Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:25][Si:26]([CH3:43])([CH3:42])[C:27]#[C:28][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.O.ClCCl.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>[C:10]1([C:8]2[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:6][C:5]3[N:4]([N:3]=[C:2]([C:28]#[C:27][Si:26]([CH3:43])([CH3:42])[CH3:25])[N:24]=3)[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1

Procedure:
300 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 53), 613 mg trimethyl[(tributylstannyl)ethynyl]silane and 46 mg Pd(PPh3)4 are suspended in 12 ml toluene under a nitrogen atmosphere. The mixture is heated (microwave irradiation) to 120° C. for 1 h. This mixture is worked up by diluting with water and extraction with dichloromethane. The organic layers are dried over Na2SO4 and concentrated to yield the crude product, which is purified by chromatography on silica gel (ethyl acetate/dichloromethane).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), [4-(hydroxymethyl)phenyl]boronic acid (32 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][P:14]([O:19]CC)([O:16]CC)=[O:15].C[Si](Br)(C)C>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][P:14]([OH:19])([OH:16])=[O:15]
Reactant: CCOP(=O)(COc1ccc(C(C)(C)C)cc1N)OCC
Agent: C[Si](C)(C)Br
Product: CC(C)(C)c1ccc(OCP(=O)(O)O)c(N)c1

Procedure:
The compound 2-amino-4-tert-butyl-1-diethylphosphonomethoxybenzene was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 15.01) as a solid. HPLC Rt=4.45 min; negative ion electrospray MS M-1 found: 258.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[F-:19].[Cs+].S1(CCCC1)(=O)=O.CCCCCC>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[F:19]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)C(F)F)cc(Cl)c1Cl
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: CCCCCC
Solvent: O
Product: O=[N+]([O-])c1cc(OC(F)(F)C(F)F)cc(Cl)c1F
Temperature: 110 °C

Procedure:
3,4-Dichloro-5-nitro-(1',1',2',2'-tetrafluoroethoxy)-benzene (6.4 g) was added to a pre-dried solution of caesium fluoride (4.9 g) and sulpholane (70 ml). The stirred reaction mixture was then heated to 110° C. for a total of 27 hours. After allowing to cool to the ambient temperature, the reaction mixture was diluted with water and poured into hexane. The organic layer was water washed, dried over anhydrous magnesium sulphate, and the solvent removed by evaporation under reduced pressure to give 3-chloro-4-fluoro-5-nitro-(1',1',2', 2'-tetrafluoroethoxy)-benzene as an orange oil. 1H NMR δ(CDCl3): 7.85(1H,m), 7.62(1H,m), 5.95(1H,tt).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>CN(C)C=O.[Cl-].[Na+].O.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:10](=[O:12])[C:9]2[C:4](=[N:5][C:6]([S:15][CH3:16])=[N:7][CH:8]=2)[NH:3][C:25]1=[O:26]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (5.26 g, 131 mmol) was added to a solution of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (20.0 g, 94 mmol, US 2005/0020590) in N,N-dimethylformamide (700 mL) at 0° C. After 10 minutes, 1-chloro-2-isocyanatobenzene (15.9 mL, 131 mmol) was added dropwise to the mixture. The reaction was warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with brine (200 mL) and water (1000 mL) and extracted with ether (700 mL 2×). The aqueous layer was acidified with 5% citric acid (until pH=4-5), treated with brine, and extracted with ethyl acetate (2×). The combined organic layers were washed with water (2×), dried over MgSO4, filtered, and concentrated to remove most of the solvent. The mixture was filtered, and the solid was washed with cold ethyl acetate, and oven dried to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].Cl.Cl.[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1.C(Cl)(=O)C.NC1C=CC=CC=1>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:50][C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([N:43]([CH3:51])[CH3:42])[CH:45]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Agent: Cl
Solvent: CCCCO
Solvent: Nc1ccccc1
Solvent: CC(=O)Cl
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(N(C)C)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 3, in n-butanol (2 mL) is mixed with N,N-dimethyl-1,3-phenylenediamine dihydrochloride (52.3 mg, 0.25 mmol) or mixed with acetyl chloride (17.8 μL, 0.25 mmol) and aniline and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-dimethylamino-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (23.2 mg, yield 71%); 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.65 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.82 (d, J=3.9 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.32 (d, J=3.6 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 2.92 (s, 6H), 2.45 (s, 3H), 2.35 (s, 3H); ESIMS m/z 654.2 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](O)[NH:5][C:6]2=[O:11].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11]
Reactant: O=C1NC(O)c2c(F)cccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.05 g (about 24.2 mmol) of 4-fluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one were initially charged in 10 ml of dichloromethane, 22.4 ml (290.8 mmol) of trifluoroacetic acid and 7.7 ml (48.5 mmol) of triethylsilane were added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 3:1 to 1:1). This gave 890 mg (24.2% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>O1CCCC1>[CH3:1][C:2]1[CH2:6][CH2:9][C:8](=[C:7]([CH3:17])[CH3:12])[C:4](=[O:5])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CC=O
Solvent: C1CCOC1
Product: CC1=CC(=O)C(=C(C)C)CC1
Yield: 78 %

