Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[N:17]=[C:13]3[NH:12][C:11]([CH3:25])=[C:10]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][CH:4]=1)#[N:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[N:17]=[C:13]3[N:12]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:11]([CH3:25])=[C:10]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nc(NC(=O)C(F)(F)F)nn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)C(F)(F)F)nn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-5-methyl-2-[(trifluoroacetyl)amino]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (45 mg, 107 μmol) and 3-(trifluoromethyl)phenylboronic acid (61 mg, 321 μmol, 3 eq.) were initially charged together with anhydrous copper(II) acetate (58 mg, 321 μmol, 3 eq.) and molecular sieve (0.1 g, 4 Å) and, under an atmosphere of argon protective gas, suspended in abs. dichloromethane (3 ml). Abs. pyridine (69 μl, 856 μmol, 8 eq.) and triethylamine (45 μl, 321 μmol, 3 eq.) were then added. After 12 h of stirring, more 3-(trifluoromethyl)phenylboronic acid (20 mg, 107 μmol, 1 eq.), anhydrous copper(II) acetate (19 mg, 321 μmol, 1 eq.) and pyridine (35 μl, 428 μmol, 4 eq.) were added, and the mixture was stirred for a further 24 h. The mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethan and methanol and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.3 mg, 17% of theory).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=[N:23]C2N(O)N=NC=2C=1.C(=O)([O-])O.[NH4+]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:11](=[O:12])[NH2:23])[CH3:10])[CH3:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: On1nnc2cccnc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](C(N)=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
Boc-N-methyl-L-alanine (3.12 g, 15.3 mmol), EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and ammonium hydrogencarbonate (3.63 g, 45.9 mmol) were added to DMF (20 mL) and stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with aqueous potassium hydrogen sulfate solution (×2), dilute aqueous sodium carbonate solution and brine. The EtOAc was evaporated to give the title compound as a white solid (1 g). 1H NMR (400 MHz, DMSO-d6): 7.19 (1H, br), 6.95 (1H, br), 4.60-4.20 (1H, m), 2.73 (3H, s), 1.39 (9H, s), 1.24 (3H, d).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]([CH3:20])=[O:21]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 147.4 g of dibenzothiophene in 1.6 liters of carbon tetrachloride, cooled in an ice bath, was added a filtered solution of 122.7 g of anhydrous aluminum chloride in 425 ml of dichloromethane and 65.4 ml of acetyl chloride at 10° C., over 45 minutes. The mixture was stirred for 20 minutes, then a mixture of 2.5 liters of crushed ice and 500 ml of concentrated hydrochloric acid was added in one portion. This mixture was stirred vigorously until the yellow color disappeared. The aqueous layer was separated and washed in 100 ml of carbon tetrachloride. The wash was combined with the organic layer, washed with two 2 liter portions of water, dried and evaporated. The residue was crystallized from 250 ml of toluene and 750 ml of ether, giving 85.9 g of the desired product as colorless crystals, mp 107°-110° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:38][C:39]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)=[O:40]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.05 g, 0.13 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.04 mL, 0.52 mmol) and t-butylacetyl chloride (0.04 mL, 0.26 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05 g, 71%), m.p. 128° C.;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([OH:9])[C:6]([OH:8])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][C:44]1[CH:45]=[C:46]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[NH2:50].O>CN(C=O)C.C(OCC)(=O)C>[NH2:43][C:44]1[CH:45]=[C:46]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[NH:50][C:6](=[O:8])[C@@:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: CS(=O)(=O)Nc1ccc(N)c(N)c1
Reactant: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)C(=O)Nc1ccc(NS(C)(=O)=O)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-ethoxy-2-(4-fluorobenzyl)-2-hydroxy-3-oxopropanoic acid (1.28 g, 5 mmol), HATU (1.9 g 5 mmol), N-(3,4-diaminophenyl) methanesulfonamide (1 g, 5 mmol) in 4 mL of DMF was stirred at rt overnight. To this mixture was added water (20 ml) and ethyl acetate (50 ml). The organic layer was separated and washed with water (10 ml) and then concentrated in vacuo after being dried over anhydrous MgSO4. The residue was purified by PREP-HPLC to give the product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12]([O:16]C)(=O)[CH:13]=[CH2:14].[CH3:18][CH2:19]C([O-])(C)C.[K+].C1(C)C=CC=CC=1.[OH-].[K+]>CC1CCCO1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][CH2:13][C:12](=[O:16])[CH2:19][CH2:18]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CC(=O)OC
Reactant: CCC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
6-Bromo-2,3-dihydro-1H-inden-1-one (800 g, 3.79 mol) and methyl acrylate (787 mL, 8.72 mol) in 2-methyl-tetrahydrofuran (4 L) were stirred at 28° C. Potassium tert-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55 mol) was added dropwise keeping the temperature between 30° C. and 43° C. The mixture was stirred for 0.5 h at 25° C. Water (4 L) was added and after 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated to reflux and the organic solvent was distilled off during 4 h. The mixture was cooled to 10° C., and the formed precipitate was filtered off and dried in vacuo to give the title compound (837 g, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.74-1.85 (m, 2 H), 1.94 (m, 2 H), 2.34 (m, 2 H), 2.52-2.60 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.79-7.83 (m, 1 H), 7.89 (m, 1 H); MS (ES+) m/z 293 [M+H]|.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:41])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34](Cl)[C:35]([O:37]CC)=O)=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=O)C.[NH2:42][C:43](N)=[S:44].S1(CCCC1)(=O)=[O:47].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:41])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH:34]3[S:44][C:43](=[O:47])[NH:42][C:35]3=[O:37])=[CH:31][CH:32]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2
Reactant: NC(N)=S
Reactant: CCCCCCCCC1(COc2ccc(CC(Cl)C(=O)OCC)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: CCCCCCCCC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 2.1 g of ethyl 3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 18). 0.35 g of thiourea and 2.5 ml of sulfolane was heated for 7 hours at 120°-130° C. under a nitrogen atmosphere. A mixture of 3.6 ml of 2N aqueous hydrochloric acid and 5 ml of ethylene glycol monomethyl ether was then added to the reaction mixture, after which it was heated for a further 5 hours at 85°-90° C. The reaction mixture was then poured into water and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, using a 10:1 by volume mixture of benzene and ethyl acetate as eluent, to give the title compound as a slightly yellow, foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].CN1CCC[C:15]1=[O:19]>C[O-].[Na+].CO>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][CH3:15])[CH:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN1CCCC1=O
Reactant: Nc1cc(Cl)cc(N)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])c(N)c1

