Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:8])=[O:5])C.C[O-].[K+].Cl[CH2:18][C:19]#[N:20]>CO>[C:19]([C:18]1[S:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][C:4]=1[OH:5])#[N:20]
Reactant: N#CCCl
Reactant: CCCCOC(=S)CC(=O)OCC
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCCOc1cc(O)c(C#N)s1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
205 g of O-n-butyl 2-ethoxycarbonylthioacetate were added at 30° C. to a solution of 70 g of potassium methylate in a liter of methanol and the mixture was stirred for 10 minutes at 30° C. 75.5 g of chloroacetonitrile were added all at once to the mixture which was stirred for an hour at 40° C. and then a solution of 70 g of potassium methylate in 300 ml of methanol. The mixture was stirred for 6 hours at room temperature and was evaporated to dryness. The residue was washed with ethyl acetate and ether and was dried. The residue was then dissolved in water and the aqueous solution was acidified with concentrated hydrochloric acid and was vacuum filtered. The recovered precipitate was washed with water, dried and chromatographed over silica gel. Elution with 6-4 cyclohexane-ethyl acetate yielded 81 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene melting at 107° C.
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:20]=O>C(O)=O>[CH3:20][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=O
Reactant: CCCCCCC(C)NCCCCc1ccccc1
Solvent: O=CO
Product: CCCCCCC(C)N(C)CCCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with diborane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>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:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][C:16]=2[F:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(F)cc2F)cc1Cl
Yield: 28.9 %

Procedure:
In a round bottom flask, 4-bromo-2-chlorobenzonitrile (3 g, 13.85 mmol), 2,4-difluorophenylboronic acid (2.63 g, 16.63 mmol) and K3PO4 (8.83 g, 41.56 mmol) were added in dry DMF (50 mL). The mixture was purged under argon for 30 min and Pd(PPh3)4 (1.6 g, 1.38 mmol) was added. The mixture was heated for 48 hr at 80 C. Water (100 mL) was added and the aq layer was extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (3×50 mL), dried, evaporated and purified on silica gel (EtOAc/hexanes:1/19) to give the product (1 g, 29%), 1H.NMR (acetone-d6) δ: 7.2-7.28 (m, 2H), 7.72-7.79 (m, 2H), 7.91 (t, 1H, J=1.4 Hz), 8.02 (d, 1H, J=8.1 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:46]=[CH:45][CH:44]=[CH:43][C:21]=1[C:22]([NH:24][CH2:25][C@H:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][C@H:28]([NH:32][C:33](=[O:39])[O:34]C(C)(C)C)[C@@H:29]1[CH2:31]O1)=[O:23]>CS(C)=O>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:46]=[CH:45][CH:44]=[CH:43][C:21]=1[C:22]([NH:24][CH2:25][C@@H:26]([CH2:27][C@H:28]1[C@H:29]([CH2:31][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[O:39][C:33](=[O:34])[NH:32]1)[CH:40]([CH3:42])[CH3:41])=[O:23]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Reactant: O=C1CCCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H]1NC(=O)O[C@H]1CN1CCCCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one, 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.26 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)—(R)-oxiranylpentyl)-carbamate (Example 1b) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71 (s,1H).
Reaction SMILES: [C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[C:2]=2[C:11]([O-:13])=[O:12].[Na+:14].[Na+]>O.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])C1=C2CCC(C2)C1C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of disodium bicyclo[2.2.1]heptene-2,3-dicarboxylate (10.0 g) in water (100 g) was added 0.5 g palladium on activated carbon (5 wt %). The mixture was transferred into a Parr reactor and was subjected to hydrogenation (50 psi, room temperature) for 8 hours. The activated carbon was filtered out. Water is removed in vacuo at 75° C. The resulting product was dried and milled (m.p >300° C.).
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6]([O:8]CC)=O)C.Cl.[CH3:13][O:14][CH2:15][C:16]([NH2:18])=[NH:17].C[O-].[Na+].CO>CO>[CH3:13][O:14][CH2:15][C:16]1[N:18]=[C:4]([OH:11])[CH:5]=[C:6]([OH:8])[N:17]=1
Reactant: COCC(=N)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1nc(O)cc(O)n1

