Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[I:27]N1C(=O)CCC1=O.N.ClCCl>FC(F)(F)C(O)=O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([I:27])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26]
Reactant: O=C1CCC(=O)N1I
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
42 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (0.1 mmol) is dissolved in 2 ml of trifluoroacetic acid and mixed with 22 mg of N-iodosuccinimide (0.1 mmol). After 15 minutes of stirring at room temperature, ice is added, it is made alkaline with ammonia, and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed. The pure substance crystallizes from dichloromethane, yield 9 mg (16% of theory).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl.[CH3:33][O:34][NH2:35].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[I-].[Na+]>[CH3:33][O:34][NH:35][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: CON
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Product: CONCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
The mixture of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol) in DMSO (2.0 mL), were added O-methylhydroxylamine hydrochloride (83.5 mg, 1.0 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg). The reaction solution was heated to 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1°/o TFA 10-90%) to give the title compound (20.7 mg, 43%).
Reaction SMILES: [CH3:1][C:2]([CH3:50])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](C)=[O:5].[F-].[CH2:52]([N+:56](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[CH3:50][C:2]([CH3:1])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([OH:40])[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](=[O:5])[NH:56][CH3:52]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)N[C@H](C(C)=O)C(C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 5.13 g (7.027 mmol) of the product of Example 29 dissolved in 75 mL of THF was added 17.6 mL (0.01 8 mmol) of a 1.0M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at room temperature for 4 h and then diluted with ether. The resulting solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (gradient: 1:3-1:1) to provide 2.78 g (64%) of the desired product as a colorless oil. Electrospray Mass Spec: 617.5 (M+H)+.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][CH:15]=[CH:14]1.O1CCCC1.C[O:25][C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])=O>C(N(CC)CC)C>[OH:18][C@@H:17]1[CH2:16][CH:15]=[CH:14][C@H:13]1[N:12]1[C:26](=[O:25])[C:28]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]2[C:30]1=[O:31]
Reactant: N[C@@H]1C=CC[C@H]1O
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A 31.3 g. (0.115M) quantity of dl-trans-3-amino-4-hydroxycyclopentene toluenesulfonate is dissolved in 240 ml. of tetrahydrofuran and 47 ml. (0.46M) of triethylamine. The resultant stirred solution is cooled to 5° and treated dropwise with 22.8 g. (0.115M) of o-methoxycarbonylbenzoylchloride. The reaction is then allowed to warm to 25°. After 48 hours the reaction is partitioned between Ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and concentrated in vacuo leaving 29.6 g. of residue. This residue is chromatographed over silica gel 60 eluted with 5 l. (10-90) and 7.5 l. of (20-80) acetone-methylene chloride. Three hundred ml. fractions are collected. The product is isolated in fractions 25-35, which upon standing crystallizes to yield 14.2 g. of dl-trans-4-hydroxy-3-phthalido-cyclopentene, m.p. 114°-116°.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:12]=1[CH2:13][CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16]>CO>[NH2:7][C:6]1[N:8]=[C:15]([OH:16])[C:14]([CH2:13][C:12]2[CH:23]=[C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][C:11]=2[O:10][CH3:9])=[C:20]([CH3:21])[N:5]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1cc(CC(=O)OC)ccc1OC)C(C)=O
Agent: O=C(O)O
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(Cc2c(C)nc(N)nc2O)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Guanidine carbonate (0.443 g) was added to a solution of the product from step (iii) (0.52 g) in MeOH (10 ml) and stirred at 50° C. for 15 h. The solvent was evaporated and the residue stirred in EtOAc (10 mL) and water (10 mL), the resulting solid was filtered off. Further product was collected by evaporation of the filtrate, the solids were combined to give the subtitle compound as a yellow solid, 0.607 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-])=O.C(N(CC)CC)C.[C:18]([Cl:23])(=[O:22])[CH2:19][CH2:20][CH3:21].C(O)(C)C.Cl>C1COCC1.CO.[Pd]>[ClH:23].[CH2:19]([C:18]([NH:1][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])=[O:22])[CH2:20][CH3:21]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCC(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)O
Product: CCCC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-nitroaniline, 5.3 g, 0.038 moles, in 100 ml THF was added 25 ml of triethylamine followed by butyryl chloride. 5.0 g, 0.035 moles. The reaction then was stirred at room temperature for 18 hours. The triethylamine hydrochloride was removed by filtration. To the filtrate was added 100 ml of ethyl acetate, and the organic phase was then washed with 1N hydrochloric acid, 100 ml (twice), and then with 2N sodium hydroxide, 100 ml (twice). The organic phase was dried over magnesium sulfate and the solvent was evaporated to yield an oil. The oil was then dissolved in 100 ml of methanol and 20 ml of isopropanol/hydrochloric acid and to this solution was add 250 mg of 10% palladium on carbon. The reaction was then hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was crystallized from hot isopropanol and ethyl acetate, and was collected by filtration to yield 3-(((propyl)carbonyl)amino)aniline hydrochloride, 2.3 g. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.O.NN>CO.O1CCCC1>[NH2:23][CH2:22][CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[Br:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCN)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-1H-indole-6-carboxylate (3.96 g, 7.78 mmol) in methanol (50 ml) and tetrahydrofuran (30 ml) was added hydrazine monohydrate (1.88 ml, 38.7 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was filtered with celite and washed with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1-15:1) to give methyl 1-(2-aminoethyl)-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.95 g, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(=O)(=O)(O)O.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:19][NH2:20])=[O:12]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1c(F)cccc1F

