Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+].[CH3:24][OH:25]>O>[CH3:24][O:25][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([O:13][CH3:19])=[O:12])[CH:4]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxyisophthalic acid (16.0 g) in methanol (150 mL) was added conc. sulfuric acid (5 mL), and the mixture was heated for 22 hours under reflux. Then, the reaction solution was allowed to stand for cooling down to room temperature, diluted with water (150 mL), and added with sodium bicarbonate (15 g). The resulting precipitate was filtered, washed successively with water/methanol (1:1, v/v) (150 mL) and water, and dried to give the title compound (17.45 g).
Reaction SMILES: [CH3:1][P:2]([CH3:11])([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[Li][N+:13]([O-:15])=[O:14]>CN1C(=O)N(C)CCC1.[Cl-].[Na+].O.CC(O)C>[CH3:1][P:2]([CH3:11])([C:4]1[CH:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: CP(C)(=O)c1ccc(F)cc1
Reactant: [Li][N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)O
Product: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 45.1 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 3.90 g (22.7 mmol) of 1-(Dimethyl-phosphinoyl)-4-fluoro-benzene and 6.0 g (113.3 mmol) of LiNO2 (for prep see, W. C. Ball and H. H. Abram J. Chem. Soc. 1913, 103, 2130-2134) in 27 mL of DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) was stirred at ambient temperature for 5-10 min (to dissolve fluoro compound) then heated at 190° C. for 3 days. The resulting dark brown solution was cooled to ambient temperature, diluted with 300 mL of brine, then extracted with EtOAc (10×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over MgSO4 and concentrated. The excess DMPU was removed via short-path distillation (120° C./0.3 mm) to provide a semi-solid, which was dissolved in a minimum amount of iPrOH and purified by silica gel flash chromatography (eluted with 5% iPrOH/DCM, then 10% iPrOH/DCM, then 15% iPrOH/DCM) to provide 2.04 g of an yellow solid: 1H NMR (300 MHz, DMSO-d6) δ8.34 (dd, J=8.7, 1.9 Hz, 2H), 8.07 (dd, J=10.6, 8.8 Hz, 2H), 1.75 (s, 3H), 1.70 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ37.89.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccc4ccccc34)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-1-yl)pyrazin-2-amine (7d) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) at. 0° C. and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11d (442 mg, 653 μmol, 55.9%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.19 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.24 (s, 2H), 6.54-6.60 (AA′BB′, 2H), 6.65-6.72 (AA′BB′, 2H), 6.91-6.98 (AA′BB′, 2H), 7.36-7.54 (m, 4H), 7.61-7.69 (m, 1H), 7.87-8.08 (m, 4H, includes AA′BB′), 9.09 (s, 1H), 10.27 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.94, 25.48 (3C), 25.55 (3C), 119.4 (2C), 120.4 (2C), 125.0, 125.4, 125.7, 126.2, 126.8, 128.0, 128.15, 128.21 (2C), 128.6, 128.9 (2C), 129.9, 130.7, 133.4, 134.8, 138.2, 144.4, 147.9, 148.3, 153.5, 156.7, 169.3 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 492, 538, 675, 718, 779, 806, 839, 914, 1007, 1080, 1115, 1169, 1260, 1362, 1420, 1441, 1472, 1510, 1605, 1670, 2857, 2886, 2930, 2955, 3046, 3223; HRMS (ESI+) m/z 698.3205 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:34][O:35][C:36](=[O:42])[C@H:37]([C@@H:39]([CH3:41])[OH:40])[NH2:38].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH:38][CH:37]([C:36]([O:35][CH3:34])=[O:42])[CH:39]([OH:40])[CH3:41])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
An ice-cooled solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 168) (6.40 g, 21.45 mmol) in dichloromethane (75 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (3.19 g, 23.60 mmol), threonine methyl ester hydrochloride (4.00 g, 23.60 mmol), N,N-diisopropylethylamine (7.85 ml, 45.10 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.52 g, 23.58 mmol) and the mixture was stirred for 17 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate then washed sequentially with water, aqueous citric acid solution (10% w/v), a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was dissolved in diethyl ether (100 ml) and treated with pentane (150 ml) to produce a white precipitate. This was filtered off and washed with pentane to afford the title compound as a white powder (6.48 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:13]2[C:14](=[O:21])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:22])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To 3-(4-bromophenyl)propan-1-ol (4.70 g, 21.9 mmol), isoindoline-1,3-dione (3.54 g, 24.0 mmol) and triphenylphosphine (6.88 g, 26.2 mmol) in a 500 mL round bottomed flask equipped with a stir bar, nitrogen, and addition funnel, and cooled in an ice water bath was added diisopropyl azodicarboxylate (5.10 mL, 26.2 mmol). The reaction was allowed to warm to room temperature over the weekend. The reaction mixture was adsorbed onto Celite®. Purification by flash column chromatography using 5-20% ethyl acetate/hexanes as eluent provided a solid which was dried overnight at 50° C. in vacuo to afford the title compound as a white solid (6.51 g, 87%): mp 88-90° C.; 1H NMR (400 MHz, CDCl3) δ 7.86-7.79 (m, 2H), 7.71 (dd, J=5.5, 3.0 Hz, 2H), 7.38-7.32 (m, 2H), 7.11-7.04 (m, 2H), 3.73 (t, J=7.1 Hz, 2H), 2.68-2.59 (m, 2H), 2.07-1.96 (m, 2H); ESIMS m/z 346 [(M+2)+].
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].Br[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([NH:23][CH2:22][CH2:21][CH2:20][N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[O:38])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
A mixture of 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (50.0 mg, 2.0 mmol), N-(3-bromopropyl)-2,2-diphenylacetamide (64.2 mg, 0.2 mmol), K2CO3 (55.0 mg, 4.0 mmol), and Nal (45.0 mg, 0.3 mmol) in 2 mL of DMF was stirred at room temperature for 10 minutes followed by heating to 80–90° C. for 12 h. The reaction mixture was cooled to room temperature and purified by preparative TLC (silica gel, EtOAc/NH3 (2 M in MeOH); 95:5) to afford N-[4-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2-methylpropanamide as a colorless oil (15.7 mg, 32%): ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25].Cl>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCCCCNCCCCCO
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0.0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1 N aqueous HCl (200 mL) and was extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1H NMR (CDCl3) δ8.03 (m,1H), 6.88-6.59 (m,2H), 6.45 (bs,1H), 3.68 (t,2H,J=6.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1SC.[NH2:22][OH:23]>C(O)(C)C>[OH:23][NH:22][C:7]1[N:6]([CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=2[O:2][CH3:1])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CN1Cc2ccccc2N=C1SC
Reactant: NO
Solvent: CC(C)O
Product: COc1ccccc1CN1Cc2ccccc2N=C1NO

