Azzindani/Open_Reaction_Data huggingface dataset:
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])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-methoxy-benzoyl chloride (0.51 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the product was isolated by filtration, washed with MeCN (10 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methoxy-benzamide as a white solid (0.99 g, 79% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.58 min (97.92%); mp: 215-217° C.; 1H NMR (DMSO-d6) δ 1.94-2.20 (m, 1H, CHH), 2.39-2.70 (m, 2H, CHH, CHH), 2.78-3.04 (m, 1H, CHH), 3.82 (s, 3H, CH3), 4.63 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.02 (d, J=8.9 Hz, 2H, Ar), 7.76-7.97 (m, 5H, Ar), 9.08 (t. J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.55, 48.99, 55.37, 113.60, 121.91, 123.53, 126.11, 129.11, 129.74, 131.59, 133.40, 147.87, 161.75, 165.91, 167.00, 167.15, 169.82, 172.73; LCMS: MH=422; Anal Calcd for C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.40; H, 4.46; N, 10.12.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[I:1])=[CH:7][CH:8]=1)([CH3:20])[CH3:19]
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(I)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-iodo-2-naphthol, as described in Step A, (2.75 g, 10.2 mmol) in dry DMF (25 mL), under argon, were added imidazole (1.39 g, 20.4 mmol) and triisopropylsilyl chloride (2.55 g, 13.2 mmol). The resulting mixture was stirred at ambient temperature for 4 hrs, then quenched with 10% aqueous citric acid (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-50% hexane to yield the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]([CH3:36])([CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(C#Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C#Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of 7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.035 g, 0.07 mmole) in 5 mL of a 4:1 THF/methanol mixture was treated with a solution of 0.1 g of lithium hydroxide monohydrate in 2 mL of water and stirred at 40° C. for 2 hours. The mixture was diluted with 5 mL of water and the pH adjusted to 2 with 2N HCl solution. The mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 0.03 g of 7-[3-(4-carboxy-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a yellow oil
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=O)[NH:32][CH:33]=2)=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:26][C@H:24]1[NH:25][C@@H:20]([CH3:19])[CH2:21][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][CH:33]=2)=[O:28])[CH2:23]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (74 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22]C(=O)C.N1C=CC=CC1=O.[F:33][C:34]([F:41])([F:40])[S:35]([O:38]C)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[F:33][C:34]([F:41])([F:40])[S:35]([O-:38])(=[O:37])=[O:36].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N+:10]([CH3:21])[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[O:14][CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(Br)c2)c1
Reactant: CC(C)=O
Reactant: COS(=O)(=O)C(F)(F)F
Agent: O=c1cccc[nH]1
Solvent: ClC(Cl)Cl
Product: COc1c(-c2ccccc2)c[n+](C)cc1-c1cccc(Br)c1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
A 10 g. portion of 3-(3-bromophenyl)-1-methyl-5-phenyl-4(1H)-pyridinone was made from 22 g. of the corresponding 2-propanone as described in Example 1. A 3.4 g. portion of the intermediate pyridinone was dissolved in chloroform and 1.8 g. of methyl trifluoromethanesulfonate was added. The reaction mixture was allowed to stand overnight, and the volatile portions were then evaporated under vacuum. The residue was identified as 3-(3-bromophenyl)-4-methoxy-1-methyl-5-phenylpyridinium trifluoromethanesulfonate, molecular weight 339 by mass spectroscopy.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Li][CH2:8][CH2:9][CH2:10]C.ICCC>C1COCC1>[CH3:1][CH:2]([CH2:3][C:4]#[C:5][CH2:8][CH2:9][CH3:10])[CH3:6]
Reactant: [Li]CCCC
Reactant: C#CCC(C)C
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC#CCC(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 4-methylpent-1-yne (0.588 mL, 5 mmol) in THF at −78° C. was added BuLi, 2.5 M in hexanes (2.200 mL, 5.50 mmol). After stirring 15 minutes at −78° C., the reaction mixture was allowed to warm to room temperature, 1-iodopropane (0.488 mL, 5.00 mmol) was added and the reaction mixture was stirred at rt for 3 days. The reaction mixture was quenched with water (50 mL) and the resulting mixture was transferred to a separatory funnel. The mixture was extracted with ether (75 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford 2-methyloct-4-yne (555 mg, 4.47 mmol, 89% yield) as a light yellow liquid. 1H NMR (400 MHz, chloroform-d) δ ppm 0.91-0.99 (m, 9H) 1.45-1.53 (m, 2H) 1.70-1.81 (m, 1H) 2.03 (dt, J=6.5, 2.4 Hz, 2H) 2.12 (tt, J=7.0, 2.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(F)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-fluoro-1H-indazole-3-carbaldehyde (0.0428 g, 0.261 mmol) synthesized in Example B8, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-fluoro-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][CH:14]=[C:7]1[CH:6]=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:20]=[C:21]([SH:23])[CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:20]=[C:21]([S:23][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[C:12]([CH3:15])=[N:13][CH:14]=[C:7]2[CH:6]=[CH:5]3)[CH:22]=1
Reactant: N#CC1(c2cc(F)cc(S)c2)CCOCC1
Reactant: Cc1ncc2ccc3cc(Br)ccc3n12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ncc2ccc3cc(Sc4cc(F)cc(C5(C#N)CCOCC5)c4)ccc3n12
Temperature: 80 °C

