Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:18][CH:19](O)C>CC(C)=O>[CH2:7]([S:18][CH2:19][CH2:1][OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)S
Reactant: CCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCSCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
Under nitrogen, to a suspension of potassium carbonate (27 g, 200 mmol) in acetone (100 ml) was added decyl bromide (10 ml, 50 mmol) and mercaptoethanol (4.4 ml, 63 mmol). The suspension was stirred at room temperature for 2 days, then partitioned between water and 80% hexane/ethyl acetate. The organic phase was washed with 2N sodium hydroxide, dried over magnesium sulfate, and the volatiles removed under vacuum to give 2-(decylthio)ethanol (10.2 g, 47 mmol) as a colorless liquid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(-c2cc([Si](C)(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3-Bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) was dissolved in 100 ml toluene and the volume reduced by approximately 3/4 by distillation. The cooled solution was diluted with 130 ml diethyl ether, cooled to ~10° and treated with 1.55 M n-butyl lithium (15.5 ml, 1.2 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of trimethylsilyl chloride (3.1 ml, 1.2 equiv.) in 5 ml diethyl ether. The reaction mixture was stirred overnight at room temperature and then quenched with water.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:11][C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:16]3)=[N:9][CH:8]=1)=[O:6].N1C=NN=N1.[CH2:35]([O:42][P:43](N(C(C)C)C(C)C)[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClC1C=CC=C(C(OO)=[O:67])C=1>ClCCl.C(#N)C>[C:24]1([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C@@H:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C:10]3[S:11][C:7]([C:5]([NH:4][CH2:3][CH2:2][O:1][P:43](=[O:67])([O:42][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:6])=[CH:8][N:9]=3)[CH:14]=2)[O:19]1
Reactant: Cc1ccccc1[C@@H]1CCc2cc(Oc3ncc(C(=O)NCCO)s3)ccc2O1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1[C@@H]1CCc2cc(Oc3ncc(C(=O)NCCOP(=O)(OCc4ccccc4)OCc4ccccc4)s3)ccc2O1
Temperature: 0 °C
Reaction time: 1.17 h

Procedure:
To a suspension of 2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (1 g, 2.44 mmol) and tetrazole (222 mg, 3.17 mmol, 1.3 eq) in dichloromethane (14 ml) and acetonitrile (14 ml) at 0° C., dibenzyl-N,N-diisopropylphosphoramidite (1.01 g, 2.92 mmol, 1.2 eq) was added and the mixture stirred at 0° C. for 70 min. To the resulting solution 3-chloro-perbenzoic acid (65%, 776 mg, 2.92 mmol, 1.2 eq) was added in one portion and vigorous stirring at 0° C. was continued for 10 min. The mixture was diluted with dichloromethane and the organic layer washed with a saturated aqueous solution of sodium hydrogencarbonate and subsequently with a saturated aqueous solution of ammonium chloride. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate). Phosphoric acid dibenzyl ester 2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl ester was obtained as a colorless oil (1.30 g, 80%).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6]O)#[N:2].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[I-:37].[Na+]>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][I:37])#[N:2]
Reactant: N#CC(CCCO)(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: N#CC(CCCI)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
To a solution of 4-cyano-4,4-diphenylbutan-1-ol (2.2 g, 8.7 mmol.) and pyridine (2.69 ml, 33 mmol.) in acetonitrile (20 ml) was added p-toluenesulfonyl chloride (1.66 g, 8.7 mmol.). To the mixture was added 4-dimethylaminopyridine (a catalytic amount), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added ethyl acetate, which was washed with a 1N HCl and a saturated aqueous saline solution, and, then, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in acetone (30 ml), to which was added sodium iodide (1.96 g, 13 mmol.). The mixture was refluxed for one hour. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and a dilute aqueous solution of sodium thiosulfate, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (1.3 g).
