Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH:2]=[CH2:3].[CH3:7][NH:8][C:9](=S)[NH:10][NH2:11].C(O)C.NC(NNC(=O)N)=O>P(Cl)(Cl)(Cl)=O>[CH2:1]([NH:4][C:5]1[S:6][C:9]([NH:8][CH3:7])=[N:10][N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCN=C=S
Reactant: CNC(=S)NN
Agent: NC(=O)NNC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: C=CCNc1nnc(NC)s1
Temperature: 2 °C
Yield: 21.4 %

Procedure:
A stirred suspension of allyl isothiocyanate (19.8 g, 0.2 mole) and of 4-methyl-3-thiosemicarbazide (21.0 g, 0.2 mole) in 150 ml denatured ethanol (5% methanol) was refluxed for one hour. The crystalline suspension was briefly chilled, and the 1-allyl-6-methyl-2,5-dithiobiurea was collected and vacuum dried. A stirred solution of this biurea (30.6 g, 0.15 mole) in phosphorous oxychloride (150 ml) was refluxed for 11/2 hours. Unreacted phosphorus oxychloride was removed in vacuo, and the residue carefully partitioned between 1.2 M hydrochloric acid (150 ml) and chloroform (150 ml) while maintaining this mixture at 2° C with ice-bath cooling. The chloroform phase was extracted with another portion of 1.2 M hydrochloric acid (100 ml), and the combined acid layer was carefully made alkaline with conc. ammonium hydroxide. The resultant alkaline suspension was extracted with two portions of chloroform, and the combined chloroform extract was washed with a small portion of distilled water. After drying this chloroform extract over magnesium sulfate, the solvent was removed under reduced pressure to yield a colorless solid. Crystallization of the product from ethyl acetate gave 7.3 g (29 percent) of 2-allylamino-5-methylamino-1,3,4-thiadiazole (a colorless solid). Analysis confirmed the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:16])=[C:7]([O:13][CH2:14][CH3:15])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCl.CO>C1COCC1>[C:17]1([NH:23][C:24]([NH:1][C:2]2[CH:12]=[C:11]3[C:5]([C:6]([Cl:16])=[C:7]([O:13][CH2:14][CH3:15])[O:8][C:9]3=[O:10])=[CH:4][CH:3]=2)=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCOc1oc(=O)c2cc(N)ccc2c1Cl
Agent: CCl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1oc(=O)c2cc(NC(=S)Nc3ccccc3)ccc2c1Cl
Yield: 55 %

Procedure:
This compound was prepared by reaction of 7-amino-4-chloro-3-ethoxyisocoumarin with phenyl isothiocyanate at r. t. in THF for 24 hrs. The product was obtained as yellow solid: yield 55%, m.p. 176°-177° C. (dec.); TLC, Rf =0.76 (CH3Cl:MeOH=9:1), MS m/e=374 (M+). Anal. Calcd. for C18H15N2O3ClS: C, 57.62; H, 4.00. Found: C, 57.77; H, 4.04.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.Br[C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1.Br[C:22]1[CH:23]=[C:24]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>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>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[O:14][C:10]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:23]=2)=[CH:11][CH:12]=1
Reactant: Fc1cc(Br)cc(-n2ccnc2)c1
Reactant: Brc1ccc(-c2ccccn2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Product: Fc1cc(-c2ccc(-c3ccccn3)o2)cc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 19 h
Yield: 65.8 %

Procedure:
Title compound synthesis: Pd(PPh3)4 (10 mg, 0.009 mmol) was added to absolution of hexamethylditin (169 mg, 0.52 mmol) and 5-bromo-2-(2-pyridyl)-furan (90 mg, 88% purity, 0.36 mmol) in toulene (2 mL) under argon. The resulting solution was stirred at 80° C. for 19 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (10 mg, 0.009 mmol) and 1-(3-bromo-5-fluoro-phenyl)-1H-imidazole (86 mg, 0.36 mmol) were added and the resulting solution was stirred at 110° C. for 36 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5 g silica gel SPE tube, 0–3% methanol in 1:1 chloroform:ethyl acetate) afforded 72.3 mg (66%) of 2-(2-pyridyl)-5-(5-fluoro-3-(1-imidazolyl)phenyl)-furan. 1H-NMR (CDCl3), δ (ppm): 8.63 (d, 1H), 7.93 (s, 1H), 7.78 (m, 2H), 7.57 (s, 1H), 7.45 (m, 1H), 7.35 (s, 1H), 7.23 (m, 3H), 7.03 (m, 1H), 6.91 (d, 1H).
