Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[N:19]2[CH:20]=[CH:21][N:22]=[C:23]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:18]2=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([NH:29][C@H:26]3[CH2:27][CH2:28][N:24]([C:23]4[C:18]5[N:19]([N:15]=[CH:16][CH:17]=5)[CH:20]=[CH:21][N:22]=4)[CH2:25]3)=[O:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3nccc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3nccc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (0.093 g, 0.49 mmol, 1.4 eq) and (S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.10 g, 0.36 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.20 mL, 1.4 mmol, 2.6 eq) and HATU (0.21 g, 0.55 mmol, 1.5 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-1-phenyl-N-(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide (0.095 g, 0.25 mmol, 52%). 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1 H), 8.16 (d, J=2.4 Hz, 1 H), 8.09 (d, J=5.8 Hz, 1 H), 7.86 (d, J=7.8 Hz, 2 H), 7.60-7.46 (m, 4 H), 7.19 (d, J=5.5 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.78-3.80 (br, 4 H), 2.62-2.40 (m, 2 H); MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)(=[O:47])=[O:46].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:49][CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(S(C)(=O)=O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 4-(methylsulfonyl)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (3.5 mg, 20%). LCMS: m/e 591.61 (M−H)−, 6.74 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.92 (s, 6H), 0.98 (s, 6H), 1.00 (s, 3H), 1.02-1.77 (m, 17H), 1.68 (s, 3H), 1.79-1.97 (m, 2H), 2.05-2.23 (m, 2H), 2.32 (t, J=13.47 Hz, 1H), 2.90-3.06 (m, 1H), 3.19 (s, 3H), 4.58 (s, 1H), 4.71 (s, 1H), 5.29 (d, J=5.57 Hz, 1H), 7.36 (d, J=6.44 Hz, 2H), 7.85 (d, J=8.20 Hz, 2H).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.O.CC[O:28]CC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Ag+].C(O)(=O)C>[CH:12]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2](=[O:28])[C:8]=2[CH:9]=[CH:10][C:11]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CCOCC
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2Br
Agent: [Ag+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 120 °C
Yield: 15 %

Procedure:
1.0 Gm. of silver p-toluenesulfonate and 0.5 gm. of 2-(5-bromo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid are stirred in 50 ml. of acetonitrile in the dark for 6 hours. Water, ether and 2.0 ml. of acetic acid are added. The ethereal layer is washed, dried and evaporated. The products, 2-(5-p-toluene-sulfonyloxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, is dissolved in 10 ml. of dimethylsulfoxide and heated to 120° C. for 5 minutes, then cooled, poured into water and extracted with ethyl acetate. The solution is washed, dried and evaporated. The residue is chromatographed on silica gel, eluting with 40:60:1 ethyl acetate: acetic acid, so as to isolate a 15% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23](Br)[N:24]=1>>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Brc1csc(Br)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nccs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromothiazole (2.53 g, 10.4 mmol) according to the general procedure IVc protocol b. Obtained as a side product as a light yellow solid (0.065 g, 2%). MS (ISP) 321.2 [(M+H)+]; mp 103° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[C:14]([N:15]=1)=[CH:13][C:12]1[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8][C:7]=1[CH:6]=2.[CH2:18]([NH2:20])[CH3:19]>COCCOC>[CH2:18]([NH:20][C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[C:14]([N:15]=1)=[CH:13][C:12]1[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8][C:7]=1[CH:6]=2)[CH3:19]
Reactant: CCN
Reactant: CN1CCc2cc3c(cc2C1)nc(Cl)n[n+]3[O-]
Solvent: COCCOC
Product: CCNc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Temperature: 20 °C
Yield: 88.7 %

Procedure:
A solution of chloride 257 (500 mg, 2.0 mmol) and ethylamine (0.4 mL, 6.0 mmol) in DME (15 mL) was heated at 60° C. for 4 h in a sealed pressure tube. The solution was cooled to 20° C., the solid filtered off and solvent evaporated. The combined residue was purified by chromatography, eluting with a gradient (2-4%) of MeOH/DCM, to give 1-oxide 258 (460 mg, 88%) as a yellow solid: mp 193-196° C.; 1H NMR δ 8.03 (s, 1H, H-10), 7.27 (s, 1H, H-5), 5.07 (br s, 1H, NH), 3.69 (s, 2H, H-6), 3.53 (dq, J=7.2, 5.8 Hz, 2H, CH2N), 3.05 (t, J=6.0 Hz, 2H, H-8), 2.72 (t, J=6.0 Hz, 2H, H-9), 2.48 (s, 3H, NCH3), 1.29 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 158.6, 147.0, 144.4, 132.5, 129.6, 122.8, 119.3, 58.2, 52.6, 46.0, 36.3, 29.1, 14.8; MS (APCI) m/z 260 (MH+, 100%). Anal. calcd for C13H17N5O: C, 60.2; H, 6.6; N, 27.0. Found: C, 59.9; H, 6.6; N, 26.9%.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[C:12]=1[CH2:11][CH2:10][CH2:9]2)=[O:4].CN.[C:21](#[N:23])C.C>C(Cl)Cl>[CH3:21][NH:23][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[C:12]=1[CH2:11][CH2:10][CH2:9]2)=[O:4]
Reactant: CC#N
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CCC2
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2cccnc2)n2c1CCC2
Temperature: 20 °C
Reaction time: 7 h

