Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1I.B([C:18]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[C:26]1[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[CH:18][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23]
Reactant: CN(C)S(=O)(=O)c1ccc(I)c(Cl)c1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N(C)C)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (ii) and the product from example 146 step (iv).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[N+:17]([O-:19])=[O:18].N1CCCCC1.CN(C=O)C>CC(O)C>[N+:17]([C:16]1[NH:15][CH:14]=[N:13][C:12]=1/[CH:11]=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([O-:19])=[O:18]
Reactant: Cc1nc[nH]c1[N+](=O)[O-]
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: N#Cc1ccc(/C=C/c2nc[nH]c2[N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 47.9 %

Procedure:
4-Cyanobenzaldehyde (75 g, 0.57 mol) was heated to 110° C. Once melted, 4-methyl-5-nitroimidazole (15 g, 0.12 mol) and piperidine (5 g, 0.06 mol) were added and heating continued for a further 24 hours. DMF (15 mL) and IPA (150 mL) were then added and the precipitate filtered from solution and washed with IPA (50 mL) to leave the product as a yellow solid (13.8 g, 49%). mp>300° C. δH (DMSO-d6) 7.95 (1H, s), 7.88 (2H, d, J=6.8), 7.78 (2H, d, J=6.8), 7.78 (1H, d, J=16.8), 7.50 (1H, d, J=16.8); IR (cm−1) 2239 (C≡N), 1502, 1348 (NO2); MS (m/z) 241.1 (C12H9N4O2 (M+1)).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:27]=[CH:26][C:25](=[O:28])[N:24](C(=O)C2C=CC=CC=2)[C:23]1=[O:37])[C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C)[Na]>CO>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]1=[O:37])[C@H:11]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:15])[CH3:16])[CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(=O)n(C(=O)c2ccccc2)c1=O
Agent: CO[Na]
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(=O)[nH]c1=O
Reaction time: 15 h
Yield: 88.3 %

Procedure:
To a solution of 16 (about 4.6 mmol) in 100 ml of MeOH as added 2 ml of 25% NaOCH3 in MeOH. After being kept at room temperature for 15 hrs the reaction was quenched by adding 1.5 g of solid triethylammonium chloride and concentrated. The resulting material was partitioned between water and ethyl acetate. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated to an oil, which was then chromatographed on silica eluting with a gradient of ethyl acetate (33-50%) in hexane. Concentration of the pure product fractions afforded 1.7 g (about 88%) of 17 as a white crystalline solid. 1H NMR (DMSO-d6): δ 11.18 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.28 (m, 5H), 5.47 (d, J=7.8 Hz, 1H), 4.38 (s, 2H), 3.97 (m, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.38 (m, 2H), 2.02 (m, 1H), 1.13 (d, J=5.7 Hz, 3H), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[CH3:14][NH:15][CH:16]([CH3:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1>>[C:26]([CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:16]([N:15]([CH3:14])[CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:30])=[CH:19][CH:20]=1)([O:28][CH3:29])=[O:27]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: CNC(C)Cc1ccc(OCC(=O)OC)cc1
Product: COC(=O)COc1ccc(CC(C)N(C)CC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and N-methyl-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=40:1 as eluant.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)=[O:6].ON>CO.C(Cl)Cl.CCOCC>[NH:10]1[CH:11]=[C:7]([C:5]2[O:6][N:2]=[CH:3][CH:4]=2)[N:8]=[CH:9]1
Reactant: CN(C)/C=C/C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: NO
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: c1cc(-c2c[nH]cn2)on1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A mixture of (E)-3-(dimethylamino)-1-(1-trityl-1H-imidazol-4-yl)prop-2-en-1-one (54.0 g, 133 mmol) and HONH2*HCl (10.13 g, 146 mmol) in MeOH (800 mL) was heated to reflux for 18 h. The mixture was then allowed to cool to RT and was concentrated in vacuo. The residue obtained was taken up in DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was stirred in Et2O, and the suspension was filtered. The filter cake was dried in vacuo at 40° C. The aqueous phase was then concentrated in vacuo and the residue obtained was placed in a Soxlet apparatus and continuously extracted with DCM for 36 h. The organic phase was then concentrated in vacuo and the residue obtained was stirred in DCM. The suspension was then filtered and the filter cake was dried in vacuo at 40° C. The two filter cakes were then crystallized in AcOEt to give the title compound (5.44 g). UPLC-MS: MS 136.1 (M+H+); UPLC rt 0.33 min.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[CH2:32]([N:39]1[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][C:41]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[C:51]([CH3:56])[CH:50]=2)=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:44](=[O:45])[C:43]([CH2:46][OH:47])=[CH:42][C:41]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[C:51]([CH3:56])[CH:50]=2)=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccccc3)n2)ccc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: Cc1cc(-c2cc(CO)c(=O)n(Cc3ccccc3)n2)ccc1F

