Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([O:11][CH:9]([CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCOc1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(CCOc1ccc(F)cc1)OS(C)(=O)=O
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred and cooled mixture of 10 parts of 4-(4-fluorophenoxy)-2-butanol and 30 parts of pyridine were added portionwise 7.4 parts of methanesulfonyl chloride at a temperature below 10° C. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was allowed to stand overnight in an ice-box. Then it was poured onto water and the product was extracted with dichloromethane. The extract was washed with a cold hydrochloric acid solution 20% and with water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10 parts (64%) of 4-(4-fluorophenoxy)-2-butanol methanesulfonate (ester) as an oily residue (intermediate 28).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][CH2:3]1.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:16])([CH3:1])[CH2:3][NH:4][C:5]2=[O:15])=[CH:10][CH:9]=1
Reactant: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)CNC(=O)c2cc(N)ccc21
Yield: 97.7 %

Procedure:
Palladium/Carbon (10% wt) (25 mg, 0.13 mmol) was added to a stirred solution of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (250 mg, 1.13 mmol) and ammonium formate (350 mg, 5.65 mmol) in anhydrous DMF (10 ml) at room temperature. The resulting suspension was then heated at reflux for 1 hrs, then cooled and filtered through a pad of celite. The solvent was evaporated and the crude residue purified by flash column chromatography (5% methanol in dichloromethane) to afford the title compound as a pale yellow solid (210 mg, 98%). HPLC retention time 1.00 min. Mass spectrum (ES+) m/z 191 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:15]=1[CH2:16][O:17][CH3:18])=[C:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]=[CH:10][CH:9]=3)#[N:2].Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:18][O:17][CH2:16][C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:7][C:6]=2[CH:5]=[N:4][C:3]=1[C:1](=[N:27][OH:28])[NH2:2]
Reactant: NO
Reactant: COCc1c(C#N)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCc1c(C(N)=NO)ncc2[nH]c3cccc(Oc4ccccc4)c3c12

