)acetamide (1.14 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.50 g.) in ethyl acetate (7.5 ml.) and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above all at once at -10° C., and stirred at the same temperature for 30 minutes. Water (15 ml.) and ethyl acetate (15 ml.) were added to the resultant solution. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (15 ml.) and water (10 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.634 g.).
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[CH3:10][N:11]([CH3:24])[C:12]1[CH:23]=[C:16]2[C:17]([O:19][C:20](=O)[NH:21][C:15]2=[CH:14][CH:13]=1)=O.C[N:26](C)C=O>O>[NH2:26][C:20]1[C:4]([C:5]#[N:6])=[C:17]([OH:19])[C:16]2[C:15](=[CH:14][CH:13]=[C:12]([N:11]([CH3:10])[CH3:24])[CH:23]=2)[N:21]=1
Reactant: N#CCC(O)C#N
Reactant: CN(C)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(O)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of 4 g of malonitrile in 50 mL of dimethylformamide in several portions 2.4 g of sodium hydride 60% oily dispersion is added. To the clear solution 8 g of 5-dimethylamino-isatoic anhydride is added and the mixture is stirred at room temperature for 10 hours. The mixture is diluted with 70 mL of water and extracted with 2×30 mL of ethyl acetate. The aqueous phase is evaporated in vacuum, the solid residue is dissolved in 20 mL of water, the pH is adjusted to 6 with acetic acid. The precipitated material is filtered off, and washed with water. After drying 6.5 g of the title compound is obtained, m.p.: 360° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CO.C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:19]([S:21][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1)=[S:20]
Reactant: ClCc1ccc(Cl)cc1
Reactant: S=C=S
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: C[C@H]1c2[nH]c3ccccc3c2C[C@@H](CO)N1C(=S)SCc1ccc(Cl)cc1
Yield: 70.1 %

Procedure:
In the same manner as described in Example 13 by using (1S,3S)-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (216 mg), 2N NaOH (1.5 ml), CS2 (228 mg), 4-chlorobenzyl chloride (480 mg) and 80% ethanol (5 ml), there is prepared the title compound (292 mg, 70%) as white powder, [α]D20 +136.4° (c=1.1, methanol). NMR (CDCl3, δ): 1.63 (d, J=6.5 Hz, 3H, C1 --CH3), 4.57 (s, 2H, CSSCH2 -C6H4 -p-Cl), Mass m/e: 291 (M+ -CH2C6H4 -p-Cl), 258 (M+ -p-Cl-C6H4 -CH2SH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Reactant: NCCO
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
Prepared as described above in Example 60 starting from 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminoethanol to give the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.92 (s, 6H), 2.12 (s, 3H), 2.95 (br s, 2H 3.30 (br s, 2H), 3.45 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.92 (m, 2H), 7.17 (m, 5H). LC MS (m/e)=419.4 (MH+). Rt=1.84 min
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)=[N:7][C:8]=1[OH:9])=O.N1CCCCC1.C(O)(=O)C.[C:34](OCC)(=[O:39])[CH2:35][C:36]([CH3:38])=[O:37]>CCO>[C:36]([C:35]1[C:34](=[O:39])[O:9][C:8]2=[N:7][C:6]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]3)=[CH:5][CH:4]=[C:3]2[CH:1]=1)(=[O:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C=O)c(O)n2)CC1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)c1cc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)nc2oc1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)-1,4-diazepane-1-carboxylate (600 mg, 1.87 mmol) in EtOH (4 mL) were treated with piperidine (239 mg, 2.8 mmol), acetic acid (511 mg, 9.35 mmol) and ethyl acetoacetate (487 mg, 3.74 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 hours. The mixture was concentrated, quenched with a saturated NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were combined, dried over K2CO3, filtered and concentrated. The residue was purified on silica gel with methanol (0-10%) in dichloromethane to provide tert-butyl 4-(3-acetyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (450 mg, 62%). MS m/z 388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Si:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:20][CH:21]=1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: C[Si](C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Product: C[Si](C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 497.4/499.3 (100/48) (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(Cl)c(OCc2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-benzyloxy-4-chlorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3-benzyloxy-4-chlorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 243-244° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)#[N:2].[C-:14]#[N:15].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl.O>[C:14]([CH:9]1[C:10]2[C:5](=[C:4]([CH2:3][C:1]#[N:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#N
