Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([CH2:27][CH2:28][CH3:29])[C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([OH:12])[CH2:10][C:9](=[O:13])[C@@H:8]1[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:23](C)C)=[O:21].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:30])([CH2:27][CH2:28][CH3:29])[C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([OH:12])[CH2:10][C:9](=[O:13])[C@@H:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: [H][H]
Reactant: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of 15-dehydroxy-17,17-difluoro-13,14-dihydro-16-oxo-PGE2 isopropyl ester (20) (0.303 g) obtained in Example 3 in ethyl acetate (20 ml) was subjected to hydrogenation with a catalytic amount of 5% Pd-C and hydrogen gas. The reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was chromatographed on a Rober column to give the titled compound (35).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])[O-].[Na+].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.ClCCl>O1CCCC1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(CNS(=O)(=O)c1ccc(C)cc1)OC
Reaction time: 72 h

Procedure:
5.25 g (50 mmol) of aminoacetaldehyde dimethylacetal was dissolved in 400 ml of tetrahydrofuran. 106 g (1 mol) of sodium carbonate and 11.44 g (60 mmol) of p-toluenesulfonyl chloride were added to the obtained solution. They were stirred for 3 days and then treated with dichloromethane as the extracting solvent in an ordinary manner to obtain the title compound. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[NH:14][CH2:15][C:16]([NH:18][CH:19]2[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[NH:14][CH2:15][C:16]([NH:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reaction time: 1 h

Procedure:
To a solution of the compound (1.92 g), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added under ice cooling. The resulting mixture was stirred for one hour, followed by concentration under reduced pressure. The residue was washed with hexane-ether, followed by evaporation of the solvent, whereby 2.78 g of the title target compound were obtained. The product was provided for the subsequent step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:32])(=[O:31])[NH2:33])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.2 mmol) of 3-(4-chlorobenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.75 g (16.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 4.70 g (yield: 74.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:7]2.[C:30]1([S:36]([N:39]=C=O)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:39][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[NH:7]2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-[2-(t-butoxycarbonylamino) benzoyl]-1,4-dihydroquinol-4-one (2 mmol) and benzenesulfonyl isocyanate (2.2 mmol) in acetonitrile (9 mL) and heat at reflux for 48 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](C)=[C:8](O)[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4].N1C=CC=CC=1.[C:31]([O:34][C:35](=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:35][O:34][C:31](=[O:33])[CH3:32])[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4]
Reactant: COC(=O)c1c(NC(=O)c2ccc(OC)c(OC)c2)sc(O)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(COC(C)=O)sc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 12 h
Yield: 67 %