Procedure:
A mixture of 200 parts of 3,3-dimethylacrolein and 600 parts of tetrahydrofuran is heated with 0.008 part of p-toluenesulfonic acid in an autoclave for three hours at a pressure of 50 atmospheres and a temperature of 210°C. The reaction product is worked up by distillation. 72.5 parts of piperitenone is obtained. The yield is 78% of theory at a conversion of 52%.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CCCCC1.C(N(CC)CC)C.[F:31][C:32]([F:36])=[C:33](F)F.CN(C)C=[O:40]>>[F:31][CH:32]([F:36])[C:33]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:40]
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 9 h
Yield: 91 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.52 g, 2.0 mmol), piperidine (0.51 g, 6.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.3 liter/hr), with vigorous stirring at 50° C. for 9 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3(3-trifluoromethylphenyl)-5-methylthiazoline (0.61 g, 1.8 mmol, yield 91%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([NH:42][C@H:43]([C:48](O)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41].ON1C=CC=CC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:74][S:75]([OH:78])(=[O:77])=[O:76]>C(OCC)(=O)C.O.O1CCCC1>[CH3:74][S:75]([OH:78])(=[O:77])=[O:76].[C:18]([NH:17][C:15]([C@@H:14]1[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][N:5]1[CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:48](=[O:49])[C@H:43]([CH2:44][C:45](=[O:47])[NH2:46])[NH:42][C:40]([C:31]1[CH:32]=[CH:33][C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)=[O:41])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: O=c1ccccn1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Yield: 95.9 %

Procedure:
125.9 g (312 mmol) of 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-t-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, 94.6 g (328 mmol) of N-(2-quinolylcarbonyl)-L-asparagine and 3.5 g (31 mmol) of 1-hydroxy-2(1H)-pyridone were treated with a mixture of 75 ml of tetrahydrofuran and 1925 ml of ethyl acetate. A solution of 70.9 g (344 mmol) of dicyclohexylcarbodiimide in 500 ml of ethyl acetate was subsequently added dropwise at 25° within 30 minutes while stirring. The reaction mixture was stirred for 10 hours. Then, 50 ml of water of low ion contents were added and the suspension was cooled to 2°-3° and stirred at this temperature for 1 hour. The dicyclohexylurea was then filtered off and washed on the filter with 2 500 ml portions of ethyl acetate. The filtrates were combined and treated slowly at 50° with a solution of 32.5 g (338 mmol) of methanesulphonic acid and 250 ml of ethyl acetate. The suspension was subsequently stirred at 20° for 14 hours. The crystals were then filtered off under suction, washed with a total of 600 ml of ethyl acetate and subsequently dried at 45°/2000 Pa for 24 hours. 229.5 g (95%) of N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulphonate having a HPLC content of 97.1% were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[Cl:11][C:12]1[C:13]([OH:21])=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:22][C:23]3=[CH:27][CH:26]=[N:25][N:24]23)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1cc(Cl)cc(Cl)c1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3,5-dichloro-2-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19]C(OC(C)=O)=O.[NH2:26][C:27]1([CH2:31][OH:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:32][CH2:31][C:27]1([NH:26][CH:19]=[C:3]([C:2](=[O:1])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=2[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)OC(C)=O
Reactant: NC1(CO)CCC1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1(CO)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl iorthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9]
Reactant: Cc1c(Br)cccc1Br
Reactant: O=[N+]([O-])O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1Br
Temperature: 0 °C

