Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl>[C:31]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(O[C@H]2CC[C@H]3[C@@H]4CC[C@H]5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 17β-(4-aminophenoxy)-4-methyl-5α-4-azaandrostan-3-one hydrochloride (7mg) in CH2Cl2 (100 μl) was added acetic anhydride (30 μl) followed by adding pyridine (50 μl). The mixture was stirred at room temperature for 2 hr and then concentrated to dryness. The residue was purified via a silica gel plate developed with 5% MeOH--EtOAc (Rf =0.3) to give the title product, mp. 340° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[H][H].[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][C:16]=1[Cl:23])=[O:13]>CN(C)C=O>[CH3:10][C:11]([CH3:25])([CH3:24])[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:17][C:16]=1[Cl:23])=[O:13]
Reactant: CC(C)(C)C(=O)Oc1ccc(CBr)cc1Cl
Reactant: [H][H]
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1ccc(Cn2cccn2)cc1Cl
Temperature: 10 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 15.3 g of pyrazole, 89.9 g of sodium hydride (60% oil dispersion) and 200 ml of anhydrous N,N-dimethylformamide was stirred at 60° to 70° C. under a nitrogen atmosphere for 2 hours. After the evolution of hydrogen gas ceased, the mixture was cooled to 10° C. To this mixture was added dropwise an anhydrous N,N-di-methylformamide (300 ml) solution of 68 g of 4-bromomethyl-2-chlorophenyl 2,2-di-methylpropanoate at room temperature under stirring over 1 hour, and the mixture was stirred at 80° C. for 1 hour. After cooling, the mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 39.5 g of 2-chloro-4-(1-pyrazolyl)methylphenyl 2,2-dimethylpropanoate as a colorless oil. Yield, 60%.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:36]=4[F:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
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: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(F)cc3F)c2)c(=O)c2[nH]c(Cl)nc21
Yield: 38.4 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol) and sodium carbonate (85 mg, 0.8 mmol) were stirred in dry DMF (2 ml) with 2,4-difluorobenzyl bromide (166 mg, 0.8 mmol) at 45° C. for 18 h. The mixture was degassed and stirred with tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and morpholine (176 mg, 2 mmol) at rt for 6 h. The reaction was worked up and purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH, eluting with DCM-MeOH (1:1) with 5% added AcOH) to yield the title compound (37.7 mg) as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1

Procedure:
A mixture of 7.7 g (0.023 mol) of 4-benzyloxy-3-(N-methylsulphonylamino)phenyl acetate, 4.75 g (0.035 mol) of crushed potassium carbonate and 3.3 ml (0.0276 mol) of benzyl bromide in 150 ml of anhydrous acetone is stirred at reflux temperature for 4 hours. After filtration and evaporation, the compound of the title is obtained, which is recrystallized in ethyl acetate.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:24]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[CH:47][CH:46]=[N:45]1)([CH3:43])[CH3:42].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[C:47]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([S:36]([CH3:39])(=[O:37])=[O:38])=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=3)[C:17]=2[CH3:16])[CH:46]=[N:45]1)([CH3:43])[CH3:42]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)n1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h

Procedure:
A solution of 560 mg (2.7 mmol) of 1,3-dicyclohexylcarbodiimide in 5 mL of acetonitrile was added with stirring to a mixture of 2-methyl-4-methylsulfonyl-3-(4-methylsulfonylphenyl)benzoic acid and 378 mg (2.7 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole in 15 mL of acetonitrile. The mixture was allowed to react for 1 hour and was then filtered. The solids were washed with a little acetonitrile. Triethylamine (1.13 mL, 8.1 mmol) and 274 microliters (2.7 mmol) of acetone cyanohydrin were added with stirring to the combined filtrate and acetonitrile wash. After 3 hours, the mixture was diluted with dichloromethane and the resulting solution was washed with 2N aqueous hydrochloric acid, filtered, and concentrated by evaporation under reduced pressure. The residue was dissolved in the minimum amount of hot ethanol and the solution was then cooled. The precipitate that formed was collected by filtration and dried to obtain the title compound as a pale yellow powder melting at 187-188° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[CH:12]=1>>[F:10][C:11]1[C:19]([N+:1]([O-:4])=[O:2])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled mixture of fuming nitric acid (2.5 mL) and conc. sulfuric acid (25 mL) was slowly added to 4-fluoro-2-methyl-benzoic acid (9 g, 58.3 mmol) at 0° C. under N2 atmosphere over a period of 45 min. Reaction mixture was allowed to stir at 0° C. for 1 h. Starting material consumption was monitored by the TLC. Upon completion of the reaction the reaction mass was poured onto crushed ice and extracted in ethyl acetate (3×100 mL). Combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The solid obtained was washed with pet ether to afford the pure product 4-fluoro-2-methyl-5-nitro-benzoic acid.
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)([CH2:6][OH:7])[CH2:8][OH:9]
Reactant: CC(=O)NC(CO)(CO)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CCCc1ccc([N+](=O)[O-])cc1
Yield: 29.1 %