Procedure:
0.024 mole (4.5 g) of 2,6-diamino-4-chloronitrobenzene in 9 ml of N-methylpyrrolidone and 22.5 ml of 30% sodium methylate in methanol were refluxed for 4 hours 30 minutes. Upon dilution of the reaction medium with water, the desired product precipitated out. After filtering, water washing and vacuum drying in the presence of P2O5, the product obtained was recrystallized from toluene; a black insoluble product was eliminated by hot filtration. The desired product melted at 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.[CH:22]([N:25]([CH:28](C)C)CC)(C)C.C(#[N:33])C>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:22](=[N:25][C:28]#[N:33])[N:13]([C:14]4[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC#N
Reactant: COc1ccc(Nc2c(N)cnc3ccc(Br)cc23)cn1
Reactant: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2c(=NC#N)[nH]c3cnc4ccc(Br)cc4c32)cn1
Temperature: 25 °C

Procedure:
Diphenyl cyano carbonimidate (3.48 mmol) was added to a solution of 6-bromo-N4-(6-methoxypyridin-3-yl)quinoline-3,4-diamine (compound of step 3, 2.90 mmol) in dry acetonitrile (10 ml), followed by the addition of di-isopropyl ethyl amine (4.35 mmol). The resulting reaction mixture was refluxed for 48 h. The reaction mixture was cooled to RT, concentrated under vacuum and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.81 (s, 1H), 8.96 (s, 1H), 8.53 (d, J=3 Hz, 1H), 8.10 (d, J=3 Hz, 1H), 8.06 (d, J=9 Hz, 1H), 7.80 (dd, J=9 Hz, 3 Hz, 1H), 7.20 (d, J=9 Hz, 1H), 7.13 (d, J=3 Hz, 1H), 4.00 (s, 3H); MS (m/z): 395 (M+1)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH:27]([C:29]1[O:30][C:31](=[O:45])[C:32]2[C:37]([C:38]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:28])(C(C)(C)C)(C)C>C1COCC1.C(Cl)Cl.O>[OH:26][CH:27]([C:29]1[O:30][C:31](=[O:45])[C:32]2[C:37]([C:38]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:28]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
1.0 M TBAF in THF (1.43 mL, 1.43 mmol) was added dropwise to a solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(pyridin-2-yl)-1H-isochromen-1-one (intermediate B58.1, 0.394 g, 1.3 mmol) in THF (15 ml). The resulting mixture was stirred at RT for 2 hrs. The mixture was diluted with DCM and water was added. The mixture was extracted twice with DCM, the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel Biotage cartridge (cyclohexane to cyclohexane:EtOAc=10:90) to afford title compound (0.284 g, 1.06 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:20]1[CH2:24]CC[CH2:21]1.CNC.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:21][N:20]([CH3:24])[C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])=[O:10]
Reactant: COc1ccsc1C(=O)O
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccsc1C(=O)N(C)C
Reaction time: 36 h
Yield: 193.6 %

