Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][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.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[K+].[K+].[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:48](=[CH2:53])[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CC#N>[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH:48]([C:49]([O:51][CH3:52])=[O:50])[CH2:53][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])=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004087714 from commercially available methyl indole-6-carboxylate) in MeCN (0.08 M) were added 6 eq of K2CO3 and 1.2 eq of methyl 2-[bis(tert-butoxycarbonyl)amino]acrylate. The mixture was stirred at RT for 16 h before being filtered and concentrated in vacuo to afford the title compound as a viscous oil which solidified on standing (quantitative); MS (ES+) m/z 659 (M+Na)+, 661 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=O)=[N:29][CH:30]=1.CN([C:37]([O:41]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:37]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:41])=[N:29][CH:30]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Cc1ccc(Cl)cn1)NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 83.2 %

Procedure:
Using compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (60 mg, 0.188 mmol) (the product of step (e) in Example 1), 5-chloropyridin-2-carboxylic acid (36 mg, 0.225 mmol), HATU (107 mg, 0.282 mmol), and TEA (38 mg, 0.376 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid compound 74 mg, yield: 85.85%.
Reaction SMILES: [CH2:1]([C:8]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:10].[K+].[O:12]1[CH:14]([CH2:15][CH3:16])[CH2:13]1>CN(C)C=O>[CH2:15]([CH:14]1[O:12][C:8](=[O:10])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13]1)[CH3:16]
Reactant: [OH-]
Reactant: CCC1CO1
Reactant: N#CCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CC(c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 117 g. (1.0 m) benzyl cyanide, 72 g. (1.1 m) powdered 86% potassium hydroxide and 250 ml. dimethylformamide under a nitrogen atmosphere is added dropwise 74 g. (1.0 m) 1,2-epoxy-butane at 5° C. The temperature is held at 5° C. for 30 minutes and allowed to warm to room temperature. The reaction mixture is poured into 1,500 ml. water and extracted with 5×200 ml. toluene. To the combined toluene extracts is added 50 ml. of 50% hydrochloric acid and the mixture is heated on a steam bath for one hour. The toluene layer is then water washed until it is neutral, dried over sodium sulfate and filtered. The solvent is removed under vacuum to give 135 g. of a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].CS[C:13](=[N:16]C1C=CC(C(N2C=CN=C2)C(C)N(C)C)=CC=1)SC.CSC(SC)NC1C=CC(C(N2C=NC=N2)C(CC)CC)=CC=1>CS(C)=O>[S:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:13]1[NH2:16]
Reactant: Nc1ccccc1S
Reactant: CSC(=Nc1ccc(C(C(C)N(C)C)n2ccnc2)cc1)SC
Agent: CCC(CC)C(c1ccc(NC(SC)SC)cc1)n1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOH (6.35 ml; 20 N) was added at RT to a solution of 2-aminobenzenethiol (0.0637 mol) in dimethylsulfoxide (115 ml). The mixture was stirred at RT for 30 minutes. (±)-β-[4[[bis(methylthio)methylene]amino]phenyl]-N,N,α-trimethyl-1H-imidazol-1-ethanamine (0.0637 mol), prepared according to intermediate (19a), was added. The mixture was stirred at 110° C. overnight, then poured out on ice, extracted with EtOAc and washed with HCl (3 N). The aqueous layer was basified with a concentrated NH4OH solution and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was separated by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 90/10/0.1). Two pure fractions (F1 and F2) were collected and their solvents were evaporate F1 was crystallized from 2-propanone. The precipitate was filtered off and dried. The residue was taken up in K2CO3 (10%), filtered and the solvent was evaporated, yielding 1.12 g (5%) (±)-(A)-N-[4-[2-dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine (comp. 1). F2 was crystallized from 2-propanone. The precipitate was filtered off and dried. The residue was recrystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (4%) of (±)-(B)-N-[4-[2-dimethylamino)-1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine (comp. 2).