Procedure:
0.6 g (2.01 mmol) 3-(2-methoxybenzyl)-2-(methylthio)-3,4-dihydroquinazoline and 265 mg hydroxylamine in 10 mL isopropanol were heated at reflux for approx. 36 hours. For workup, the mixture was evaporated, the resulting residue was recrystallized in a mixture of diethyl ether/methyl tert-butyl ether 1:1 and then lyophilized by MPLC (silica gel: Bischoff Prontoprep 60-2540-C18E, 32 μm; mobile phase: CH3CN/H2O+0.1% acetic acid). 300 mg white solids.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)#[N:3].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([NH:18][NH2:19])=O>CO>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:3]=[C:2]([C:4]2[CH:9]=[N:8][CH:7]=[CH:6][N:5]=2)[NH:19][N:18]=1
Reactant: NNC(=O)c1cnccn1
Reactant: N#Cc1cnccn1
Agent: [Na]
Solvent: CO
Product: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reaction time: 1 h
Yield: 35.5 %

Procedure:
Sodium (50 mg.) is added to 2-cyanopyrazine (1 gram, 0.01 mole) in 20 ml. of methanol. The solution is allowed to stand 1 hour at room temperature and is added to a suspension of pyrazine carboxylic acid hydrazide (1.4 grams, 0.01 mole) in 50 ml. of methanol. The reaction mixture is heated at reflux for 2 hours and then at room temperature for 16 hours. After cooling, the intermediate acylamidrazone is removed by filtration and is then heated at temperatures beteen 200° to 260° C. over two and one-half hours. After cooling and recyrstallization from methanol-water, 0.8 grams of 3,5-dipyrazinyl-1,2,4-triazole, m.p. 269°-270.5° C. is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[N:17]([CH3:18])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1)=O.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>C(O)C>[CH3:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:8][O:7][C:6]1[CH:19]=[CH:20][C:3]([CH:1]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:4][CH:5]=1
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 79.2 %