Procedure:
Subsequently, crude 2-(3,4-dimethoxy-benzoylamino)-5-hydroxy-methyl-thiophene-3-carboxylic acid methyl ester (crude 35 mg) synthesized by the above process was dissolved in anhydrous methylene chloride (5 ml). Pyridine (24 mg: dissolved in 1 ml of anhydrous methylene chloride) and acetic anhydride (31 mg: dissolved in 1 ml of anhydrous methylene chloride) were added dropwise to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-acetoxymethyl-2-(3,4-dimethoxy-benzoylamino)-thiophene-3-carboxylic acid methyl ester as a useful intermediate (26 mg, 3 steps, yield 67%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].O.[NH2:13][NH2:14]>>[NH:13]1[C:6]2[C:7](=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:8]=[N:14]1
Reactant: N#Cc1cc(F)cc(C=O)c1
Reactant: NN
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Cyano-3-fluorobenzaldehyde (4 g, 26.8 mmol) was dissolved in hydrazine hydrate and stirred at room temperature for 18 hours. The solution was poured onto ice and the resultant solid was separated by filtration and then dried under vacuum at 60° C. to afford the title compound (1.27 g) as a pink solid. Further material was isolated from the aqueous layer. MS (ES): C8H5N3 requires 143; found 144 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(Cl)Cl.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (Synthesis, 606, 1981) (3.5 g, 13.3 mmol) and 10% Pd/C (0.5 g) in 100 mL of ethanol/methylene chloride (2:1) was pressurized with 30 psi hydrogen and shaken over 1 hours. The catalyst was then removed by filtering through a short pad of silica gel to give the title compound (2.8 g, 90%) as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85–2.00 (m, 4 H), 3.00–3.10 (m, 4 H), 3.93 (s, 4 H), 6.60 (d, J=6.0 Hz, 2 H), 6.80 (d, J=6.0 Hz, 2 H); MS (ES) m/z: 235.2 (MH+); HRMS Calcd. for C13H18N2O2: 234.1380. Found: 234.1371.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[N:43]1([CH2:52][CH2:53]O)[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]1>>[OH:51][CH2:50][CH2:49][N:46]1[CH2:45][CH2:44][N:43]([CH2:52][CH2:53][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:48][CH2:47]1
Reactant: OCCN1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCN2CCN(CCO)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(piperazine-1,4-diyl)diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl ester, dimer. MS (ES+) m/z calcd. for C70H73Cl4F4N8O8: [(M+H)+]1369. found: 1369.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C
Temperature: 115 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 4-methyl-3-(methyloxy)phenol (Reference Intermediate R2, 400 mg) in dry N,N-dimethylformamide (15 mL), potassium carbonate (1200 mg, 8.69 mmol) and then 2-chloro-5-nitropyridine (551 mg, 3.47 mmol) were added and the reaction mixture was stirred for 2 hours at 115° C. The reaction was quenched with water (10 mL), diluted with brine (20 mL) and extracted with ethyl acetate (3 times 30 mL). The organic layer was washed with ice cold brine (2 times 30 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP column) with a gradient cyclohexane/ethyl acetate from 10/0 to 8/2. Evaporation afforded the to title compound as a light yellow oil (570 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CCC(=O)O)cc2OCC3)n(C(C)C)n1

Procedure:
Methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoate was treated with lithium hydroxide to give 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)propanoic acid. M/z 382.2, calc. 381.18.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([OH:13])=NC(O)=[N:9]2)=[N:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[NH2:9][C:10]1[C:5]([C:6]([OH:13])=[O:14])=[N:4][CH:3]=[C:2]([CH3:1])[N:11]=1
Reactant: Cc1cnc2c(O)nc(O)nc2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C(=O)O)c(N)n1
Temperature: 150 °C