Procedure:
2-Acetamido-2-[3-(4-nitrophenyl)propyl]-1,3-propanediol (400 mg) was dissolved in 50 ml of methanol and 6.7 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours and neutralized with dilute hydrochloric acid. The solvent was distilled away and chloroform was added to the residue for extraction. The chloroform layer was washed and dried, and the solvent was distilled away. The residue was purified by silica gel column chromatography (methanol:chloroform=1:4) to give 100 mg of 2-amino-2-[3-(4-nitrophenyl)propyl]-1,3-propanediol as a red, oily substance.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[S:46][CH:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[S:46][CH:47]=1
Reactant: COCc1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (64 mg, 0.33 mmol) in CH2Cl2 (3.0 mL) was treated at rt with DMAP (10 mg, 0.08 mmol), HOBt (55 mg, 0.39 mmol), EDC (157 mg, 0.82 mmol) and DIPEA (0.25 mL, 1.48 mmol) and the resulting mixture was stirred for 15 min at rt. A solution of 2-((4-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (74 mg, 0.33 mmol) in CH2Cl2 (3.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (15.0 mL), the layers were separated and the org. phase was washed with 1N HCl (15.0 mL), water (10.0 mL), followed by brine (10.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 90:10 hept-EA to 60:40 hept-EA) gave the title compound as a white solid. TLC: rf (7:3 hept-EA)=0.15. LC-MS-conditions 07: tR=0.83 min, [M+H]+=397.21
Reaction SMILES: BrC1C=C(F)C=CC=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1S(Cl)(=O)=O>>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Agent: COC(=O)c1c(N)ccc2c1OCC1CC21
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 41, starting from methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42) and 2-fluorobenzenesulfonyl chloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]#N)=[O:7].Cl.[OH2:11].C.C[OH:14]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:7])[C:8]([OH:14])=[O:11]
Reactant: O
Reactant: N#CC(=O)c1ccco1
Reactant: CO
Agent: Cl
Product: O=C(O)C(=O)c1ccco1
Reaction time: 24 h

Procedure:
The 24.5 g. of crude 2-furoylcyanide was mixed with 160 ml. concentrated hydrochloric acid at 25° C. with intermittent stirring. The reaction was stored for 24 hours at 25° C. and diluted with 80 ml. of water. The reaction was stirred for 5 minutes and filtered. The filtrate was saturated with sodium chloride and extracted with 5 × 120 ml. of 1:1 ether-ethyl acetate solution. The extracts were combined, dried over anhydrous magnesium sulfate and evaporated at 30° C. (15 mm.) to give a brownish-orange solid. The solid was dissolved in methanol, treated with charcoal and evaporated under reduced pressure (15 mm.) to dryness to yield 17 g. of the acid.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:21][C:12]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:20][C:13]=1[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)NCc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)c(CNS(C)(=O)=O)c1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
Dissolve zinc (II) bromide (313 mg, 1.20 mmol) in tetrahydrofuran (2.5 mL) and treat with triethylamine (0.64 mL, 4.80 mmol). After 4 min add N-(5-bromo-2-fluorobenzyl)methanesulfonamide (282 mg, 1.00 mmol), (prepared as described in PREPARATION 35), trimethylsilylacetylene (0.30 mL, 2.12 mmol), and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol) to the reddish solution. Heat to 60° C. in a sealed tube overnight, cool to room temperature and filter through diatomaceous earth with ethyl acetate. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (220 mg, 74%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:52][CH:53]1[C@H:57]2[C@H:58](OC3CCCCO3)[N:59](C(OC(C)(C)C)=O)[C:60]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[C@H:25]2[C@H:26](OC3CCCCO3)[N:27](C(OC(C)(C)C)=O)[C:28]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:19]([O:20][CH:21]1[C@@H:25]2[CH:26]=[N:27][C:28]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=3[C:30](=[O:31])[N:24]2[CH2:23][CH2:22]1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:52][CH:53]1[C@@H:57]2[CH:58]=[N:59][C:60]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][C:61]=3[C:62](=[O:63])[N:56]2[CH2:55][CH2:54]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 89.5 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15j (210 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16j (112 mg, 0.17 mmol, 89%) as a solid: [α]20D=+637° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.24-1.51 (m, 16H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H; 17′-H); 1.78-1.93 (m, 4H, 13-H, 13′-H), 1.98-2.11 (m, 4H, 2-H, 2′-H), 2.25-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.68-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.89 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.14 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 28.9, 29.3, 29.5, 29.5, 29.6, 46.6, 53.7, 56.1, 69.1, 110.4, 111.5, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3338, 2926, 1599, 1506, 1456, 1431, 1381, 1261, 1216, 1092, 1023 cm−1; MS (FAB) m/z (relative intensity) 723 ([M+2×MeOH]+., 9), 691 ([M+MeOH]+., 15), 659 (M+., 100).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH3:10].[C:11]([C:15]1[O:16][C:17]2[C:23]([S:24](Cl)(=[O:26])=[O:25])=[C:22]([Cl:28])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])([CH3:13])[CH3:12].O>O1CCCC1>[CH3:8][N:9]([CH3:10])[S:24]([C:23]1[C:17]2[O:16][C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])=[N:19][C:18]=2[CH:20]=[CH:21][C:22]=1[Cl:28])(=[O:25])=[O:26]
Reactant: CNC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
12.9 ml (93 mmol; 3.0 eq) of triethylamine and 93 ml of 2 M dimethylamine in tetrahydrofuran were added dropwise to a solution of 9.55 g (31 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzoxazole-7-sulfonyl chloride in 200 ml of tetrahydrofuran cooled to 0° C. The reaction medium was stirred at 0° C. for 3 hours and was then treated with water. The reaction medium was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over magnesium sulfate, filtered and evaporated. 9.12 g of 2-tert-butyl-6-chlorobenzooxazole-7-sulfonic acid dimethylamide were obtained in the form of a beige solid. Yield=93%.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:18]=[CH:17][NH:16][N:15]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[NH3:5].[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:18]=[CH:17][NH:16][N:15]=3)[CH:9]=2)[CH2:3][CH2:4][N:5]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:7]1
Reactant: BrCCCc1ccccc1
Reactant: CC1(c2cccc(-c3nc[nH]n3)c2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc(-c3nc[nH]n3)c2)CCN(CCCc2ccccc2)CC1
Product: N
Yield: 26.7 %