Procedure:
A mixture of 329 mg (0.001 mol) of 3-cyano-4-methoxymethyl-5-phenoxy-beta-carboline, 100 mg of hydroxylamine hydrochloride, 20 ml of ethanol (99%) and 0.52 ml of a 20% aqueous potassium carbonate solution is refluxed for 22 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is mixed with 10 ml of water, the crystalline solid is filtered off and washed with water.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][OH:8].O[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[I:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: Cc1nn(C)c(CO)c1I
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C)c(COc2ccc(C(F)(F)F)cc2)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of (4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methanol (75 mg), 4-hydroxybenzotrifluoride (48 mg), 40% diisopropyl azodicarboxylate (90 mg, toluene solution), triphenylphosphine (117 mg) and tetrahydrofuran (3.0 mL) was stirred at a room temperature overnight. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=90:10 to 50:50), so as to obtain the title compound (34 mg) in the form of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]1[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]1=[O:21].S>[NH4+].[OH-].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]1[C:17](=[O:18])[CH2:16][C:15]([CH3:19])([CH3:20])[CH2:14][C:13]1=[O:21]
Reactant: CC1(C)CC(=O)C(c2c(Cl)cc([N+](=O)[O-])cc2Cl)C(=O)C1
Agent: S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)C(c2c(Cl)cc(N)cc2Cl)C(=O)C1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A solution of 20.0 g (0.0606 mol) of 2-(2',6'-dichloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione in 150 ml conc. NH4OH and 150 ml of ethanol was stirred at room temperature while passing H2S gas through the solution at such a rate that all of the H2S was absorbed. After the solution was saturated with H2S, it was refluxed 24 hours while continuously passing H2S slowly through the solution. The reaction mixture was cooled to room temperature, the precipitated sulfur removed by filtration, and the filtrate evaporated to dryness under reduced pressure. To the residue was added 300 ml of 0.25N NaOH, and the solution filtered once more. The filtrate was cooled and acidified to pH=4 with 6N HCl. A tan solid formed which was collected by filtration to give 11.2 g when dry. This material was washed with methylene chloride to give 8.2 g (45%) of 2-(2',6'-dichloro-4'-aminophenyl)-5,5-dimethyl-1,3-cyclohexanedione as a white powder, m.p. 243° d.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1.[CH3:21][O:22][C:23]1[CH2:24][C:25]2[CH2:26][CH2:27][C@@H:28]3[C@@H:37]([C:38]=2[CH2:39][CH:40]=1)[CH2:36][CH2:35][C@@:33]1([CH3:34])[C@H:29]3[CH2:30][CH2:31][CH:32]1[OH:41].O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:21][O:22][C:23]1[CH2:24][C:25]2[CH2:26][CH2:27][C@@H:28]3[C@@H:37]([C:38]=2[CH2:39][CH:40]=1)[CH2:36][CH2:35][C@@:33]1([CH3:34])[C@H:29]3[CH2:30][CH2:31][C:32]1=[O:41]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)CC[C@@H]32)C1
Agent: CC(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C1CCCCC1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 109 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a stirred solution of 106.3 g (0.52 mmol) of aluminum isopropoxide in 2000 ml of dry toluene 720 ml of cyclohexanone, 0.35 g of 2,6-ditert-butyl-4-methyl-phenol and 100 g (0.307 mol) 3-methoxy-17-hydroxy-estra-2,5(10)-diene were added, then the reaction mixture was stirred at 108-110° C. for 1 h. The reaction was followed by TLC. After completion of the reaction the mixture was cooled to 20-25° C., 200 ml of water was added and the so obtained mixture was stirred for 1 h. The precipitated aluminum hydroxide was filtered off and the filtrate was concentrated to a volume of 250 ml under reduced pressure. A mixture of 200 ml of methanol and 100 ml of water was added to this concentrated warm—about 60° C.—solution, the obtained suspension was cooled to 20-25° C. and stirred for 1 h. The precipitated crystalline product was filtered off and dried below 40° C. in vacuum to yield 76.4 g (87%) of the title compound.
Reaction SMILES: [N+](=C[Si](C)(C)C)=[N-].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([F:19])[CH:10]=1.[N+](=[CH2:22])=[N-]>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:22])=[O:17])=[C:11]([F:19])[CH:10]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: C=[N+]=[N-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(Br)cc1F
Yield: 91 %

Procedure:
Diazomethyl-trimethyl-silane (11.6 mL of 2.0 M, 23.2 mmol) was added dropwise to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (4.50 g, 19.3 mmol) in toluene (7.7 mL) and MeOH (7.7 mL) under a nitrogen atmosphere at room temperature. A persistent yellow color remained after complete addition of diazomethane. The reaction was then quenched with a few drops of acetic acid and the solvents were removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 0-10% EtOAc in hexanes to yield methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.32 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.63 (d, J=1.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:13][C:12]([CH3:14])=[CH2:11])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(C)CCl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)Cn1ncc(Cl)c(Cl)c1=O
Temperature: 40 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To 50 ml of N,N-dimethylformamide were suspended 10 g of 4,5-dichloro-3(2H)-pyridazinone, 27 g of 3-chloro-2-methylpropene and 8.4 g of potassium carbonate. The mixtured solution was stirred for 5 hours at 40° C. Then, the procedures in Preparation Example 2 were repeated to give 4.9 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:25])([CH2:23][OH:24])[C:19]([F:22])([F:21])[F:20])=[O:15].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:24][CH2:23][C:18]([CH2:17][NH:16][C:14]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])([OH:25])[C:19]([F:22])([F:21])[F:20])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Nc1c(C(=O)NCC(O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)(CNC(=O)c2cnn(-c3ccc(F)cc3)c2N)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-1-(4-fluorophenyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]-1H-pyrazole-4-carboxamide (2.47 g, 6.82 mmol) in anhydrous dichloromethane (20 ml) and anhydrous pyridine (20 ml) cooled in an ice bath under a nitrogen atmosphere was added p-toluenesulphonyl chloride (1.7 g, 8.9 mmol). The mixture was stirred for 6 hours at ice bath temperature before being allowed to warm to room temperature and stirred overnight. The solution was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and water (30 ml). The separated organic phase was washed with 2M hydrochloric acid (2×30 ml), water (30 ml), saturated sodium hydrogen carbonate (30 ml), water (30 ml) and saturated brine (50 ml) before being dried over sodium sulphate and evaporated under reduced pressure to give a foam (3.45 g). This foam was purified on a Flashmaster column of Silica (100 g) using a 0-100% ethyl acetate in cyclohexane gradient over 1 hour. This afforded the title compound (2.8 g, 79%) as a foam.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:18]([CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][CH3:37])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[C:22]([O:21][C:19]([N:18]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH2:36][CH3:37])[CH:16]([CH3:17])[CH2:15][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([C:13]#[N:14])[CH:10]=1)[NH:4][CH2:5][CH2:6]2)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Yield: 86.8 %