Procedure:
Following the procedure of Example 1 (8), 2-benzyl-4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 28.4%).
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CCCNCCC
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N(CCC)CCC)ncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 152 mg of dipropylamine, followed by stirring at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 179 mg of 4-(2-butynyloxy)-6-(dipropylamino)pyrimidine (the present compound (113)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 5.360 g (15.6 mmol) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol, and 17.67 g (78.2 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 1½ hours and added ice water. Made basic with sodium bicarbonate. Stirred for 2 hours extracted with chloroform. Added brine to the separatory funnel to help separate layers. Stirred organic layer with Darco and dried with sodium sulfate. Filtered, stripped solvent and dried in vacuo, giving 4.460 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=312.9, 315.0.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[C:9]([Mg]Br)#[CH:10]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]#[CH:10])[OH:8])[N:6]=1
Reactant: O=Cc1csc(Br)n1
Reactant: C#C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#CC(O)c1csc(Br)n1

Procedure:
Using the procedure of Example 1, 2-bromo-4-thiazole carboxaldehyde and ethynyl magnesium bromide were reacted to obtain the desired product with a Rf=0.17 [hexane-ethyl acetate (7-3)].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:12])=[O:11])([O-:3])=[O:2].[C:27](=O)([O-])[O-].[K+].[K+].CI.ClCCl>CC(C)=O.O>[CH3:27][N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)NCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: CCCCOC(=O)NCCCCCN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tent-butyl (5-{[(2-nitrophenyl)sulfonyl]amino}pentyl)carbamate 55 (32.6 g, 84 mmol) in acetone (300 mL) was added potassium carbonate (23.2 g, 168 mmol). The resulting mixture was stirred at room temperature for 30 minutes then methyl iodide (17.88 g, 126 mmol) was added drop wise. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured in water and dichloromethane was added. The organic layer was separated and successively dried over MgSO4 filtered and concentrated. The residue was triturated with di-isopropyl ether to yield 31.6 g 93% of tent-butyl (5-{methyl[(2-nitrophenyl)sulfonyl]amino}pentyl)carbamate 56 as a white powder m/z 402 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH2:7]3)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 3-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as an off-white solid (0.52 g, 90% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 9.26 min (96.05%); mp: 215-217° C.; 1H NMR (DMSO-d6) δ 1.88-2.12 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.03 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.37-4.54 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.85 (t, J=5.9 Hz, 1H, NH), 6.90-7.07 (m, 1H, Ar), 7.10-7.34 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 7.61-7.78 (m, 2H, Ar), 8.88 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.80, 47.13, 51.59, 116.12, 117.10, 120.73, 121.91, 122.94, 126.91, 130.22, 130.33, 133.09, 141.95, 142.39, 144.64, 155.00, 167.93, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.82; H, 4.22; N, 13.03; Cl, 8.32.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3): δ 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOCC1
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1F
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOCC3)cc2)cc1F

Procedure:
The title compound was prepared from rac-[1-(3-fluoro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 442.4 (M−H)−.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:18])[C:15]([OH:17])=[O:16].[Mg].[CH3:20]I.Cl>CCOCC.C(O)(=O)C>[CH3:20][C:14]([OH:18])([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)[C:15]([OH:17])=[O:16]
Reactant: CI
Reactant: O=C(O)C(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(O)(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled solution of fluorene-2-glyoxylic acid (4.5 g) in ether (150 ml) is treated dropwise over a 45 minute period with Grignard reagent prepared from magnesium (2.1 g) and methyl iodide (6.5 ml) in ether (145 ml). The mixture is then stirred for 2 hours at room temperature and poured into ice water. The mixture is treated with 250 ml 50% acetic acid and finally acidified to pH 2.0 with 10% HCl. The ether layer is separated, and the aqueous extracted with additional ether. The combined ether extracts are washed with sodium chloride solution and water, dried (MgSO4) and evaporated to give the title compound (3.7 g, mp 164°-168°). Recrystallization from ethvl acetate-hexane raises the mp to 170°-171°, λKBr 3400 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[CH2:8][CH:9](C(OCC)=O)[C:10](=[O:11])[C:4]=2[CH:3]=1.[Na+].[Cl-].O>CS(C)=O>[I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CC(=O)Nc2ccc(I)cc2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCC(=O)c2cc(I)ccc2N1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (iii-a) (4.84 g, 13.2 mmol) in dimethyl sulfoxide (66 mL) was added a solution of NaCl (81 mg, 15.9 mmol) in H2O (475 μL, 26.4 mmol). The reaction mixture was heated to 150° C. for 2 h, and subsequently cooled to 0° C. for 30 min. H2O (120 mL) was added and the solution was allowed to stir for an additional 1.5 h at 0° C. The resulting precipitate was filtered to provide iv-a (3.2 g, 81%) as a purple/brown solid: MS m/z=302 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][OH:17])[C:9]([F:12])([F:11])[F:10])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 64 °C
Reaction time: 24 h