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 300 mg (0.0024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.
Reaction SMILES: [C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of 1.8 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 2, in 20 ml of pyridine, 2.8 g of tosyl chloride in 15 ml of pyridine were slowly added. After the addition had been completed, the mixture was stirred for about six hours and was then poured into cold water and extracted with dichloromethane. The organic layer was evaporated off and the residue was chromatographed over 18 g of silica gel using dichloromethane with increasing amounts of methanol (from 0 to 4 percent) as the eluant. 2 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-tosyloxymethyl-ergoline were obtained, melting at about 150° to 152° C.
Reaction SMILES: [F:1][C:2]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)([C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[I-].[CH3:16][S+](C)(C)=O.CS(C)=O>O1CCCC1>[C:5]([C:4]1([C:2]([F:1])([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH3:3])[CH2:16][O:9]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)C(C)(F)n1cncn1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(C(C)(F)n2cncn2)CO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
12.0 g of 2-fluoro-2-(1H-1,2,4-triazol-1-yl)-4,4-dimethyl-3-pentanone are added dropwise to a mixture of 13.2 g of trimethylsulfoxonium iodide, 7.3 g of potassium tertiary butylate, 20 ml of dimethyl sulfoxide and 80 ml of tetrahydrofuran, and the reaction mixture is stirred for 18 hours at 80° C. After cooling, the mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Distillation of the oily residue gives 6 g 2-tert.-butyl-2-[1-fluoro-1-(1H-1,2,4-triazol-1-yl)-ethyl]-oxirane, boiling point 60°-61° C./0.013 mbar.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.CN1CCOCC1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:27]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:24]1=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
Trifluoro-methanesulfonic anhydride (14.35 mL, 77.3 mmol) was added to a CH2Cl2 (150 mL) solution of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (11.40 g, 70.3 mmol), N-methylmorpholine (8.5 mL, 77.3 mmol) and DMAP (130 mg, 1 mmol) in 5 min at −80° C. The mixture was warmed to 0° C. in 1 h then poured into a cold solution of saturated NH4Cl. The mixture was diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the crude compound which was purified by column chromatography (silica, 0 to 60% CH2Cl2 in hexane) to provide the title compound.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:66]=[CH:65][C:46]3[N:47]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:48]([C:50]4[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:61]([N:47]1[C:46]2[CH:65]=[CH:66][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)(C)n1c(-c2cc(F)ccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of acetic acid (52 mg, 0.86 mmol) and HATU (326 mg, 0.86 mmol) in DMF (4 mL) is added triethylamine (0.12 mL, 0.86 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-N-hydroxy-benzamidine (300 mg, 0.72 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (30 mL) is added and the organics washed sequentially with saturated NaHCO3 solution (30 mL) and H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via flash chromatography (10 g silica gel, 1.5-3% MeOH/CH2Cl2) affords the title compound (43 mg, 10%). LCMS (ESMS): m/z 444.32 (M++1)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:24]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([Cl:13])[CH:23]=3)=[O:25])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc(Cl)nc2ccccc12

Procedure:
To 3.16 gm. (0.0195mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 3.5 gm. (0.015 mole) of 2-chloro-4-quinolinecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue recrystallized twice from isopropyl ether-ethyl acetate. The product (0.7 gm.; 13%) melted at 127°-219° C.