Procedure:
To a solution of 1-acetyl-5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (167 mg) in ethanol (2.2 ml) was added a 5N-sodium hydroxide solution (1.1 ml), and the mixture was reacted at room temperature for 2.5 hours. The reaction mixture was neutralized by adding acetic acid, and extracted with methylene chloride. The extract was washed with water and a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 133 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile as an oil.
Reaction SMILES: C[N:2]1[CH:11]2[C:6]([C:7]3[N:14]=[C:13]([NH:15]C(=O)C(C)C)[S:12][C:8]=3[CH2:9][CH2:10]2)=[CH:5][CH2:4][CH2:3]1.N#CBr.C(Cl)(Cl)[Cl:25]>>[ClH:25].[ClH:25].[N:14]1[C:7]2[C:6]3[CH:11]([CH2:10][CH2:9][C:8]=2[S:12][C:13]=1[NH2:15])[NH:2][CH2:3][CH2:4][CH:5]=3
Reactant: CC(C)C(=O)Nc1nc2c(s1)CCC1C2=CCCN1C
Reactant: ClC(Cl)Cl
Agent: N#CBr
Product: Cl
Product: Nc1nc2c(s1)CCC1NCCC=C21

Procedure:
A solution of 5.00 g (17.15 mmol) of (±) N-(4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]quinolin-2-yl)-2-methylpropanamide (Example 15) in 150 ml of chloroform containing 20.6 ml (19.25 mmol) of a 1.07 M solution of cyanogen bromide in chloroform is refluxed, under nitrogen, for 12 hours. The solution is concentrated and the resultant yellow oily solid is refluxed in 150 ml of 10% hydrochloric acid for 12 hours. The solution is cooled, basified with ammonium hydroxide and extracted into chloroform. The chloroform extract is dried (magnesium sulfate), filtered and concentrated to a brown oil. Medium pressure chromatography (silica gel, 5% methanol--2% ammonium hydroxide--93% ethyl acetate) followed by salt formation and recrystallization from methanol/diethyl ether affords the title compound as a tan solid; mp 277°-279° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23]OC(=O)C(OC)=O.C[O-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
3-Methoxyandrosta-3,5-dien-17-one (I, 50.0 g) was dissolved in THF containing TEA (1 ml). Dimethyloxalate (55.5 ml) was added and the mixture cooled to 2°. Sodium methoxide (25%) in methanol (45.7 ml) was added slowly over 10 minutes. The ice bath was removed and the reaction warmed to 24° over five minutes with stirring. The mixture was stirred at 20°-25° for 55 minutes, then cooled to 5° over 10 minutes. Acetic acid (2.4 ml) was added, immediately followed by TEA (17.4 ml), then paraformaldehyde (7.49 g), followed by methanol (63 ml). The ice bath was removed and the mixture warmed to 20°-25° over 5 minutes. The mixture was stirred at 28° for 5 hrs and stored in a freezer (-20°) overnight. The mixture was then warmed to 20°-25° and stirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°. Water (300 ml) and ethyl acetate (300 ml) were added, the mixture stirred and the layers separated. The organic layer was washed with saline (2×100 ml). The aqueous portion is backextracted with ethyl acetate (2×100 ml, washing each with 50 ml of saline). The organic phases are combined, concentrated under reduced pressure to an oil, taken up in methylene chloride (450 ml) and ethyl acetate (200 ml). This mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to a solid. Trituration of the solid with boiling methanol (100 ml) containing 1% TEA gives the title compound in crystalline form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[O:4].[CH3:13][CH:14]([SH:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:16][CH:14]([CH3:15])[CH3:13])=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(C)nc1Cl
Reactant: CC(C)S
Product: COC(=O)c1cnc(C)nc1SC(C)C
Yield: 90 %