Procedure:
7-Methyl-pteridine-2,4-diol (prepared by the procedure of ‘Synthesis of 2,6-Disubstituted pyrazines and Related Derivates.’, Sharefkin, D. M. J. Am. Chem. Soc., 1959, 345) (4 g, 22.5 mmol) is suspended in a solution of NaOH (2.17 g, 53 mmol) in H2O (20 ml), in an autoclave, and the mixture is heated to 150° C. for 3 days. The reaction mixture is cooled to room temperature and the pH is adjusted to 2.5 by the slow addition of 6M HCl (98 ml). The resulting suspension is cooled in a fridge for 1.5 hours, and the solid is then collected by filtration, washed with cold H2O, and MeOH, and dried in vacuo to yield 3-amino-5-methyl-pyrazin-2-carboxylic acid as a beige solid. [M+H]+ 154
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]2[CH:24]=[C:23]([F:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)[C:9]2[C:10]([C:15](O)=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:14])[CH:13]=3)[C:15](=[O:16])[N:18]2[C:19]2[CH:24]=[C:23]([F:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(C(Nc2cc(F)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)n1
Solvent: CCOCC
Product: Cn1cc2c(n1)C(=O)N(c1cc(F)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid (Step 14.4). Trituration in Et2O was done after purification on silica-gel. tR: 3.46 min (HPLC 1); tR: 0.76 min (LC-MS 2); ESI-MS: 373 [M+H]+ (LC-MS 2); Rf=0.44 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.46 (s, 3H) 3.98 (s, 3H) 6.21 (s, 1H) 7.26 (d, J=7.3 Hz, 2H) 7.38 (d, J=7.3 Hz, 2H) 7.66 (d, J=11.4 Hz, 1H) 7.76-7.87 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC.[OH-].[Na+]>O.C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[C:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: Cn1nccc1-c1cc(Cl)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cn1nccc1-c1cc(Cl)ccc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A 50-mL round-bottom flask was charged with 5-(2-bromo-5-chlorophenyl)-1-methyl-1H-pyrazole (992.0 mg, 3.65 mmol), diethyl ether (18 mL), and triisopropyl borate (1 mL, 4.38 mmol). The flask was cooled in a dry ice-acetone bath for 10 min, then n-BuLi (1.91 mL, 4.38 mmol) was added dropwise over a couple of minutes. Following the addition, the cooling bath was removed, and the mixture was warmed to room temperature. An aq. 2N NaOH solution (20 mL, 40 mmol) was added, and the resulting mixture was stirred vigorously for 2 h. The mixture was diluted with water and diethyl ether. The layers were separated, and the ethereal layer was extracted with water (2×). The aq. layers were combined, and the combined aq. mixture as washed with diethyl ether. The etheral layer was back-extracted once more, and the aq. layers were all combined. The combined aq. solution was acidified to about pH 1 with 3N aq. HCl to give a clear solution. The aq. solution was extracted with EtOAc (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM and concentrated in vacuo to give (4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (660 mg, 2.79 mmol, 76% yield) as a light-yellow foam. m/z (ESI) 237.0 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>II.C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of I2 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2,1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2)[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:11]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH2:10][CH2:9][OH:8])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:15]=2[CH:23]=1
Reactant: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccn3)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: OCC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of [(S)-3-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propyl](7H-purin-6-yl)amine (465 mg, 0.8 mmol) in anhydrous DCM (8 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron tribromide (1.0 M in DCM, 2.4 mL, 2.4 mmol). The reaction mixture was stirred at 0° C. for 1 h. MeOH was added and the volatiles removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% MeOH in DCM) to afford 304 as a white solid (143 mg, 44%). LCMS (Method K): RT 2.73 min [M+H]+ 404.9. 1H NMR (DMSO-d6, 400 MHz): δ 9.56-9.48 (1H, m), 8.65-8.57 (2H, m), 8.49 (1H, s), 8.11 (1H, td, J=7.74, 1.90 Hz), 7.83-7.74 (2H, m), 7.56 (1H, t, J=6.09 Hz), 7.28-7.16 (2H, m), 6.07-5.97 (1H, m), 3.59-3.45 (2H, m), 2.39-2.29 (1H, m), 2.24-2.12 (1H, m)
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][CH2:3][OH:4])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OCCOc1ccc(Br)cc1C(F)(F)F
Reaction time: 6 h

Procedure:
2-Bromoethanol (23.3 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (30 g) and potassium carbonate (34.4 g) in acetonitrile (200 ml). The above mixture was refluxed for 8 hours then another portion of 2-bromoethanol (8 g) was added and the reflux continued for another 6 hours. After diluting with ethyl acetate (500 ml), the mixture was washed with water (300 ml) then 0.1 M sodium hydroxide (200 ml). Organic layer was dried over magnesium sulphate, solvent removed under reduced pressure, the residue was taken into heptane by heat, 2-(4-bromo-2-(trifluoromethyl)-phenoxy)-ethanol crystalised and collected by filtration (17 g).
Reaction SMILES: [CH2:1]([N:21]=[N+]=[N-])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[CH2:1]([NH2:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN
Yield: 51 %

Procedure:
The crude azide was reduced to the title amine as follows: To a magnetically stirred solution of 132 mg (0.43 mmol) of arachidonyl azide in 3 mL of dry diethyl ether was added 4 mL of 1.0 M solution of lithium aluminum hydride (4.0 mmol) in THF dropwise at room temperature. The reaction mixture was refluxed for 3 hours and then quenched with wet diethyl ether. The white suspension was filtered, and the filtrate was evaporated to dryness. Chromatography on silica gel (10–50% MeOH in dichloromethane) gave 65 mg (51%) of arachidonylamine as a white solid: TLC (20% EtOAc—CH2Cl2) Rf 0.33; 1H NMR (200 MHZ, CDCl3) δ5.38 (m, 8H), 2.82 (m, 6H), 2.70 (t, J=6.6 Hz, 2H), 2.08 (m, 4H), 1.40 (m, 4H), 1.26 (m, 6H), 0.89 (t, J=6.4 Hz, 3H). Anal. (C20H35N)C, H, N.