Reaction SMILES: [C:1]1([CH:7]([N:11]([CH2:17][CH:18](OC)OC)[C:12](=O)[CH:13]([CH3:15])[CH3:14])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1.C(N(CC)CC)C.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C.O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:12]([CH:13]([CH3:14])[CH3:15])[N:11]3[CH:17]=[CH:18][C:2]4[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:7]=23)=[CH:28][CH:29]=1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: COC(CN(C(=O)C(C)C)C(C(=O)O)c1ccccc1)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(F)cc2)c2c3ccccc3ccn2c1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetic acid (32.1 g) and methyl 4-fluorophenylpropiolate (22.5 g) in acetic anhydride (120 ml) was treated with triethylamine (16 ml) and the resulting amber solution was stirred at room temperature under argon for 24 hours. The solution was then added, dropwise during 10 minutes, to concentrated sulphuric acid (200 ml), stirring and cooling by means of an icebath. The mixture was stirred for 30 minutes and then it was poured into iced water (2.5 liters), and extracted with dichloromethane (3×400 ml). The combined extracts were washed with water (250 ml) and with brine (250 ml), dried over magnesium sulphate and evaporated, to give a brown solid, which was recrystallised from methanol, to give methyl 1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]isoquinoline-2-carboxylate in the form of an off-white solid, m.p. 170°-173° C.
Reaction SMILES: CC1[N:3]=[CH:4][NH:5]C=1CSCCN.[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CSC(=N)[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[NH2:3][C:4]([NH2:5])=[NH:20]
Reactant: CSC(=N)N
Reactant: Cc1nc[nH]c1CSCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[ (4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([C:14]([OH:16])=O)=[CH:5]2.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1>>[O:23]=[S:20]1(=[O:24])[CH2:21][CH2:22][N:17]([C:14]([C:6]2[N:7]([CH:11]([CH3:12])[CH3:13])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:16])[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(O)ccc21
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(O)ccc21

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 3, the title compound was synthesized from 5-Hydroxy-1-isopropyl-1H-indole-2-carboxylic acid (Example 20, step 3) and thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201). The desired product was obtained in a yield of 75% as white solid. MS (m/e): 335.5 (M−H, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: Nc1ccc(Cl)nc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nc3)cccc12
Reaction time: 72 h
Yield: 42.7 %

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (1.35 g), 5-amino-2-chloropyridine (0.64 g), pyridine (0.4 g) and 4-dimethylaminopyridine (0.02 g) in dichloromethane (20 ml) was allowed to stand for three days. The solution was divided into two equal portions and each portion was applied to a separate silica gel Mega Bond Elut column. The columns were eluted with dichloromethane and the product-containing fractions were concentrated by evaporation. The residue was triturated with ether to give 5-(dimethylamino)-N-(2-chloro-5-pyridyl)-1-naphthalenesulphonamide (0.77 g); m.p. 145°-146° C.; mass spectrum (+ve FAB, methanol/NBA): 362(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]3[C:24]([CH3:41])=[N:25][C:26]([CH:29]4[CH2:33][CH2:32][N:31](CC5C=CC=CC=5)[CH2:30]4)=[CH:27][CH:28]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:42])[O:4][N:3]=1.ClC(OC(Cl)C)=O.CO>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:23]3[C:24]([CH3:41])=[N:25][C:26]([CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:27][CH:28]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:42])[O:4][N:3]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CC#N
