Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=2)[CH:6]=1.Cl.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]2[C:46](=[O:55])[NH:47][C:48]3[C:53]([CH:54]=2)=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>>[O:55]=[C:46]1[C:45]([CH:42]2[CH2:43][CH2:44][N:39]([C:1]([O:2][C@H:3]([CH2:4][C:5]3[CH:13]=[C:12]([CH3:14])[C:11]4[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[N:10]=4)[CH:6]=3)[C:23]([O:25][CH3:26])=[O:24])=[O:27])[CH2:40][CH2:41]2)=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47]1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of 1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)ethyl 4-nitrophenyl carbonate (0.859 mmol) was added 3-(piperidin-4-yl)quinolin-2(1H)-one-hydrochloride (682 mg, 2.58 mmol), in one portion, followed by dropwise addition of diisopropylethylamine (0.37 mL, 2.15 mmol) at room temperature. The resulting yellow suspension was stirred at room temperature overnight. The mixture was extracted with ethyl acetate (2×2 mL) and the organic phase was washed with brine and dried over sodium sulfate. The crude product was purified using preparative HPLC to afford (R)-1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (157 mg, 30%). Mass spec. 619.24 (MH+). 1H-NMR (CDCl3, 400 MHz) δ 8.0 (s, 1H), 7.53 (br s, 2H), 7.47-7.43 (m, 1H), 7.34-7.31 (m, 1H), 7.21-7.18 (m, 1H), 6.96 (s, 1H), 5.7 (s, 2H), 5.23 (dd, J=8.6, 4.6 Hz, 1H), 4.28 (br s, 2H), 3.74 (s, 3H), 3.61 (m, 2H), 3.13 (m, 3H), 2.93 (m, 2H), 2.59 (s, 3H), 1.94 (m, 2H), 0.92 (m, 2H), −0.064 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[C:6]([Br:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19].BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19]
Reactant: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(N)c(O)c(Br)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
4-Amino-6-bromo-5-methoxy-2-methylbiphenyl-3-carbonitrile (I-40) (44.5 mg, 0.14 mmol) was dissolved in dichloromethane (dewatered, 1.4 ml) under nitrogen atmosphere, and cooled in a dry ice-methanol bath at −70° C. 1 M Tribromoborane (dichloromethane solution, 0.42 ml) was dropwise added to it at −70 to −68° C., followed by stirring for 1.5 hours with heating up to 0° C. The reaction liquid was diluted with cold water, and controlled to have a pH of 6 to 7 with aqueous 10% sodium carbonate solution added thereto. The organic matter was extracted with ethyl acetate, washed with saturated brine, then dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain the entitled compound (42.4 mg, quant.) as a pale brown solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20]O)[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11].O>C(Cl)Cl>[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20][F:7])[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CC)C(=O)n1cc(CO)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)n1cc(CF)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 1 h
Yield: 95 %

Procedure:
20 μl of diethylaminosulfur trifluoride were added at 0° C. to a solution of 54 mg of 1-(diethylcarbamoyl)-3-(2-methyl-3-chlorophenylsulfonyl)-4-hydroxymethylpyrazole (prepared as described in Example 10) in 1.8 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with an 8:1 by volume mixture of hexane and ethyl acetate, to afford 51 mg (yield 95%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])=[O:12])[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[O:12])[NH:5][S:38]([CH3:37])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 400 mg (0.8 mmol), was dissolved in 4 mL anhydrous tetrahydrofuran, and 550 μL (3.2 mmol) diisopropylethylamine added, followed by methanesulfonyl chloride, 181 mg (1.6 mmol). The reaction mixture was purged with argon and stirred overnight. After adding a further 275 μL (1.6 mmol) diisopropylethylamine, then tris(2-aminoethyl)amine-polystyrene resin, 480 mg (1.6 mmol), the mixture was agitated for 6 hours, then filtered and the filtrate evaporated to dryness under vacuum, giving N-(methanesulfonyl)-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 397 mg. Purity was verified with ELSD and identity verified with 1H and 31P NMR.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[S:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[C:13]=1[N:19]1[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:20]1=[S:21]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: C#CCNCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (14.1 g), 2,6-dimethylphenylisothiocyanate (16.3 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (100 mL), then with water. The organic layer was separated, dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid w, as collected by filtration. Recrystallization from hexane-EtOAc afforded the title compound (12.5 g) as yellow solid, m.p. 117°-121° C. Anal. Calcd. for. C14H14N2S2O: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.23; H, 5.43; N, 10.88. Mass spectrum (EI, M.+) m/z 258.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>O>[C:6]1([CH3:12])[C:7]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 65 °C
Reaction time: 5 h