Reactant: N#CCc1cccc2cnccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1cccc2c1C=CN(C(=O)c1ccccc1)C2C#N
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
5-Cyanomethylisoquinoline (4.9 g), 5.7 g of potassium cyanide and 200 mg of benzyl triethyl ammonium chloride were dissolved in 60 ml of dichloromethane and 12 ml of water. The solution was stirred for 30 minutes, and 8.2 g of benzoyl chloride was added dropwise. The mixture was further stirred for 4 hours. After the reaction, the dichloromethane layer was washed in water, and dried, followed by distilling off the solvent. The residue was recrystallized from ether to afford 4.5 g of 1-cyano-2-benzoyl-5-cyanomethyl-1,2-dihydroisoquinoline as colorless prisms having a melting point of 66.4° to 69.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:25])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.124 g, 0.58 mmol) and triethylamine (0.09 mL, 0.62 mmol) were combined in CH2Cl2 (2 mL) and cooled to 0° C. Oxalyl chloride (0.05 mL, 0.62 mmol) was added, followed by DMF (3 drops), and the mixture was slowly warmed to room temperature and stirred for 2 hours to give the title compound, which was used directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.I[C:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.34 g (12 mmol) sample of the compound from step 1c above was dissolved in 15 mL of DMF, and (Ph3P)2PdCl2 (0.6 mmol), CuI (0.74 mmol) and triethylamine (14.25 mmol) were added. The mixture was stirred at room temperature for 1 hour, then 3.14 g (14.4 mmol) of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was added. The reaction mixture was stirred at 60° C. for 16 hours. The solution was cooled, diluted with toluene, and the volatiles were removed under reduced pressure. The residue was dissolved in 1 N HCl, and this solution was extracted with ether. The acidic aqueous layer was adjusted to pH 10 with K2CO3, and this solution was extracted with CH2Cl2. The CH2Cl2 extract was washed with 20% Na,OH, dried over MgSO4, and evaporated. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH to give 980 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H), 1.90-2.20 (m, 4H), 2.95-3.15 (m, 2H), 5.05 (m, 1H), 6.68 (s, 1H), 7.15 (br s, 1H), 7.67 (d, 1H, J=8 Hz), 8.48 (d, 1H, J=3 Hz); MS m/z: 289 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([NH:39][C:40]2[NH:41][CH2:42][CH:43]([OH:46])[CH2:44][N:45]=2)[CH:38]=1)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH:20]=1)[CH2:13][C:14]([O:16]CC)=[O:15])=[O:10])=[O:6].O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([NH:39][C:40]2[NH:45][CH2:44][CH:43]([OH:46])[CH2:42][N:41]=2)[CH:38]=1)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([OH:35])([CH3:34])[C:30]([F:31])([F:32])[F:33])[CH:20]=1)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])=[O:6]
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(C(F)(F)F)cc(C(C)(O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(O)(c1cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido) acetamido)-3-(3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)phenyl)propanoate (from step 2 above) (˜708 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide mono hydrate (150 mg, 3.575 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL) to remove the urea. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to give the desired product, after lyophilzation, as a colorless lyophilized powder (287.8 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 636 (M+H); Calcd for C26H27F6N5O7: 635.51
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.Cl>O.CO>[C:17]1([C:15]2[N:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])[O:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCc1nc(-c2ccccc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCc1nc(-c2ccccc2)co1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
Add solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (30 mL) to a solution of 7-(4-phenyloxazol-2-yl)heptanoic acid methyl ester (5.75 g, 20.0 mmol) in methanol (40 mL) at room temperature and heat the mixture at 40° C. for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (600 mL). Wash the organic extract with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by filtration to provide 7-(4-phenyloxazol-2-yl)heptanoic acid (5.01 g, 91%): APCI mass spectrum m/z 272 [C16H19NO3−H]−.