Product: Cc1nc(C2CCNC2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-{2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinyl}-N-(2-methylpropyl)benzenesulfonamide (114 mg, 0.194 mmol) in acetonitrile (3 mL) was added 1-chloroethyl chloroformate (0.027 mL, 0.252 mmol) and the reaction mixture was heated at reflux under nitrogen for 2 hours. To this was added methanol (3 mL) and the reaction mixture was refluxed under nitrogen for 1 hour. The solvent was removed in vacuo. The sample was then purified by mass directed autoprep (formic acid buffered) to give the required product as formic acid salt (33 mg). LCMS (2 min, formic) Rt 0.86 min, m/z (ES+) 499 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]CCCCCCCCC)=[N+:2]=[N-:3].[N:22](CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[NH:22][CH:11]=[CH:10][CH:9]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Yield: 65.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.249 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.137 g, 66%). 1H NMR (300 MHz, CD3OD) δ 6.88 (d, 1H), δ 6.77 (d, 1H), δ 6.14 (t, 1H), δ 3.46 (t, 2H), δ 3.37 (q, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 162.9, 125.6, 122.2, 121.9, 110.9, 109.2, 50.6, 38.9 ppm; HRMS (ESI) calcd for C7H9N5O (M+) 179.0807, found 179.0803.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([NH:20][OH:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(NO)C(=O)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
To the solution of ethyl 3-(4-bromophenyl)-3-oxopropanoate in THF (prepared in step A above), add acetic acid (160 L) and water (73 L) at an internal temperature of 8° C. To this mixture, add a solution of sodium nitrite (6.35 kg, 92.00 mol, 1.25 eq) in water (30 L) at an internal temperature of 6 to 9° C. during 90 min and stir at this temperature for 90 min. At an internal temperature of 4 to 7° C., add water (147 L) over 30 min to the reaction mixture and stir the resulting suspension for 30 min. Filter the suspension and wash the filter cake with water (59 L) and heptane (60 L). Dry the filter cake under a constant flow of nitrogen for 13 h to obtain the title compound: 18.731 kg according to loss of drying (23.044 kg wet); white powder; 1H NMR (DMSO-d6, 500.0 MHz): δ 1.22 (t, J=7.1 Hz, 3H), 4.27 (q, J=7.1 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H, 7.83 (d, J=8.8 Hz, 2H), 13.18 (s, 1H); 13C NMR (DMSO-d6, 125.7 MHz): δ 14.36, 62.27, 129.68, 131.09, 133.08, 133.36, 148.44, 161.17, 191.08; Anal. Calcd for C11H10BrNO4: C, 44.02; H, 3.36; Br, 26.63; N, 4.67; O, 21.32. Found: C, 43.98; H, 3.31; Br, 26.65; N, 4.59; MS (ES−) 299; IR (KBr): 3281, 3219, 3049, 2983, 2870, 1728, 1680, 1586, 1446, 1400, 1302, 1262, 1029, 944 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][Mg]Br.C(OCCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:14])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (75.6 mg, 0.362 mmol) was dissolved in THF (2 mL) under argon and the flask was immersed in ice. Methyl magnesium bromide (1M solution/butyl ether 0.51 mL, 0.507 mmol) was added dropwise while the reaction was cooled in ice. After fifteen minutes at 0° C., the ice bath was removed and the reaction was allowed to stir at room temperature for two hours. 1M Hydrochloric acid was added to quench the reaction and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (3% MeOH/CH2Cl2) to yield the title compound as a clear oil (62.4 mg, 77%). 1H NMR (CDCl3) δ (ppm): 8.18 (s, 1H), 8.06 (m, 1H), 7.50 (m, 2H), 5.32 (m, 1H), 2.69 (d, 1H), 1.76 (d, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:14])[CH2:10][CH2:11][CH:12]=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Mn]([O-])(=O)(=O)=[O:17].[K+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.CC(C)=O>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:14])[CH2:10][CH2:11][C:12]([OH:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CCC=O)CCC1CCCCC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CCC(=O)O)CCC1CCCCC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A flask was charged with 7.12 g (36.3 mmol) of (R)-6-cyclohexyl-4-methyl-hexanal, 40 mL of water, 20 mL of acetone, 4 mL acetic acid, and 6.18 g (39.9 mmol) of potassium permanganate. The mixture was stirred vigorously overnight. The mixture was then treated with sat. aqueous sodium bisulfite until the liquid became clear. The liquid was extracted with hexanes. The combined hexane layers were washed with sat. aqueous sodium bisulfite until the hexane layer was clear. The hexane phases were dried with magnesium sulfate. The drying agent was filtered off and the solvent was removed under reduced pressure, which yielded 4.17 g (54% yield) of a clear oil: 1H NMR (400 MHz, CDCl3) ppm 0.89 (m, 5H), 1.13 (m, 3H) 1.25 (m, 5H) 1.66 (m, 8H) 2.40 (m, 2H). MS (APCI) m+1/z=211.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([CH2:27][N:28]=[C:29]=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:30])[C:3]1=[O:20]