Procedure:
A mixture of 0.35 g of 2-(4-formylphenoxymethyl)-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 112), 0.31 g of 2,4-thiazolidinedione, 0.26 ml of piperidine and 10 ml of ethanol was heated under reflux for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the residue was crystallized by trituration with water. The crystals were collected by filtration and washed with water and then with ethyl acetate, to give 0.38 g of the title compound, melting at 279-281° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:3]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1>>[ClH:1].[ClH:1].[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:31])[F:30])[CH:22]=3)[N:3]=2)[CH2:36][CH2:35]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(OC(F)(F)F)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3cccc(OC(F)(F)F)c3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
300 mg of the product obtained in Stage 1 above and 365 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/ methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 200 mg of expected product is recovered.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[CH3:4].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[C@@H:3]([N:5]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[C:26](=[O:27])[O:28][CH3:29])[CH3:4]
Reactant: COC(=O)Cl
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (2.00 g, 7.97 mmol) and K2CO3 (3.30 g, 23.9 mmol) in CH2Cl2 (100 mL) was added methyl chloroformate (2.25 g, 23.9 mmol) dropwise at 0° C., and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give the crude product, which was purified by chromatography to afford (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (2.0 g, 81%). 1H NMR (CDCl3): 0.92 (s, 9H), 1.12-1.21 (d, 3H), 3.02-3.11 (m, 1H), 3.27-3.49 (m, 1H), 3.66 (s, 3H), 3.98-4.23 (m, 1H), 7.06-7.17 (m, 2H), 7.92-8.08 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:21]=[O:22])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)c1coc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1c(C=O)oc2ccccc12
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 3-isopropylbenzofuran (250 mg, 1.56 mmol) in THF (1 mL) is added nBuLi (2 mL, 2 mmol) drop wise and the reaction is stirred for 30 minutes. DMF (1 mL) was added to the reaction and stirred at room temperature overnight. The solution is placed in an ice bath and carefully quenched with 5% aqueous HCl solution (2 mL), and extracted with ethyl acetate (3×5 mL), dried over sodium sulfate and concentrated. The product was purified on silica with 100% hexanes to yield title compound in as a colorless oil (250 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.55 (d, 1H, J=9.0 Hz), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.33-1.31 (2s, 6H).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C(Cl)(Cl)Cl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC=CCC=CCC=CCCCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCCCCCCCC(=O)Cl

Procedure:
To a solution of 1.000 g of 9,12,15-octadecatrienoic acid in 20 ml of dry chloroform at room temperature was added in the atmosphere of argon 0.50 ml of oxalyl chloride. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the remaining oxalyl chloride by distillation. The 9,12,15-octadecatrienoyl chloride thus produced was again dissolved in 2 ml of dry chloroform.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.IC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1cccc(I)c1
Reactant: NN
Agent: Nc1cccc(I)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(I)c1
Yield: 74 %

Procedure:
This compound was prepared using 148 mg (0.5 mmol) of 2-[(3-iodophenyl)hydrazono]-malononitrile, which was derived from 3-iodoaniline (219 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 122 mg (74%) of the title compound as a mustard coloured solid.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38](OC)[O:39]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][CH:9]([CH:38]=[O:39])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (600 mg), Amberlyst (registered trade ark) 15 ion exchange resin (120 mg), water (0.05 mL) and acetone (15 mL) was stirred at room temperature for 15 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-3:1, volume ratio) to give the title compound (560 mg, yield 100%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:20]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixture of 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate (0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12 mL). The resultant solution was purged with nitrogen for 10 minutes before tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added. The reaction mixture was heated to reflux for 65 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL with water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield the title compound as a gold oil (1.09 g). This material was used without further purification in the next step.