Procedure:
Reflux a mixture of malonic acid diethyl ester (7.96 g, 50 mmol), 2-methoxy-acetamidine hydrochloride (6.2 g, 50 mmol), and NaOMe MeOH solution (4.37 M, 22.7 mL, 100 mmol) in MeOH (30 mL) for 24 hours. Concentrate, dilute with H2O (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract with MeOH and concentrate to yield 2-methoxymethyl-pyrimidine-4,6-diol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCn1ccc2ccccc21
Temperature: 60 °C

Procedure:
A solution of indole (1.0 g) in dry DMSO (1 ml) is dropped into a suspension of sodium hydride (60% suspension in mineral oil; 0.37 g) in dry DMSO (20 ml), heating to 60° C. for 1 h. After cooling at room temperature, the resulting solution is added dropwise with a solution of n-octyl bromide (2.82 ml) in dry DMSO (2.8 ml). After a night at room temperature, the reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases are washed with a NaCl saturated solution, dried and evaporated to dryness. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane) to obtain 1.86 g of 1-(n-octyl)indole as oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+:2]=[N-:3].Cl.[CH3:17][O:18][C:19](=[O:40])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:31])=[CH:25][CH:24]=1)[NH2:21]>>[CH3:17][O:18][C:19](=[O:40])[C@H:20]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:31])=[CH:27][CH:28]=1)[NH:21][C:13]([C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: [N-]=[N+]=NCCCCC1(C(=O)O)CCCC1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCCCN=[N+]=[N-])CCCC1

Procedure:
4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(4-azidobutyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 1-[4-(azido)butyl]cyclopentane carboxylic acid and of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt using the procedure described in example 46 to give a 99% yield of a white solid, mp 195-199° C. HR MS (C27H31Cl2N5O4): Obs mass, 560.1833. Calcd mass, 560.1831 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:45]([O:47]C)=O)[CH:40]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:50]>O1CCOCC1>[C:45]([C:41]1[CH:40]=[C:39]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([CH:32]=2)[CH2:30][N:15]([C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH:12]2[CH2:11][CH2:10][CH:9]([N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:14][CH2:13]2)[CH:44]=[CH:43][N:42]=1)(=[O:47])[NH2:50]
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccnc(C(N)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyl ester 148 (50 mg, 0.07 mmol) in 1,4-dioxane (2 mL) is treated with conc. ammonia (1 mL) and the reaction stirred at RT 6 h. LC/MS at this juncture showed some residual starting material so more conc. ammonia (1 mL) is added and the reaction mixture heated 2 h at 40° C. LC/MS at this juncture showed the reaction is complete. The solvents are removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(=O)(O)[O-].[Na+].[CH2:28](Br)[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.[ClH:35]>CN(C)C=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:28][CH:29]4[O:33][CH2:32][CH2:31][CH2:30]4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4
Reactant: BrCC1CCCO1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCCO4)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A slurry of 3,14-dimethylmorphinan-6-one (6a) (0.24 g, 0.71 mmol), sodium bicarbonate (0.6 g, 7.14 mmol) and (±) tetrahydrofurfuryl bromide (0.4 g, 2.42 mmol) and dimethylformamide (15 ml) was heated at 110° C. for 16 hours with stirring under a nitrogen atmosphere. The mixture was filtered hot and the residue was washed with dimethylformamide (15 ml). The filtrate was distilled under vacuum (bath temperature 35° C.) and the resulting brownish material was treated with chloroform (50 ml) and water (20 ml). After separation, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3×20 ml) whereupon the organic extracts were combined, dried over MgSO4 and filtered. The filtrate, upon concentration, was a brownish oily solid. This material was chromatographed twice over silica gel using graded methanol/chloroform mixtures to give 0.153 g (86% theory) of a mixture of the R and S isomers of the product. A part of this material (0.03 g) was converted into the hydrochloride salt by treatment with ethereal HCl to form the title compound as a tan-colored solid.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH:9]12[CH:18]3[CH2:19][CH:15]([CH:16]=[CH:17]3)[CH:14]1[CH:13]1[CH2:20][CH:10]2[CH:11]([CH:21]=[O:22])[CH2:12]1>>[OH:22][CH:21]([CH:11]1[CH2:12][CH:13]2[CH2:20][CH:10]1[CH:9]1[CH:14]2[CH:15]2[CH2:19][CH:18]1[CH:17]=[CH:16]2)[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=CC1CC2CC1C1C3C=CC(C3)C21
Product: CC(C)(C)OC(=O)CC(O)C1CC2CC1C1C3C=CC(C3)C21
Yield: 93 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that tert-butyl acetate was used instead of 1-ethylcyclopentyl acetate, and 8-tetracyclo[4.4.0.12,5.17,10]-dodecene-3-carbaldehyde was used instead of 5-norbornene-2-carbaldehyde. There was obtained tert-butyl 3-hydroxy-3-(8-tetracyclo[4.4.0.12,5.17,10]dodecen-3-yl)propionate. Yield 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([SH:9])[CH2:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([S:9][CH3:16])[CH2:4][N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1=CC(C)=NCN1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSN1CN=C(C)C=C1C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH were dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfate were added dropwise to this mixture at room temperature over the course of 10 minutes. After 1 hour, the aqueous phase was extracted 3 times with ether and dried over magnesium sulfate, and the solvent was distilled off. 15.9 g (97%) of crude product were isolated. 1H-NMR (270 MHz): 6.7 ppm (1H, s), 2.5 (3H, s), 2.3 (6H, s).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(O)(=O)C>[NH2:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([N:20]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]2[CH3:2])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(Br)cc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C