Reactant: O=C=NCc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylmethylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 240°-242° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1>C(O)(C)C>[Cl:3][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1
Reactant: N#Cc1ccc(Nc2nccc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Phosphorous oxychloride (104 gm) was added slowly to 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (12 gm) at 0° C. and then heated to reflux for 1 hour. The solution was then cooled to room temperature, stirred for 30 minutes and filtered. The precipitated solid thus obtained was dissolved in isopropyl alcohol at 0 to 5° C. and stirred for 1 hour at 0 to 5° C. The solid obtained was collected by filtration and then dried to obtain 9.75 gm of 4-(4-chloropyrimidin-2-ylamino)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:13])O[C:11]=1[CH3:12])=[O:5])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(NC1C=CC=CC=1)(=O)C.C(NC1C=CC(C(=O)C)=CC=1)(=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:13])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: Nc1ccccc1
Agent: CC(=O)Nc1ccc(C(C)=O)cc1
Agent: CC(=O)Nc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc(=O)n(-c2ccccc2)c1C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
A mixture of 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (=ethyl isodehydroacetate, 1.967 g, 10.02 mmol), aniline (1.865 g, 20.03 mmol) and acetic acid (0.5 mL, 9 mmol) was shaken at 90 C for 5 hours, then at 55° C. for 3 days. The excess of volatiles were removed in vacuo (0.1 mbar, 70 C, 30 min). It was transferred on to a SiO2 column (50 g) with 1,2-dichloroethane/heptane 1:3 purified by flash chromatography with gradient 20% to 100% of ethyl acetate in heptane. The pure fractions gave 906 mg of the title compound as pale yellow oil, yield 33% (non-pure additional fractions gave 886 mg of the title compound contaminated with acetanilide and 4′-acetamidoacetophenone). LC-MS (m/z) 272.4 (MH+); tR=1.07. 1H NMR (600 MHz, DMSO-d6): 1.28 (t, J=7.1 Hz, 3H, Me of Et), 1.9 (s, 3H, 2-Me), 2.16 (d, J=0.9 Hz, 3H, 4-Me), 4.28 (q, J=7.1 Hz, 2H, CH2 of Et), 6.3 (s, 1H, 5-H), 7.27 (dm, J=7.7 Hz, J<1.5 Hz, 2H, two ortho-H of Ph), 7.47 (tt, J=7.4 Hz, J=1.2 Hz, 1H, para-H of Ph), 7.53 (tm, J=7.5 Hz, J<1.7 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cc(C)cc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3,5-dimethylphenyl)-2-naphthalenyl)ethynyl]-benzoate (Compound 4) 90.0 mg (0.207 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.45 (2H, s), 7.00 (1H, s), 6.97 (1H, s), 5.97 (1H, t, J=4.5 Hz), 2.31 (2H, d, J=4.5 Hz), 2.30 (6H, s), 1.29 (6H, s).
Reaction SMILES: C([C:13]1[N:14]=[C:15]([CH2:18][CH3:19])[NH:16][CH:17]=1)CCCCCCCCCCC.[CH2:20]([Cl:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:29](O)[CH2:30][CH2:31][CH3:32]>>[Cl-:28].[CH2:27]([N:14]1[CH:13]=[CH:17][N:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]1[CH2:18][CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCc1c[nH]c(CC)n1
Reactant: CCCCO
Reactant: CCCCCCCCCl
Product: CCCCCCCCCCCCN1C=CN(CCCCCCCC)C1CC
Product: [Cl-]
Temperature: 127 °C

Procedure:
1 mole of n-dodecyl-2-ethylimidazole is dissolved in 500 ml of n-butanol and reacted with 1.2 moles of n-octyl chloride. This reaction mixture is heated at 127° C for 15 hours. Then the alcohol and the excess n-octyl chloride are distilled off and the remaining residue is washed with ether. Yield: 204 grams
Reaction SMILES: CC(OC([NH:8][CH:9]([CH3:36])[C:10]([NH:12][C:13]1[N:18]=[C:17]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[CH:15][CH:14]=1)=[O:11])=O)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:8][CH:9]([CH3:36])[C:10]([NH:12][C:13]1[N:18]=[C:17]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[CH:15][CH:14]=1)=[O:11]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-[6-[2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoylamino]-2-(2-phenylethynyl)pyridin-3-yl]benzoic acid E2c (16 mg, 0.03 mmol) and DCM:TFA (9:1, 1.7 ml) is stirred at RT for 90 minutes. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 3 mg (24%). HPLC-MS: M+H=386; tR=1.03 min (*Method—1).