Procedure:
To a solution of 4-methyl-4-(3-(1H-1,2,4-triazol-3-yl)phenyl)piperidine (Preparation 45, 65 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (34 mg, 0.40 mmol) and 1-bromo-3-phenylpropane (41 μL, 0.27 mmol). The resultant mixture was heated at 50° C. for 2 h and then allowed to cool. The mixture was partitioned between water (5 mL) and dichloromethane (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (20 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by column chromatography on silica gel (5 g) eluting with MeOH:CH2Cl2:0.88 ammonia (10:90:1) to give the title compound as a clear oil (13 mg, 13%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][N:17]2C(OC(C)(C)C)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][NH:17]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(C(c2ccccc2)N2C[C@@H]3C[C@H]2CN3)cc1
Yield: 59 %

Procedure:
A solution of compound 200 (0.5 g, 1.37 mmol) in 4N HCl in dioxane (5 mL) was stirred for 1 h at room temperature and then concentrated. The residue was purified by trituration with Et2O and filtered to afford 201 (0.24 g, 59%) as a beige solid. LRMS (ESI): (calc) 264.2. (found) 265.3 (MH)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]Br)[CH:8]=1)#[N:6].C(N(CC)CC)C>CC(C)=O>[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:3]([CH3:4])[CH3:2])[CH:8]=1)#[N:6]
Reactant: CNC
Reactant: N#Cc1ccnc(CBr)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Dimethylamine hydrochloride (4.78 g, 58.6 mmol) was added to a solution of 4-cyano-2-bromomethylpyridine (3.95 g, 19.5 mmol) and triethylamine (13.58 mL, 97.7 mmol) in acetone (40 mL). The reaction mixture was stirred overnight at room temperature in a sealed tube. The reaction mixture was concentrated under reduced pressure and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and washed with water, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 99:1 methylene chloride/methanol) gave the desired 4-cyano-2-(dimethylamino)methylpyridine (2.10 g): 1H NMR (300 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 7.71 (s, 1H), 7.41 (dd, J=5.0, 1.2 Hz, 1H), 3.65 (s, 2H), 2.31 (s, 6H); ESI MS m/z 162 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.CN(C)[CH:16]=[O:17].O>CCOCC>[CH3:6][O:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:16]=[O:17]
Reactant: COCc1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCc1ccsc1C=O
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Reaction of 3-bromomethylthiophene with sodium methoxide in methanol provided 3-methoxymethylthiophene (84%). n-Butyl lithium (30 ml, 1.5 M, 45 mmol) was slowly added to 3-methoxymethylthiophene (5.0 g, 39 mmol) in dry ether (100 ml) at 25° C. After stirring for 1 h, N,N-dimethylformamide (5.7 g, 78 mmol) in dry ether (200 ml) was added dropwise and the resultant solution was stirred for an additional 18 h at 20° C. Water (5 ml) was added and the organic phase washed with 5% hydrochloric acid (100 ml) followed by water (100 ml) and dried. The solvent was removed to yield the crude product (5.2 g, 85%) which was essentially pure by n.m.r. Distillation afforded the title compound (3.80 g, 62%) as a colourless oil, b.p. 73°-75° C. at 0.25 mmHg (Found M+ : 156.0256. C7H8O2S requires M, 156.0245) which showed νmax (film) 667m, 1107m, 1200w, 1426m, 1662s, 2930w and 3100w cm-1 ; δH (CCl4) 3.35 (3H, s), 4.66 (2H, s), 7.05 (1H, d, J 5 Hz), 7.49 (1H, d, J 5 Hz), 9.87 (1H, s); m/z 156 (M+), 141 (M+ -CH3).