Reaction SMILES: C([O-])=O.[NH4+:4].C[O:6][C:7]([C:9]1[S:10][CH:11]=[C:12]([CH3:17])[C:13]=1[NH:14][CH:15]=O)=O>C(N)=O>[CH3:17][C:12]1[C:13]2[N:14]=[CH:15][NH:4][C:7](=[O:6])[C:9]=2[S:10][CH:11]=1
Reactant: [NH4+]
Reactant: COC(=O)c1scc(C)c1NC=O
Agent: O=C[O-]
Solvent: NC=O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 150 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
To a solution of ammonium formate (5.1 g, 81 mmol) in formamide (25 mL) at 150° C. was added 3-(formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (2, 5.0 g, 25 mmol) as a solid in small portions. The resulting solution was heated at 150° C. for 5 hours and then allowed to stand at room temperature for 12 hours. The precipitate that formed was collected by vacuum filtration to give 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3.4 g, 84% yield) as white needles.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:19]([O-:21])=[O:20])=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[N:9]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(Cl)Cl>>[C:22]([O:17][CH2:16][C@H:15]([N:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]=2[N+:19]([O-:21])=[O:20])[C:10]1=[O:14])[CH3:18])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-6-cyclopropyl-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (30 mg, 0.0001 mol), acetic anhydride (0.015 mL, 0.00016 mol), pyridine (0.015 mL, 0.00019 mol) and methylene chloride (4 mL, 0.06 mol), and was stirred at room temperature overnight. The solvent was removed under reduced pressure and the product was taken onto the next step without purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(Oc2ccc3ccc(NC(=O)c4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (11 g), N,N'carbonyldiimidazole (16.2 g) and 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (26.7 g). The product produced by precipitation in water (30.8 g; m.p. approximately 110° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×5 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-[7-(4-methoxyphenoxy)-1,8-naphthyridin-2-yl]benzamide (24.7 g) is produced, m.p. 171° C. 2-Amino-7-(4-methoxyphenoxy)-1,8-naphthyridine can be prepared in the following manner:
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH2:46][C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ICC>C1COCC1>[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([C:41]3[CH:42]=[N:43][N:44]([CH:46]([CH2:1][CH3:2])[C:47]#[N:48])[CH:45]=3)=[C:35]2[CH:34]=[N:33]1
Reactant: CC(C)NC(C)C
Reactant: N#CCn1cc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)n1cc(-c2ccnc3[nH]ncc23)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
A solution of diisopropylamine (229.8 mg, 318.3 μL, 2.271 mmol) in THF (10 mL) at 0° C. was treated with butyllithium (698.8 μL of 2.5 M, 1.747 mmol) and then allowed to cool to −78° C. This was then added dropwise to a solution of 2-[4-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)pyrazol-1-yl]acetonitrile (815 mg, 1.747 mmol) over a period of 20 minutes. After a further 30 minutes the reaction was treated with iodoethane (544.9 mg, 279.4 μL, 3.494 mmol) at −78° C. and the ice bath removed. The reaction was allowed to stir for 1.5 hours and then treated with brine/EtOAc and the two layers separated. The organics were dried (MgSO4), filtered and concentrated. The resultant residue was taken up in DCM (12 mL) and treated with triethylsilane (4 mL) and TFA (0.5 mL) and allowed to stir at RT for 2 hours. The reaction was concentrated in vacuo and purified by column chromatography (10% MeOH/DCM) to give the product as a pure white solid (252 mg, 57% Yield). 1H NMR (DMSO, 400 MHz) δ 0.95 (3H, t), 2.23-2.28 (2H, m), 5.79 (1H, t), 7.46 (1H, d), 8.46 (1H, s), 8.48 (1H, d), 8.52 (1H, d), 8.83 (1H, s), 13.73 (1H, br s); MS (ES+) 253.09
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Br:27]Br>>[Br:27][C:24]1[CH:23]=[C:22]([OH:25])[C:21]([OH:26])=[CH:20][C:19]=1[C:9]1[C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][C:14]=2[C:2]([Br:1])=[C:3]2[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]2
Reactant: BrBr
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O
Product: Oc1cc(Br)c(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1, 2-diol (Example 43) according to the procedure of Example 58. White solid: mp 138-140° C.: MS (EI): [M+], 2 bromine isotope pattern, 498, 500, 502; Anal. Calc. for C22H12Br2O2S: C, 52.83, H, 2.42, N, 0.00. Found: C, 52.17, H, 2.71, N, 0.05.