Procedure:
70.4 g (0.41 mol) of 2,6-difluorophenylacetic acid, 700 ml of ethanol and 35 ml of concentrated sulphuric acid are heated under reflux for 3 hours. The reaction mixture is then concentrated by evaporation, taken up in dichloromethane and the solution is extracted by shaking in succession with water, 2N sodium carbonate solution and again with water. After drying over magnesium sulphate, the organic phase is concentrated by evaporation. The residue is dissolved in 560 ml of ethanol. After the addition of 30 ml (31 g; 0.62 mol) of hydrazine hydrate, the whole is heated under reflux for 4 days. After cooling, the resulting crystals are filtered off to yield 56.4 g (74% of the theoretical yield) of 2,6-difluorophenylacetic acid hydrazide which melts at 177°-178°.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)C>[C:4]1([CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1

Procedure:
A solution of 30 g ethyl cinnamate in 100 ml ethanol containing 2.0 g catalyst, as prepared in Example 3, in a 250 ml stainless steel autoclave may be hydrogenated at 1200 psig hydrogen and 170° C. for about 1.5 hr. to afford ethyl 3-phenylpropionate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:12]2[CH2:14][O:13]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CCO>[OH:15][CH2:16][C@H:17]1[N:22]([CH2:14][CH:12]([OH:13])[C:3]2[C:2]([CH3:1])=[CH:11][C:6]3[C:7](=[O:10])[O:8][CH2:9][C:5]=3[CH:4]=2)[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)COC2=O
Temperature: 25 °C

Procedure:
A mixture of 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1(3H)-one (750 mg, 3.95 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (1.02 g, 4.74 mmol) in EtOH (5 mL) was reacted under microwave condition (140° C.) for 90 min. After cooling to r.t., the mixture was concentrated to dryness. The residue was purified by prep-TLC to give tert-butyl (3S)-3-(hydroxymethyl)-4-[2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@H:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[C@@H:59]([C@@H:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (1.78 g, 6.79 mmol) in THF (20 mL) at 0° C. were added 5-chloro-pyridin-2-ol (0.60 g, 4.63 mmol) and then DBAD (1.14 g, 4.95 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (0.98 g, 3.09 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.917 g (69%) of the title compound as a colorless oil. ES-MS m/e: 429.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([N:19]=[C:20]=[S:21])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[C:13]4=[C:12]([C:17](=[O:18])[NH:19][C:20](=[S:21])[N:14]4[C:15]=2[CH:16]=1)[CH:11]=[CH:10][CH:9]=3
Reactant: O=C(N=C=S)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2

Procedure:
A slurry of 53.7 g. (0.168 mol.) of 8-trifluoromethylphenothiazine-1-carboxylic acid isothiocyanate in 30 ml. of diphenyl ether was heated in an oil bath at 210° for one hour. The reaction mixture first became a homogenous liquid and then turned into a solid mass. The cooled reaction mixture was refluxed for several minutes in 100 ml. of toluene, cooled to ambient temperature, and the insoluble material was collected by filtration and washed with several small portions of toluene to give the title compound, m.p. 297°-299° (ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1Cl)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30](O)=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][N:35]=[C:27]([C:26]([F:37])([F:25])[F:36])[CH:28]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccnc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (103 mg, 0.30 mmol), 2-(trifluoromethyl)isonicotinic acid (86 mg, 0.45 mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 106, the title compound (102 mg, 71%) was obtained as a light blue powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].COCCOC>O.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:12]([O:16][C:17]([C:19]1[CH:24]=[C:23]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[N:10]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(C(=O)O)c(Cl)n2)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
2,6-Dichloronicotinic acid (1.20 g, 6.25 mmol), 3-(tert-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1,2-dimethoxyethane (30 mL) and water (0.5 mL) were combined under an argon atmosphere and the mixture heated at 90° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The aqueous layer was acidified to pH 3-4 using 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert-butoxycarbonyl)phenyl)-2-chloronicotinic acid (1.4 g, 67%) as an off-white foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.59 (t, 1H), 1.60 (s, 9H); m/z 334 [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]3[S:15][C:14]([CH:16]=O)=[CH:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([CH2:16][C:14]1[S:15][C:10]3[C:9]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:8][C:7]([N:6]4[C:5]5[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=5[N:3]=[C:2]4[CH3:1])=[N:12][C:11]=3[CH:13]=1)[CH2:33][CH2:32]2
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(C=O)cc2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCc4cc(F)ccc4C3)cc2n1