Procedure:
To 38 g of 2,6-dibromotoluene (0.152 mol) was added dropwise with stirring, over a period of thirty minutes, 76 ml of 70% nitric acid. An exothermic reaction was observed. The resulting mixture was stirred for an additional sixty minutes, after which time the mixture was poured into 1500 ml of ice water. The solids which separated were collected by filtration and dried to yield 44.62 g of 2,6-dibromo-3-nitrotoluene. Recrystallization of the reaction product from ethyl alcohol-water yielded material melting at 47°-48° C.
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[C:9]([CH3:34])([CH3:33])[CH2:10][O:11][C:12]=1[C:13]1[O:14][C:15]2[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:16]=2[C:17]=1[O:18][CH2:19][CH3:20])([CH3:7])([CH3:6])[CH3:5].[Na].[O:36]=[O:37]>>[C:4]([C:8]12[O:37][O:36][C:12]1([C:13]1[O:14][C:15]3[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:16]=3[C:17]=1[O:18][CH2:19][CH3:20])[O:11][CH2:10][C:9]2([CH3:33])[CH3:34])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCOc1c(C2=C(C(C)(C)C)C(C)(C)CO2)oc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CCOc1c(C23OCC(C)(C)C2(C(C)(C)C)OO3)oc2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
Adding 1 mg of TPP to 2 ml of methylene chloride dissolving 47 mg (0.066 mmol) of 4-t-butyl-5-(5-(t-butyldimethylsiloxy)-3-ethoxybenzofuran-2-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [36]), the mixture was stirred in oxygen atmosphere, at the temperature of −78° C. This solution was externally irritated with a 940 W sodium lamp for 4 hours. The reaction mixture was concentrated to obtain 5-t-butyl-1-(5-(t-butyldimethylsiloxy)-3-ethoxybenzofuran-2-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [37]) as a crude product.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[S-:23][C:24]#[N:25].[Na+]>>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:25][C:24](=[S:23])[NH:2][C:3]=2[CH2:21][CH3:22])[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCC(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
By following the same procedure as in Example 8 using 13.1 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochloride, 6.5 g of sodium thiocyanate, 3.4 ml of concentrated, and 100 ml of acetic acid and recrystallizing the reaction product from isopropanol, 6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[N:10]([CH3:11])[C:9]([CH2:12]O)=[N:8][C:7]=1[CH:14]([CH3:16])[CH3:15].CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>S(Cl)(Cl)=O.O>[N:26]([CH2:12][C:9]1[N:10]([CH3:11])[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[C:18]([Cl:20])[CH:17]=2)=[C:7]([CH:14]([CH3:16])[CH3:15])[N:8]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1nc(CO)n(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
In 5 ml of thionyl chloride was dissolved 160 mg (0.51 mmol) of [5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (59a), and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and to the residue, 5 ml of dry dimethylformamide and 80 mg (1.23 mmol) of sodium azide were added. The mixture was stirred at room temperature for 3 hours, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 150 mg of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60) (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in dry methanol (235 mL) was treated with 5 drops of concentrated H2SO4 (cat.) at room temperature. The mixture was stirred overnight to completion and was concentrated in vacuo to about 40 mL. The concentrate was partitioned between an ether and half saturated NaHCO3 solution. The aqueous portion was back-extracted once with ether, and the organics were combined. The organic portion was washed with water, then brine, dried over MgSO4, and concentrated in vacuo. The material was placed under high vacuum for one hour to afford the pure methyl 2-(4-chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.70 (s, 3H), 3.60 (2, 2H).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCc3c[nH]c4ccccc34)(CC1)C2
Product: [Br-]
Yield: 69.3 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (29.7 mg, 0.106 mmol) and 3-(2-bromoethyl)-1H-indole (40.5 mg, 0.181 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (37.0 mg, 69%). EI-MS m/z 423 (M+) Rt (1.82 min).
Reaction SMILES: [NH2:1]/[C:2](/[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:3]\[C:4]#[N:5].O.O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+].C(OCC)(=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[NH2:1]/[C:2](/[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:3]\[C:4](=[S:20])[NH2:5]
Reactant: CC(C)(C)/C(N)=C/C#N
Reactant: [S-2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)/C(N)=C/C(N)=S
Yield: 23 %

Procedure:
(Z)-3-amino-4,4-dimethyl-pent-2-enenitrile (26 g, 209.35 mmol), sodium sulfide decahydrate (5.71 g, 73.27 mmol) and tetrabutyl ammonium chloride (9.31 g, 33.49 mmol) in benzene and water (215 mL, 2.5:1, v/v) is stirred at 75° C. under hydrogen sulfide gas for three days. 200 mL of ethyl acetate is added and the layers separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. Yield 23% over three steps. ESI m/z 159=MH+