Procedure:
To a suspension of 3-methoxythiophene carboxylic acid (1.84 g, 11.61 mmol), from step A, in 60 mL of acetonitrile at room temperature was added bromotripyrroli-dinophosphonium hexafluorophosphate (PyBrop, 5.40 g, 11.60 mmol), dimethyl amine (2.0 M in THF, 14.5 ml, 29.0 mmol) and diisopropylethyl amine (5.0 mL, 28.63 mmol) successively. After stirred for 1.5 day, the mixture was concentrated under reduced pressure to a yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=40:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated to an oil, which was further dried on high vacuum, yielding 4.16 g of N,N-dimethyl 3-methoxythiophene amide (contaminated by PyBrop impurity) (MH+=186.0).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=O>>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Product: CCOC(=O)c1cnn2c(-c3ccccc3C(F)(F)F)ccnc12

Procedure:
As for Example 1, ethyl 3-aminopyrazole-4-carboxylate is reacted with 3-dimethylamino-2'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 148°-149° C.
Reaction SMILES: N[C:2]([NH2:4])=[NH:3].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([C:20](Cl)=[N:21][OH:22])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7]>C(O)C>[NH2:4][C:2]1[O:22][N:21]=[C:20]([C:11]2[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]([OH:15])=[C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])[CH:10]=2)[N:3]=1
Reactant: N=C(N)N
Reactant: CC(C)(C)c1cc(C(Cl)=NO)cc(C(C)(C)C)c1O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2noc(N)n2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.6 g (0.044 mole) of guanidine in absolute ethanol (100 ml) is added dropwise a solution of 6.2 g (0.022 mole) of 3,5-bis(1,1-dimethylethyl) -N,4-dihydroxybenzenecarboximidoyl chloride in absolute ethanol (60 ml). The mixture is stirred at room temperature for 18 hours, then evaporated to dryness (vacuum). The oil is dissolved in ethyl acetate (125 ml) and poured into water (125 ml). While stirring, the solution is acidified (pH 4.0-5.0) with 1N hydrochloric acid. The organic layer is separated, washed with water (2×100 ml), and dried (anhydrous magnesium sulfate). Evaporation of the organic layer leaves 5.0 g of crude material. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) gives 1.0 g (16%) of analytically pure 4-(5-amino-1,2,4-oxadiazol-3-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 202°-204° C.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[CH2:7](Br)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1.CCOCC>O1CCCC1.O>[CH2:7]([S:3][CH2:4][CH2:5][OH:6])[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCSCc1ccc2c(c1)OCO2

Procedure:
0.96 g (0.02 mol) of 50% sodium hydride dispersion are freed from the mineral oil with absolute tetrahydrofuran and suspended in 30 cc of tetrahydrofuran. A solution of 1.56 g (0.02 mol) of 2-mercaptoethanol in 10 cc of tetrahydrofuran is added at 20°-25° while stirring, to this suspension. The mixture is stirred at 60° over the course of 10 hours. After this period a solution of 4.3 g (0.02 mol) of piperonyl bromide in 30 cc of tetrahydrofuran is added dropwise to the mixture. The reaction mixture is stirred at 60° over the course of 8 hours, subsequently cooled to 20° and 100 cc amounts of ether and water are added. The organic phase is separated off in a separating funnel, extracted with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue may be purified by chromatography on silica gel with hexane/ethyl acetate (1:2). 2-Piperonylthio-ethanol is obtained as a colourless oil, which according to gas-chromatography is pure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:19]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:19])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a vial is added ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (180 mg, 0.61 mmol) in 3 ml of THF, followed by the addition of NaH (35 mg, 0.92 mmol). Then iodomethane (131 mg, 0.92 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 116 mg of ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amide.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[CH:18][C:17]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>ClCCl>[C:8]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]3[CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:18][C:17]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(OC[C@H]2CCCN2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.5 ml, 19.47 mmol) was added dropwise to an ice-cooled solution of 1,1-dimethylethyl (2R)-2-[({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)methyl]-1-pyrrolidinecarboxylate (may be prepared as described in Description 73; 500 mg, 0.99 mmol) in dichloromethane (15 ml). After stirring at 25° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. Half of the crude product was purified by pre-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7 min, 35%-50%; 7-14 min, 95%; RT=6.5 min) to yield the title compound as a light yellow solid. 70 mg.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:15]
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (228 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (40 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=90/10→0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (191 mg) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)C(c1ccc(F)cc1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (4.0 g, 18.6 mmol) [prepared as described in Example 1 above] and 2-chloro-3-nitropyridine (6.50 g, 41.13 mmol) in dimethylformamide (50 ml) at 0° C. was added sodium hydride (1.65 g, 41 mmol, 60% in oil) under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred for an hour. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give a dark brown oil. Purification by flash column chromatography (10% to 50% ethyl acetate/hexanes gradient) gave 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(pyridin-4-yl)ethanone as a brown oil (4.08 g).