Procedure:
Following General Procedure L for reductive amination, 2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde and 6-fluoro-1,2,3,4-tetrahydroisoquinoline were reacted to give 221. LCMS m/z: 515.6 (MH+)
Reaction SMILES: [Cl-].[Cl-].[Ca+2].O.[N+:5]([C:8]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:9]=1[NH2:10])([O-])=O.C1C=CC=CC=1>CCO.[Zn].CCOC(C)=O>[F:15][C:14]1[C:8]([NH2:5])=[C:9]([NH2:10])[C:11]([F:18])=[C:12]([F:17])[C:13]=1[F:16]
Reactant: Nc1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Nc1c(N)c(F)c(F)c(F)c1F

Procedure:
3,4,5,6-Tetrafluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al., J. Org. Chem. 55:580 (1990). A suspension of Zn powder (1.95 g, 29.8 mmol), CaCl2 (195 mg) and H2O (2.3 mL) in 7 mL EtOH was heated to reflux with stirring under N2. To this was added slowly dropwise a solution of 2-nitro-3,4,5,6-tetrafluoroaniline (2 g, 12.8 mmol) in 5 mL EtOH. The reaction mixture was refluxed 5 h. TLC analysis (silica gel, 2:1 benzene:EtOAc) indicated complete disappearance of the starting material. The Zn was removed by vacuum filtration, and the Zn rinsed with EtOH (30 mL). The solvent was rotary evaporated and the residue was dissolved in 20 mL Et2O and the solution washed with 2×15 mL H2O and 15 mL sat'd NaCl. The organic layer was dried (MgSO4) and vacuum filtered. The solvent was rotary evaporated to yield 396.6 mg (92.5%) of a purple brown solid, mp 120°-125° C., that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:27])=[C:20]([Cl:26])[CH:21]=[C:22]2[Cl:25])=[N:17]1)#[N:14]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Cl)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-chlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=441, RT=0.74 min.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4](Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:4]([N:2]([CH3:1])[NH2:3])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CN(N)C(=O)c1ccccc1
Yield: 66.6 %

Procedure:
Methylhydrazine (0.212 ml, 4.0 mmol) was dissolved in dichloromethane (10 ml) and was treated dropwise with benzoylchloride (0.232 ml, 2.0 mmol) in dichloromethane (5 ml). After stirring for 0.5h the solution was evaporated to dryness. The residue was partitioned between water and ethyl acetate. The organic phase was dried and evaporated under reduced pressure to give the title compound (0.20 g, 65%); δH (CDCl3) 3.13 (3H, s), 4.5 (2H, brs), and 7.30 (5H, s).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.CS(Cl)(=O)=O.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+]>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[C:30]1([S:36][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCSc3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate, (0.0488 g, 0.148 mmol) was dissolved in CH2Cl2 (5 mL) and stirred at rt. Triethylamine (5 mL) was added, followed by methanesulfonyl chloride (0.017 mL, 0.221 mmol, 1.50 equiv.). The reaction mixture was stirred for 2 h, and additional methanesulfonyl chloride (0.015 mL) was added. After 30 min, a mixture of thiophenol (0.065 mL, 0.592 mmol, 4.0 equiv.) and KOH (12 equiv.) in DMF (5 mL) was added, and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl, then the resulting mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by PTLC (1 mm×20 cm×20 cm SiO2 plates, developed with 1:4 EtOAc:hexane) to give tert-butyl 6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.017 g) in 28% yield as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.52, 2.92, 2.99, 3.17, 3.66-3.73, 4.28, 7.10-7.20, 7.25-7.41, 7.48; MS (ESI+) for C25H30N2O2S m/z 423 (M+H)+.