Procedure:
A mixture of Example 1A (3.3 g, 10.1 mmol) and 4-aminobenzenesulfonamide (1.74 g, 10.1 mmol) in glacial acetic acid (75 mL) was heated to 100° C. for 48 hours. After cooling the mixture was concentrated under reduced pressure. Ether (50 mL) was added to the residue and the precipitate was isolated by filtration. The pale yellow solid was washed with ether and dried. 1H NMR (CDCl3) δ ppm 1.32 (3H), 2.20 (3H), 3.50 (2H), 4.27 (2H), 6.85 (1H), 7.30-7.90 (8H); MS (ESI) m/z m/z 462/464.
Reaction SMILES: C(N(CC)CCCS(C1C=CC(N)=CC=1)(=NC(OCC1C=CC=CC=1)=O)=[O:8])C.[CH2:29]([N:31]([CH2:56][CH3:57])[CH2:32][CH2:33][CH2:34][S:35]([C:48]1[CH:53]=[CH:52][C:51]([NH:54][OH:55])=[CH:50][CH:49]=1)(=[N:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:36])[CH3:30]>>[CH2:56]([N:31]([CH2:29][CH3:30])[CH2:32][CH2:33][CH2:34][S:35]([C:48]1[CH:49]=[CH:50][C:51]([N+:54]([O-:8])=[O:55])=[CH:52][CH:53]=1)(=[N:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:36])[CH3:57]
Reactant: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc(N)cc1
Reactant: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc(NO)cc1
Product: CCN(CC)CCCS(=O)(=NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of a 3:1 mixture of 4-[S-[3-(diethylamino)propyl]-N-[(phenylmethoxy)carbonyl]sulfonimidoyl]benzeneamine and S-[3-(diethylamino)propyl]-S-[4-(hydroxyamino)phenyl]-N-[(phenylmethoxy)carbonyl]sulfoximine obtained through an incomplete reduction of S-[3-(diethylamino)propyl)-S-(4-nitrophenyl)-N-[(phenylmethoxy)carbonyl]sulfoximine (4.2 g, ~10 mmol) was dissolved in a pyridine (42 mL)-methylene chloride (12 mL) mixture. The resulting solution was cooled in an ice/water bath, and methanesulfonyl chloride (1.2 g, 10 mmol) was added. The reaction mixture was allowed to come to ambient temperature and was stirred for 4 h. The reaction mixture was then added to 200 mL of diethyl ether. The ethereal solution was decanted from the insoluble residue. The residue was triturated with an additional 100 mL of diethyl ether, and the ethereal solution was decanted and discarded. The residue was dried in vacuo to give 3.0 g of a gum that was chromatographed (flash, silica gel, 95:5-90:10 methylene chloride-methanol) to give 0.7 g of product (15%). A 200 mg sample was dissolved in ethanol and treated with ethereal HCl. The solid that formed was recrystallized from ethanol. This solid was triturated with ethyl acetate and then recrystallized from ethanol. The resulting solid was recrystallized from an ethanol/diethyl ether mixture to give 0.02 g of off-white solid, mp 76°-78° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[O:13]CC(C)(C)N=2)=[C:7]([CH:19]2[O:24]CCC[O:20]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.S(=O)(=O)(O)O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:12](=[O:13])[O:20][CH:19]2[OH:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(F)c2c(c1)C(O)OC2=O
Yield: 106.5 %