Procedure:
A suspension of 7-chloroformyl-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine hydrochloride (14.1 g) in methylene chloride (250 cc) is saturated with a stream of anhydrous methylamine, while the temperature of the reaction mixture is kept at about 25° C. for 7 hours. The solution obtained is stirred at a temperature of about 20° C. for 16 hours and then methylene chloride (250 cc) and distilled water (250 cc) are added to it. The organic phase is separated, washed 3 times with distilled water (750 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. A crude product (12.2 g) melting at 184° 0 is thus obtained. This product is dissolved in boiling acetonitrile (150 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 1 hour. The crystals which have appeared are separated off by filtration, washed twice with acetonitrile (20 cc in total) cooled to a temperature of about 4° C. and 3 times with diethyl ether (75 cc in total), and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-methyl-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide (7.1 g) is thus obtained in the form of cream crystals melting at 187° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CN1C(=O)CCC1>[C:31]([NH:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 80 mg, 0.24 mmol) and (S)—N-(pyrrolidin-3-yl)acetamide (62 mg, 0.48 mmol). To the sealed vial were then added NMP (2 ml), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (110 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.88 (s, 1H), 8.24 (d, J=6.3 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 8.01-7.96 (m, 2H), 7.65-7.59 (m, 2H), 6.87 (s, 1H), 6.29 (d, J=2.0 Hz, 1H), 4.41-4.31 (m, 2H), 2.25-2.13 (m, 1H), 2.03-1.91 (m, 1H), 1.83 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 423.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:16])[C:23](=[O:24])[C:22]2[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([F:19])[CH:21]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cc(F)c(F)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4) and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Yellow solid (33%). MS (ESI): m/z=441.103 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CN2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COCC2CN2)cc1
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 2-[(benzyloxy)methyl]-1-tritylaziridine (1.28 g, 3.16 mmol) in dichloromethane (13 mL), trifluoroacetic acid (1 mL) and triethylsilane (2.0 mL) was added and stirred at the temperature for 1 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between ether and brine. The organic extract was dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 50-100% THF in hexane. Collection and concentration of appropriate fractions provided 2-[(benzyloxy)methyl]aziridine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:18][CH2:17]1)=[O:4].[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:21]([O-:23])=[O:22])[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:17][CH2:18]1)=[O:4]
Reactant: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)ccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(1′-methyl-2′-oxo-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2 g) in acetic acid (20 ml) at 15° C. is added nitric acid (fuming, 0.8 ml) over a period of 3 min. The mixture is stirred at this temperature for 1 h and then diluted with water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated. The compound (2.25 g) is obtained as a brown semi-solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([OH:19])=O)[C:5]=1[C:20]([OH:22])=[O:21])[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:19])[O:21][C:20](=[O:22])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]2)[CH3:16]
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Temperature: 65 °C

Procedure:
1,4-Bis(ethyloxy)-2,3-naphthalenedicarboxylic acid (10.3 g, 33.8 mmol) was added to a three neck flask and chloroform (80 ml) added and stirred. Thionyl chloride (49.2 ml, 355.4 mmol) in a dropping funnel was added dropwise over 25 minutes whilst monitoring temperature (no change). The reaction was heated at relfux (65° C.) overnight. LC/MS indicated no starting material remained. Reaction mixture was cooled to room temperature and solvent evaporated. The product was azeotroped with chloroform (×2) to remove the remaining traces of thionyl chloride to give the title compound as*a pale yellow solid (9.86 g).
Reaction SMILES: [CH2:1]([S:9][C@H:10]1[C:31]2[C:22](=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:21]([S:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:20]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:12][C:11]1=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:1]([S:9][C:10]1[C:31]2[C:22](=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([S:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:20]2[C:11]=1[CH:12]=[C:13]1[C:18](=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CCS[C@H]2c3cc4ccccc4cc3[C@H](SCCc3ccccc3)c3cc4ccccc4cc32)cc1
Agent: O=C([O-])[O-]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [K+]
Solvent: c1ccccc1
Product: c1ccc(CCSc2c3cc4ccccc4cc3c(SCCc3ccccc3)c3cc4ccccc4cc23)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
A mixture of trans-6,13-Bis(phenethylthio)-6,13-dihydropentacene (0.97 g, 1.76 mmol), tetrachloro-1,4-benzoquinone (0.87 g, 3.52 mmol) and potassium carbonate (2.43 g, 17.6 mmol) in dry benzene (170 mL) was stirred at 60° C. for 48 h under an argon atmosphere in the dark. After cooling to RT, the reaction mixture was filtered and washed with CH2Cl2. After evaporation of the filtrate, the solid residue was triturated with n-hexanes, filtered, and washed with hexane. After evaporation of the filtrate, the solid residue was passed through short column of n-Al2O3 eluted with CH2Cl2 and the deep blue band was collected. The solvent was evaporated to give pure 6,13-bis(phenethylthio)pentacene as deep blue solids in 72% yield (0.70 g). 1H NMR (500 MHz, CDCl3): δ 9.63 (s, 4H), 8.00 (m, 4H), 7.40 (m, 4H), 7.19 (m, 6H), 7.06 (d, 4H, J=7.08 Hz), 3.32 (t, 4H, J=7.56 Hz), 2.86 (t, 4H, J=7.56 Hz). 13C NMR (125.68 MHz, CDCl3): δ 140.91, 140.20, 132.83, 132.19, 128.88, 128.67, 128.52, 127.01, 126.49, 126.07, 38.97, 36.46. LDI-MS m/z: 550 [M+], UV-vis λmax(nm): 618, 571, 530.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21]12CC(C=C1)C=[CH:22]2.CCN(CC)CC>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:22]=[CH:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Reactant: C1=CC2C=CC1C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 78.5 %