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.C(N1C=CN=C1)(N1[CH:24]=[CH:23]N=C1)=O.C(O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:23][CH3:24])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Reaction time: 3 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylic Acid (15 g., 0.06 mol) and 1,1' carbonyldiimidazole (9.8 g, 0.06 mol) in dimethylformamide (12 ml) and tetrahydrofuran (700 ml) is refluxed with stirring for 3 hours. Absolute ethanol (20 ml) is added and refluxing is continued for a further 3 hours. The solvents are removed under reduced pressure. The residue is shaken with hot 0.5 mol aqueous sodium bicarbonate (200 ml), cooled and filtered. The residue is washed several times with water and recrystallized from methanol to give the product (8.9 g.) mp 183°-185° C.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18](Br)[CH:19]=[N:20][CH:21]=1.[Li]CCCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([B:1]([OH:6])[OH:2])[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cncc(B(O)O)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Triisopropyl borate (29.3 mL, 128 mmol) was added over 2 min to a solution of 5-methoxy-3-bromopyridine (20.00 g, 106.4 mmol) in toluene (140 mL) and tetrahydrofuran (35 mL) at −40° C. To this solution was added 2.5 M n-BuLi (51.1 mL, 128 mmol) drop-wise over 35 min while maintaining the temperature at −40° C. After the addition was complete, the reaction was stirred an additional 30 min at −40° C. and then was warmed to −15° C. over one hour. Into the reaction was poured 1 N HCl (175 mL), and the mixture was stirred vigorously for 30 minutes. The layers were separated, and the organic washed once with water (15 mL). The aqueous phases were combined and neutralized (to pH 7) with 5 N NaOH, at which point the boronic acid precipitated out. The biphasic mixture was extracted with THF (3×150 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to yield 15.36 g of 5-methoxy-3-pyridinylboronic acid as a light brown solid (94%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1Br.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc2c(c1Br)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc2c(c1)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Yield: 79 %

Procedure:
A solution of Example 4 (1.19 g), triethylamine (2.8 mL) and 10% Pd/C (120 mg) in ethyl acetate (100 mL) was shaken under 1.5 atms. hydrogen for 15 minutes. The mixture was filtered and concentrated under reduced pressure. The residue was taken up in toluene (50 mL), washed with aqueous KHCO3, dried (Na2SO4), filtered and concentrated. The resulting material was purified on silica eluting with 25% hexane −75% CH2Cl2 to provide the titled compound (0.763 g, 80%). 1H NMR (300 MHz, CDCl3) δ 3.75 (br s, 2H), 5.95 (s, 1H), 6.14 (d, J=3 Hz, 1H), 6.50 (t, J=75 Hz, 1H, CHF2) 6.71 (dd, J=9 Hz, 3 Hz, 1H), 6.77 (dd, J=9 Hz, 1Hz, 1H), 6.87 (dd, J=9 Hz, 1Hz, 1H), 7.05 (t, J=8 Hz, H), 7.30-7.40 (m, 5H), 8.12 (d, J=9 Hz, 1H). MS (APCI) m/e 340 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][C:27]2[N:31]=[C:30]([CH2:32][CH2:33][CH2:34]O)[O:29][N:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:34][CH2:33][CH2:32][C:30]2[O:29][N:28]=[C:27]([CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:31]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: OCCCc1nc(Cc2ccccc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (205 mg, 0.73 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (190 mg, 0.87 mmol) and PPh3 (247 mg, 0.94 mmol). DBAD (217 mg, 0.94 mmol) was added in one portion and the mixture was stirred at rt under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh3)4 (84 mg, 0.073 mmol) and morpholine (636 μl, 7.3 mmol) were added. The mixture was stirred at rt under nitrogen for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq) and