Procedure:
1.8 g (5.4 mmol) of 2-(4-tert-butyl-2-1,3-dioxinan-2-yl-6-fluoro-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was weighed into a 200 mL round bottom flask fitted with a stir bar and reflux condenser. Added 75 mL of ethanol and stirred to obtain a clear solution. Added 50 mL of 50% aqueous sulfuric acid. Stirred at reflux for 18 h. Poured the reaction mixture into 400 mL water. Extracted the aqueous mixture with 2×200 mL CH2Cl2. Combined the organic extracts and washed with 200 mL brine. Dried over Na2SO4 and removed the solvent on rotavap. Dried under high vacuum to obtain 1.29 g of the title compound as on off-white solid. MS (ESI) 223 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:31]4[N:32]=[C:33]([NH2:38])[N:34]=[C:35]([NH2:37])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (160 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (163.0 mg, 0.5 mmol) was added, followed by 4-chloro-2,6,-diaminopyrimidine (79.5 mg, 0.55 mmol). The vial was capped and microwaved at 200° C. for 20 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1N

Procedure:
The title compound was prepared from ([4-chloro-2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example A25) (8.70 g, 23.5 mmol) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a yellow solid (7.94 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)=O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [O-][I+2]([O-])O
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 85 °C
Yield: 317 %

Procedure:
A mixture of 2-bromofluorene (12.61 g, 50 mmol), acetic acid (125 mL), water (9 mL), concentrated sulfuric-acid (4 mL), iodine (5.1 g, 20.1 mmol) and iodic acid (2.2 g, 12.5 mmol) was heated at 80-90° C. for 2 hours, cooled and filtered. The solids were washed with acetic acid (100 mL) and water (500 mL), to yield the product 14.7 g (79% yield), m.p. 179-185° C. Mass Spec: m/z 418 (M+ diiodo), 370, 372 (M+ iodobromo), 322, 324,326 (M+ dibromo).
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])=[CH:15][C:14]=3[CH3:32])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[Cl:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH3:32])[CH:15]=1)[CH2:12][C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCNC[C@H]21
Temperature: 20 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To a solution of cis-3-benzyl-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (25 mg, 0.055 mmol) in MeOH (1.5 mL) was added Pd(OH)2 (5.0 mg, 20 wt %) and catalytic amount of acetic acid. The reaction mixture was stirred at 20° C. for 10 h under H2 atmosphere, filtered through celite and concentrated in vacuo. The residue was chromatographed in silica gel column (CH2Cl2/MeOH 95/5) to give the title compound (16 mg, 0.044 mmol): MS (ES) 366.1 (M+H).