Procedure:
4-Chloro-2-methyl-pyrimidine-5-carboxylic acid methyl ester (0.105 g, 0.56 mmol) and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.114 g, 90%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[O:55])[CH:47]=[CH:46]3)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:43]4[CH:44]=[C:45]5[C:50](=[CH:51][CH:52]=4)[N:49]=[C:48]([NH:53][C:54]([CH:56]4[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]4)=[O:55])[CH:47]=[CH:46]5)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(c2ccc3nc(NC(=O)C4CCCCC4)ccc3c2)OC1(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC(=O)C6CCCCC6)ccc5c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (20.0 mg, 0.038 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl)cyclohexanecarboxamide (17.2 mg, 0.045 mmol) in dioxane (0.4 mL) was added Pd(PPh3)4 (2.2 mg, 0.002 mmol) and 2N K2CO3 (79 μL, 0.158 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90° C. for 10 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C41H41ClN5O4S: 734.3 (M+H+); found: 734.3 (M+H+).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH2:1]([S:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CCCCSCCC#N

Procedure:
β-n-Butylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-butanethiol (20.0 g; 0.22 moles), acrylonitrile (11.7 g; 0.22 moles) and sodium methoxide (0.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)[CH:3]=[CH:4][C:5]=1[F:29])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(-c3cncnc3)ccc2F)c2cccc(F)c21
Yield: 58 %

Procedure:
The title compound was synthesized as described for Example 1 in 58% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (59.0 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (17.17 mg, 0.14 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=O)(C)(C)C.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([CH2:28][C@@H:9]2[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:38][CH2:39][CH2:40][C:41]5[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=5)[N:22]=4)[CH:18]=[CH:19][CH:20]=3)[CH2:10]2)=[CH:30]1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CCN[C@@H](Cc5c[nH]c6ccccc56)C4)c3)n2)cc1

Procedure:
Intermediate 109 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 520. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.51 (s, 1H), 8.29 (d, 2H), 7.81 (d, 1H), 7.55 (m, 3H), 7.34 (d, 1H), 7.25 (s, 1H), 7.02 (m, 4H), 6.69 (s, 2H), 4.54 (m, 2H), 4.08 (m, 1H), 3.90 (m, 2H), 3.61 (m, 4H), 3.25 (m, 4H), 2.92 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25]N(C)C)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC=CN3C=2CN2C[C:50]([O:52]C)=[CH:49]C2=O)=CC=1.N1CCC(O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:23]3[CH2:24][CH2:25][CH:50]([OH:52])[CH2:49]3)=[CH:20][C:19]2=[O:29])=[CH:6][CH:7]=1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: OC1CCNC1
Product: O=C1C=C(N2CCC(O)C2)CN1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and pyrrolidin-3-ol. (33 mg, 32%) m/e+=409 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.46 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.61 (d, 1H, D, J=9.1 Hz), 7.46 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.84 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.57 (s, 1H), 4.53 (m, 1H), 3.55 (s, 2H), 3.2 (m, 4H), 2.1 (m, 3H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].C(O)C>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: CC(=O)c1ccccn1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=NNC(=O)c1ccccc1)c1ccccn1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A mixture of 6.81 gm (0.05 mole) of benzhydrazide, 6.06 gm (0.05 mole) of 2-acetylpyridine and 100 ml of ethanol is stirred at reflux 2 hr. Then sufficient dioxane is added to the boiling mixture to furnish a solution. The hot solution is filtered. The filtrate is diluted to the cloud point with water, cooled to room temperature, and then chilled in the refrigerator. The product is collected and dried to yield 7.61 gm (64%) of the title compound having a melting point of 151.6° C.