the organic layer separated, washed with brine, dried (MgSO4) and concentrated. The crude material was purified by an aminopropyl column using MeOH to load the compound onto the column and wash through the impurities, then with 2-4% AcOH/MeOH gradient to remove the compound from the column. Further purification was effected by MDAP to give the title compound as a white solid (75 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:17]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[O:27])=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:15])=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (25.0 g, 0.092 mol) and phthalic anhydride (17.68 g, 0.119 mol) were placed in a reaction vessel, and added with dichloromethane (700 ml). At 0° C., aluminum chloride (18.5 g, 0.138 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (23.2 g, yield 60%) was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][C:22]5[N:21]6[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]6)=[CH:15][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 126a (150 mg, 0.20 mmol) and lithium hydroxide (72 mg, 3.0 mmol) in i-propanol/THF (5:3, 8.0 mL) and water (2.0 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 126 (45 mg, 33%) as a white solid. MS: [M+H]+ 682.9. 1H NMR (500 MHz, CHCl3) δ 8.60 (dd, J=2, 5 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.37-7.35 (m, 1H), 7.14-7.12 (m, 1H), 6.96-6.94 (m, 1H), 6.82-6.80 (m, 1H), 6.31 (s, 1H), 4.77-4.71 (m, 2H), 4.67-4.62 (m, 2H), 4.58-4.55 (m, 1H), 4.41-4.40 (m, 1H), 4.29-4.25 (m, 1H), 4.13-4.09 (m, 1H), 3.91-3.80 (m, 3H), 3.77-3.74 (m, 1H), 3.70 (s, 3H), 3.18 (d, J=5.0 Hz, 1H), 3.06-3.01 (m, 1H), 2.98-2.90 (m, 2H), 2.83 (m, 2H), 2.77-2.70 (m, 2H), 2.47 (m, 1H), 2.06-2.01 (m, 2H), 1.97-1.93 (m, 1H), 1.88-1.87 (m, 2H), 0.91-0.89 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH2:13][CH:6]2[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[CH:5]2[CH2:4][C:3]=1[CH3:14].[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[N:18][CH:17]=1.[C:28]1(N)[C:33](F)=C(F)C(F)=[C:30](N)[C:29]=1F.[ClH:40].Cl>>[ClH:15].[ClH:40].[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:33][CH2:28][CH2:29][CH2:30][N:8]3[C:7](=[O:12])[CH:6]4[CH2:13][C:2]([CH3:1])=[C:3]([CH3:14])[CH2:4][CH:5]4[S:9]3(=[O:11])=[O:10])[CH2:26][CH2:27]2)[CH:19]=[N:18][CH:17]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CC1=C(C)CC2C(C1)C(=O)NS2(=O)=O
Agent: Cl
Product: CC1=C(C)CC2C(C1)C(=O)N(CCCCN1CCN(c3cncc(Cl)n3)CC1)S2(=O)=O

Procedure:
The title compound is prepared using the procedure of Example 1 using 3a,4,7,7a-tetrahydro-5,6-dimethyl-1,2-benzisothiazol-3-(2H)-one 1,1-dioxide instead of 3a,4,7,7a-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and 1-(6-chloro-2-pyrazinyl)piperazine instead of 4-(2-pyrimidinyl)piperazine. The final product is converted to its dihydrochloride salt, mp 158°-160° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C1C=CC=CC=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1cccnc1N
Agent: O=C(O)c1ccccc1
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1mmol, aniline 0.3 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), the mixture in a 500 ml pressure reactor was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 1 0.01 mmol. While the reactor was stopped with a stopper, the reactants were stirred at various temperatures (70-130° C.) as shown in the following table 10 for 1 hour. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products according to various temperatures and the results are given in Table 10, below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:21])[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][S:23]([O:26]C)(=[O:25])=[O:24].N1C=CC=C[C:29]1=O>C1C=CC=CC=1>[CH3:22][S:23]([O-:26])(=[O:25])=[O:24].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:21][CH3:29])=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[N+:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COS(C)(=O)=O
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(Br)c2)c1
Reactant: O=c1cccc[nH]1
Solvent: c1ccccc1