Procedure:
560 g of 98% sulfuric acid was dropped into 560 g of toluene while stirring. Then, while the stirring was continued, the temperature was raised at 60 to 70° C., reacting for 5 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain toluenesulfonic acid. As a result of analysis, the toluenesulfonic acid included the para compound thereof at a concentration of 85 mole % in the total of the toluenesulfonic acid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=O)[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[NH2:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1.[ClH:69]>C1COCC1.CO>[ClH:69].[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1)=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: NCc1cccnc1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(=O)NCc6cccnc6)c(O)c5C3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol) and 3-(aminomethyl)pyridine (11 mg, 0.10 mmol). The reaction mixture was stirred at room temperature under nitrogen for 7 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford a dark red solid. The solid was dissolved in methanol (2 mL) and treated with HCl (0.20 mL, 1.25 M solution in methanol) at 0° C. The solution was concentrated and triturated with diethyl ether to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-ylmethyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide hydrochloride as a mixture of diastereomers (12 mg, 21%) and as a red solid: 1H NMR (500 MHz, CD3OD) δ 8.84-8.80 (m, 1H), 8.80-8.65 (m, 1H), 8.64-8.58 (m, 1H), 8.10 (s, 1H), 8.09-8.06 (m, 1H), 6.63 (s, 1H), 6.16 (s, 0.3H), 6.01 (s, 0.7H), 5.20 (s, 0.3H), 4.95 (s, 0.7H), 4.67 (br s, 1H), 3.92-3.89 (m, 1H), 3.75 (s, 3H), 3.70-3.67 (m, 0.3H), 3.64-3.62 (m, 0.7H), 3.57 (s, 3H), 3.54 (s, 1H), 3.50 (s, 1H), 3.49-3.37 (m, 5H), 3.24-3.17 (m, 1H), 3.10-3.02 (m, 1H), 2.23 (s, 3H), 1.28 (d, J=6.5 Hz, 2H), 1.23 (d, J=6.5 Hz, 1H); MS (ESI−) m/z 772 (M−H); HPLC 96.7% (AUC), tR 10.53 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of tert-butyl 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate (290 mg, 0.689 mmol) and trifluoroacetic acid (10 mL) in DCM (10 mL) was stirred at room temperature for 16 hrs. The solvents were removed and the residue was extracted with EtOAc (150×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-19% MeCN in 0.5% NH4HCO3) to give target product of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (100 mg, 49%) as a white solid. LCMS (ESI) m/z: 364.9 [M+H]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[F:12][C:13](F)([F:21])S(OC(F)F)(=O)=O>C(#N)C.O>[F:12][CH:13]([O:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[F:21]
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: FC(F)Oc1ccc(Cl)cc1Br
Reaction time: 0.08 h

Procedure:
36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory)
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH3:7].[CH3:18]O>ClCCl>[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:18])=[O:12])[CH3:7]
Reactant: CO
Reactant: CCOc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)OC

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-ethoxybenzoic acid (50 g, 0.301 mol) in methanol (500 ml) and the resulting mixture heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). This solution was washed successively with water (150 ml), aqueous sodium bicarbonate solution (150 ml) and water (150 ml), then evaporated under reduced pressure to give the title compound (49.7 g) as an oil. δ (CDCl3): 1.44 (3H,t), 3.90 (3H,s), 4.12 (2H,q), 6.95 (2H,m), 7.44 (1H,t), 7.78 (1H,d).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A well-stirred slurry consisting of 4.64g (31 mmol) of 4-carboxybenzaldehyde and 5.92 g (31 mmol) of 4-chlorobenzenesulfonamide and 20 mg of p-toluenesulfonic acid (TsOH) in 130 mL of toluene was heated to reflux for a total of 5 hours. The water formed from the reaction was removed by a Soxhlet extractor packed with 3A molecular sieves as described above. The mixture was allowed to cool to room temperature and was filtered to provide 9.76 g (98%) of SULF-1 as a white powder: mp >245° C.; IR (Nujol) 3300-2300 (br), 3090, 1689, 1616, 1168, 1013 cm-1 ; 1H NMR (DSMO-d6, TMS ext standard, 60 MHz) δ9.15 (s, 1), 8.01 (s, 4), 7.79 (AB, 4, JAB =11, Δν=16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[C:10][C:11]([OH:13])=O.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[N:59]=[C:58]([NH:60][CH:61]3[CH2:66][CH2:65][CH:64]([OH:67])[CH2:63][CH2:62]3)[N:57]=[C:56]3[C:52]=2[N:53]=[CH:54][N:55]3[CH2:68][CH3:69])[CH:47]=[CH:48][CH:49]=1>CN(C=O)C.C(#N)C>[CH2:68]([N:55]1[CH:54]=[N:53][C:52]2[C:56]1=[N:57][C:58]([NH:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1)=[N:59][C:51]=2[NH:50][C:46]1[CH:45]=[C:44]([NH:43][C:11](=[O:13])[C:10]#[C:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:49]=[CH:48][CH:47]=1)[CH3:69]
Reactant: CCn1cnc2c(Nc3cccc(N)c3)nc(NC3CCC(O)CC3)nc21
Reactant: O=C(O)C#Cc1c(Cl)cccc1Cl
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3cccc(NC(=O)C#Cc4c(Cl)cccc4Cl)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.3 g (0.02 mol) (2,6-dichlorophenyl)-propargylic acid (M. S. Reich et al., Bull. Soc. Chim. Fr. 21, 217-225 (1917)) in 120 ml DMF and 120 ml acetonitrile are added at RT 4.23 ml (0.025 mol) N,N-di-isopropyl-N-ethylamine, followed by a solution of 5.94 g (0.02 mol) TPTU (O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, Fluka, Buchs, Switzerland) in 100 ml DMF. The resulting solution is stirred at RT for 5 minutes and then added dropwise to a solution of 7.36 g (0.02 mol) 4-[6-(3-amino-phenylamino)-9-ethyl-9H-purin-2-ylamino]-cyclohexanol (example 77, stage 1.2) in a 1:1 mixture of DMF and acetonitrile (240 ml). The addition takes 1.25 hrs and stirring at RT is continued for an additional hour. A second portion of preactivated (2,6-dichlorophenyl)-propargylic acid [prepared by adding 2.0 g (0.0066 mol) TPTU in 30 ml DMF to a solution of 1.3 g (0.0066 mol) (2,6-dichlorophenyl)-propargylic acid in 30 ml DMF and 30 ml acetonitrile and stirring for 5 minutes at RT] was then added dropwise over 30 minutes. After stirring for another 1.5 hrs the solvent is evaporated under reduced pressure and the residue taken up in a mixture of ethyl acetate and 10% aqueous citric acid. The aqueous phase is extracted with ethyl acetate and the combined organic layers are washed with water, saturated sodium bicarbonate solution and brine. After drying (anhydrous sodium sulfate) the ethyl acetate solution is concentrated until the product crystallises. It is collected by filtration, re-suspended in a small amount of ethyl acetate, filtered and vacuum dried. N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-3-(2,6-dichlorophenyl)-propargylic acid amide (7.0 g, 60%), is obtained as a colourless solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([NH:21][CH:22]=[O:23])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([NH:21][CH:22]=[O:23])=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(NC=O)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(NC=O)cc2)C(=O)OC1=O
Reaction time: 0.67 h