Procedure:
A stirred mixture of hydrazonoyl chloride 65 (1.55 g, 4.99 mmol), bicyclo[2.2.1]hepta-2,5-diene (1.25 mL, 24.6 mmol) and Et3N (2.0 mL, 14.3 mmol) in toluene (10 mL) was heated to 70° C. for 1 h. The mixture was cooled and filtered, the filter cake was washed with toluene (10 mL) and the organic fractions were combined and evaporated. The residue was refluxed in xylenes (30 mL) for 2 h. Column chromatography on silica gel, eluting with hexanes, firstly gave xylenes, and then further elution with CH2Cl2 gave ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carboxylate (66) (1.176 g, 79%) as a white solid: mp 76-78° C.; 1H NMR (CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [O:1]1CCCOC1.[Cl:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C@@H:14]2[CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18]CC(C)(C)[O:15]2)=[CH:10][CH:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Cl:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C@@H:14]([OH:15])[CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][OH:1])=[CH:10][CH:9]=1
Reactant: C1COCOC1
Reactant: CC(C)(C)OC(=O)NC1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CO)[C@H](O)/C=C/c1ccc(Cl)cc1
Yield: 92 %

Procedure:
1,3-Dioxane, 2-boc amino (10C) (18 mg, 0.05 mmol) and 10 mol % TsOH (1.0 mg, 0.005 mmol) were combined in 5.0 mL 80% EtOH (in H2O) and stirred at reflux for 1 h, until the starting material was consumed as indicated by TLC (5:3/CH2Cl2:EtOAc). The reaction mixture was quenched with 5% NaHCO3, and removed in vacuo. Purification by flash column chromatography on silica gel afforded the desired product as a white solid (92%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[O:16])=[CH:11][C:10]=1[F:25]>ClCCl>[Br:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][C:10]=1[F:25]
Reactant: COc1ccc(C(=O)c2ccc(OCCBr)c(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
BBr3 (0.5 mL, 5.29 mmol) was added to (4-(2-bromoethoxy)-3-fluorophenyl)(4-methoxyphenyl)methanone (930 mg, 2.63 mmol) in dichloromethane (6 mL) at 0° C. Stirring was continued at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The extract was washed with water and brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=5/1 to 2/1) to give 536 mg (60%) of the subtitle compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.4 Hz, 2H), 7.59 (d, J=12.4 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 5.88 (s, 1H), 4.44 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1C(C)=CC(C)=C[C:33]=1C(C1CC1)=O>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:1]([CH:2]1[CH2:33][CH2:32]1)=[O:3])=[O:14])(=[O:21])=[O:22]
Reactant: Cc1cc(C)c(N)c(C(=O)C2CC2)c1
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C2CC2)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that cyclopropyl 2-amino-3,5-dimethylphenyl ketone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=23)[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccn2ncc(-c3cccc(Cl)n3)c2c1
Reactant: CC(C)(C)CN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CNc1cccc(-c2cnn3ccc(C#N)cc23)n1
Reaction time: 16 h
Yield: 35.5 %

Procedure:
An oven dried resealable Schlenk tube was charged with 3-(6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 6, 30 mg, 0.12 mmol), (2,2-dimethylpropyl)amine (14 μL, 0.12 mmol), cesium carbonate (77 mg, 0.24 mmol), 1,1-binaphthalene-2,2′-diylbis(diphenylphosphine) (3 mg) and toluene (1.5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and palladium (II) acetate (5 mg) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 120° C. and stirred for 16 h. The mixture was then cooled and ethyl acetate was added. The organic layer was washed with water, dried (MgSO4) and the solvents were evaporated. Purification of the residue by flash chromatography (dichloromethane to 150:1 dichloromethane/methanol) gave the title compound (13 mg, 34%) as a yellow solid.