Product: COc1c(-c2ccccc2)c[n+](C)cc1-c1cccc(Br)c1
Product: CS(=O)(=O)[O-]

Procedure:
A mixture of 4.0 g. of 5-(3-bromophenyl)-1-methyl-3-phenyl-4(1H)-pyridinone and 20 ml. of methyl methanesulfonate in benzene was heated under reflux for 6 hours. The mixture was cooled and the solvent removed in vacuo. The product failed to crystallize. The product was passed over a silica gel column in ethyl acetate. After the front-running spot was removed the column was flushed with ethanol. The ethanol fractions were again placed on a silica gel solumn and front-running impurities removed. The column was flushed with ethanol and the ethanol removed to yield 0.75 g. of a hard glass. The nmr spectrum of the product was consistent with the structure of the expected salt. For example, there was an N-CH3 peak at 4.4 ppm and a peak at 8.7 ppm attributed to the hydrogens at the 2- and 6-positions of the pyridine ring. As is characteristic of pyridinium salts, both these peaks were shifted from the corresponding peaks in the starting pyridinone.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([N:35]1[CH2:36][CH2:37][C:26]2[C:27](=[N:28][C:29]([NH:30][CH:31]([CH3:33])[CH3:32])=[C:24]([N:21]3[CH2:20][CH2:19][CH:18]([O:17][C:16]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=4[F:8])[CH2:23][CH2:22]3)[N:25]=2)[CH2:34]1)(=[O:1])[CH3:4]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(C#N)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (33.5 mg, 0.064 mmol) in DCM (639 μL) at 0° C. was added pyridine (15.5 μL, 0.192 mmol), followed by acetic anhydride (12.0 μL, 0.128 mmol). The reaction was allowed to stir for 45 min, gradually warming to room temperature. The reaction was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 nm, ID 30×75 mm column was used, using a 40% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (7.1 mg, 20%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.31 (m, 6H), 2.02 (m, 2H), 2.20 (m, 5H), 2.74 (t, J=5.9 Hz, 0.7H), 2.85 (m, 1.3H), 3.14 (m, 2H), 3.43 (m, 2H), 3.83 (t, J=5.9 Hz, 1.3H), 3.87 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (m, 2H); ESI-MS m/z [M+H]+ 453.5.
Reaction SMILES: C([Li])CCC.[Br-].[C:7]1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41](C2C=CC=CC=2C(=O)C)(=[O:43])=[O:42])=[O:39])[N:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:13]([CH3:7])=[CH2:14])(=[O:42])=[O:43])=[O:39])[N:30]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
to a stirred mixture of 0.02 mol of n-butyllithium in 20 ml of anhydrous tetrahydrofuran is added 3.6 g of triphenylmethylphosphonium bromide. The above solution is stirred at room temperature for 4 hours. A slurry of 3.8 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-acetylbenzenesulfonamide in 30 ml of dry tetrahydrofuran is then added dropwise. The resulting mixture is refluxed overnight and allowed to cool to room temperature. The precipitate is removed by suction filtration and washed with methylene chloride. The combined filtrates are then washed with diluted hydrochloric acid, water, dried and evaporated to dryness to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]([CH3:14])([CH3:13])[C:10]([O-:12])=[O:11].[CH:15]1([C:18]2[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:35][CH2:34]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>[CH:15]1([C:18]2[N:23]=[CH:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:34][CH3:35])=[O:11])=[CH:20][CH:19]=2)[CH2:17][CH2:16]1
Reactant: OB(O)c1ccc(C2CC2)nc1
Reactant: CC(C)(Sc1ccccc1Br)C(=O)[O-]
Reactant: C1COCCO1
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: [Na+]
Product: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccc(C2CC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 2-(2-bromophenylthio)-2-methylpropanoate (1 eq), 6-cyclopropylpyridin-3-ylboronic acid (1 eq), aqueous sodium carbonate solution (2 M, 4 eq), and Pd(PPh3)4 (0.05 eq) in dioxane is degassed. The mixture is sealed, heated at 80° C., washed with water, extracted with ethyl acetate, dried (MgSO4), concentrated and purified by chromatography.