Procedure:
To a boiling solution of 2.67 g. (0.0123 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 50 ml. of methanol is added 1.8 g. (0.0132 m.) of p-aminoformanilide. Additional methanol is added (30 ml.) and reflux is continued for 40 minutes. The reaction mixture is filtered and the solid recrystallized to yield 5-acetyl-3-[1-(p-formamidophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6 (3H)-dione, m.p. 247°-248° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Cl-].[Na+].[OH-].[Na+].[O:11]1[CH:20]2[CH:12]1[CH2:13][C:14]1[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[N:1]1([C@@H:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20][C@H:12]2[OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
A solution of 10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described by Mousseron et al., Bull. de Soc. Chim. de France, 1946, p. 629-630] was slowly added to 10.8 ml of demineralized water and after increasing the temperature to 65° C., the mixture was stirred for 90 minutes at 65° C. 20 ml of demineralized water were then added and excess pyrrolidine was distilled off at reduced pressure to obtain an oil phase and an aqueous phase. The aqueouse phase was saturated with sodium chloride and 1 ml of 32% sodium hydroxide was added thereto. The mixture was extacted with ether and the ether phase was dried and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica and eluted with ethyl acetate containing 5% of triethylamine to obtain 8.81 g of trans (±) 2,3-dihydro-1-(pyrrolidin-1-yl)-1H-inden-2-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1cc(C(F)(F)F)c(-c2cccnn2)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2cccnn2)c(C(F)(F)F)cc1N
Temperature: 110 °C
Yield: 46 %

Procedure:
2-Amino-5-pyridazin-3-yl-4-trifluoromethyl-benzoic acid (165 mg, 0.583 mmol) was dissolved in MeOH (15 mL). Concd H2SO4 (360 μL) was added and solution was heated to 110° C. for 11.5 h. The solution was concentrated in vacuo and the residue was dissolved in water (2 mL). The aqueous layer was neutralized with aq NaOH (2 N) and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes (1:4 to 1:1)) to give the title compound (79 mg, 46%). API-ES: m/z 298.1 [M+H]+, rt 3.48 min
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[OH:12])([CH3:4])[CH3:3].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[C:13]([Si:17]([O:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:20])[CH3:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cccc(F)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a 100 mL round-bottomed flask were added a stir bar, 2-(1,1-dimethylethyl)-6-fluorophenol (2.62 g, 15.6 mmol), tert-butyldimethylchlorosilane (4.84 g, 31.1 mmol), imidazole (1.46 g, 21.5 mmol) and dry DMF (48 mL). The flask was purged with nitrogen and heated at 60° Celsius for 24 hours. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The EtOAc layer was washed with water followed by brine. The organic layer was dried over Na2SO4 and concentrated. Purification by FCC yielded tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (4.2 g, 96%). 1H NMR (600 MHz, CDCl3) δ 7.04 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 1.56 (s, 6H), 1.39 (s, 9H), 1.01 (d, J=0.7, 9H).