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].S(Cl)([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CCl
Yield: 88.1 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, the mixture was cooled in an ice-water bath, then N, N-dimethylformamide (2 drops) was added and thionyl chloride (0.64 mL, 10 mmol) was added dropwise, after the addition was complete, the reaction was conducted under reflux for 6 hours and quenched by adding water. After the reaction solution was separated, the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.4 g, yield: 90%.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH:22](=[O:26])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:3][C@H:2]([C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21
Yield: 80 %

Procedure:
A solution of N-propionyl-2-benzoxazolone (100.0 g) in anhydrous CH2Cl2 (1100 mL) was cooled to 3° C. with mechanical stirring under N2 atmosphere. TiCl4 (58.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting yellow slurry was stirred vigorously for 40 minutes, then triethylamine (87.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting deep red solution was stirred for 80 minutes. Butyraldehyde (58.9 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 20 minutes), and the reaction was followed by thin-layer chromatography (4:1 hexanes/ethyl acetate). After stirring for 90 minutes, the reaction was quenched by addition of 450 mL of 2 N HCl. The phases were separated, and the aqueous phase was extracted 3 times with 750-mL portions of ether. The organic phases were combined and washed three times with 200-mL portions of 2 N HCl. The acidic washes were combined and back-extracted 3 times with 150-mL portions of ether. The combined organic extract was washed once with 300 mL of sat. aq. NaHCO3, and once with 300 mL of sat. aq. NaCl. The organic phase was then dried over MgSO4, filtered, and concentrated under vacuum to a yellow slurry. The product was collected by vacuum filtration and rinsed with hexanes to yield a colorless solid. Concentration of the filtrate yielded a second crop of product, which was collected in the same manner, giving a combined 103 g (80% yield) of crystalline product; mp=123–4° C. The mother liquor can be chromatographed (4:1 hexanes/ethyl acetate) to yield additional product. 1H-NMR (CDCl3, 400 MHz): δ 8.10 (1H,m), 7.23–7.32 (3H,m), 4.12 (1H,m), 3.98 (1H,dq,J=3, 7), 2.26 (1H, br s), 1.38–1.64 (4H,m), 1.34 (3H,d,J=7), 0.98 (3H,t,J=7). 13C-NMR (CDCl3, 100 MHz): δ 176.4, 151.1, 142.2, 127.8, 125.5, 124.9, 116.3, 109.9, 71.3, 43.7, 36.2, 19.2, 13.9, 10.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COC(=O)C1CC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Yield: 274.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tetrahydrofuran (12 L), 1,4-dibromobenzene (2020 g, 8.56 mol, 1.03 equiv), followed by the addition of n-BuLi (3566 mL, 1.03 equiv, 2.4 M) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Into another 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 3-oxocyclobutane-1-carboxylate (1064 g, 8.30 mol, 1.00 equiv) in tetrahydrofuran (4 L). To this was added the resulting solution in the first flask dropwise with stirring at −78° C. The resulting solution was stirred overnight at 25° C. This reaction was repeated for 2 more times. The reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl, concentrated under vacuum, diluted with 15 L of H2O and extracted with 2×5 L of ethyl acetate. The organic layers were combined, washed with 1×8 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 6500 g (92%) of methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate as a dark red oil.