Procedure:
To a solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3.12 g, 11.5 mmol) and MeOH (50 mL) was added hydroxylamine hydrochloride (4.00 g, 57.5 mmol) and sodium acetate (5.90 g, 71.9 mmol). The resulting mixture was heated at 64° C. for 19 h, after which time additional hydroxylamine hydrochloride (2.40 g, 34.5 mmol) and sodium acetate (3.54 g, 43.1 mmol) were added. Heating was continued for 24 h and the mixture filtered to remove solids. The filtrate was diluted with EtOAc (150 mL), washed with water (150 mL), dried (Na2SO4) and concentrated. The title compound was obtained as a 70:30 ratio of the E and Z oxime isomers (3.28 g, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]4[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:13]=[CH:14][CH:15]=3.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]1([CH:20]2[N:10]3[C:11]4[C:16]([C:17]5[C:5]([O:4][CH2:3][CH2:2][N:37]6[CH2:36][CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:39][CH2:38]6)=[CH:6][CH:7]=[CH:8][C:9]=53)=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2cccc4c2n3C(c2ccccc2)CO4)CC1
Temperature: 85 °C

Procedure:
To a mixture of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole (0.453 g, 1.24 mmol) in dry DMF (6 mL) is added tert-butyl-1-piperazinecarboxylate (0.232 g, 1.24 mmol), sodium iodide (0.018 g, 0.124 mmol), and potassium carbonate (0.342 g, 2.48 mmol). The mixture is heated at 85° C. for 20 h. The mixture is then cooled and partitioned between Et2O and water. The organic layer is washed twice with water (200 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH2Cl2/CH3OH (98/2) yielded 0.487 g (76%) of tert-butyl 4-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}-1-peperazinecarboxylate; mp 72° C.;.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([S-:15])=[S:14])[CH2:9][CH2:8]1.[Na+].[CH:24](I)([CH3:26])[CH3:25]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:18]=1[O:19][CH3:20])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]([S:15][CH:24]([CH3:26])[CH3:25])=[S:14])[CH2:11][CH2:12]1
Reactant: CC(C)I
Reactant: COc1cc(CN2CCN(C(=S)[S-])CC2)cc(OC)c1OC
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CN2CCN(C(=S)SC(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
In 2 ml of ethanol was suspended 364 mg of sodium 4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioate, and to the suspension was added 204 mg of isopropyl iodide. The resulting homogeneoussolution was stirred overnight at room temperature. Ethanol was distilled off from the solution, and to the residue were added ether and water. The ether portion was taken out, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to evaporate the solvent. The residue was purified by silica gel column chromatography to give 270 mg of the desired compound asa colorless oil, yield 70.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:33])[F:34])([OH:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
6,7-Dichloro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (220 mg, 0.41 mmol) was dissolved in anhydrous THF-EtOH (10 mL, 1:1). KOH (117 mg, 2.06 mmol) in H2O (7 mL) was added and then stirred at room temperature for 30 min. and then at 55° C. for 20 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure to provide the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to afford the title compound as a white solid (130 mg, 76%). 1H NMR (500 MHz. DMSO-d6, δ in ppm) 8.17 (bs, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 2.82-2.78 (m, 1H), 2.70-2.64 (m, 1H), 2.42 (s, 1H), 2.28-2.20 (m, 1H), 2.12-2.01 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:20]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(O)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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 34.3 %

Procedure:
A solution of 4-Hydroxyphenylboronic acid (30 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA56 (12 mg, 32% yield). ESI-MS (M+H)+ m/z calcd 270.1, found 270.1.