Procedure:
4d (80 mg, 0.3 mmol) and 4-(3-Fluoro-5-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (4e, 88 mg, 0.37 mmol) were dissolved in 1,4-dioxane (3 mL) and degassed for 10 minutes with N2. iPr2NEt (0.10 mL, 0.6 mmol), Pd2dba3 (14 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol) were added, and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 4f.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29](=O)[CH2:30][CH2:31][CH3:32])[C:24](OCC)=[O:25])=[CH:18][CH:17]=1)#[N:9]>ClC1C=CC(Cl)=CC=1Cl>[CH3:1][C:2]1[N:3]=[C:4]2[NH:7][C:24](=[O:25])[C:23]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([C:11]4[C:10]([C:8]#[N:9])=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:17][CH:18]=3)=[C:29]([CH2:30][CH2:31][CH3:32])[N:5]2[N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Yield: 54.2 %

Procedure:
A solution of 5-methyl-4H-1,2,4-triazol-3-amine (1.7 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.1 g) in 1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (3.6 g, 44%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(COC)OC.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]1([C:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: COC=C(C(=O)OC)c1ccccc1CC(=O)c1ccccc1
Temperature: 50 °C
Yield: 29 %

Procedure:
A solution of 5 g (17.5 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate and 2.5 g (17.8 mmol) of benzoyl chloride in 50 ml of dimethoxyethane is added dropwise to 2.3 g (0.035 mol) of zinc powder and 600 mg (0.9 mmol) of Pd(Ph3P)2Cl2 under nitrogen and the mixture is then heated at 50° C. for 30 minutes. Water is added, the mixture is extracted with ethyl acetate and the organic phase is dried and evaporated down. The residue is chromatographed over silica gel using hexane/ethyl acetate. 1.6 g of compound No. 1 (Table 1) are obtained as a pale yellow solid of melting point 97°-99° C. Yield: 29%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:25])=O.Cl.CO.C([BH3-])#N.[Na+]>CO>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH:21][CH:23]([CH3:25])[CH3:22])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A portion (1.0 g) of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-amine obtained in step 2 of Example 17 was dissolved in methanol (10 mL) and, following the addition of acetone (0.53 mL) and 10% HCl-methanol solution (0.1 mL), the mixture was stirred at room temperature for 4 days. The reaction solution was cooled with ice and, following the addition of sodium cyanoborohydride (0.23 g), the mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated and, to the residue was added water followed by extraction with ethyl acetate; the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol) to yield the titled compound as pale yellow crystals (0.80 g).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:15][CH2:14]3)[C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[C:23]2=[O:40])[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:13]1([N:9]2[C:10](=[O:12])[CH2:11][N:7]([CH2:6][C:5]3[CH:17]=[CH:18][C:2]([C:27]4[CH:28]=[C:29]5[C:24](=[CH:25][CH:26]=4)[C:23](=[O:40])[N:22]([CH:19]4[CH2:21][CH2:20]4)[CH2:30]5)=[CH:3][CH:4]=3)[C:8]2=[O:16])[CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccc(-c3ccc(CN4CC(=O)N(C5CC5)C4=O)cc3)cc2CN1C1CC1
Yield: 53.1 %

Procedure:
1-(4-bromobenzyl)-3-cyclopropylimidazolidine-2,4-dione (7H5) (0.1 mmol, 30 mg), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.1 mmol, 31.0 mg), tris(dibenzylidineacetone)dipalladium (0.005 mmol, 4.59 mg), tricyclohexylphosphine (0.012 mmol, 3.37 mg) and potassium phosphate (0.17 mmol, 36.1 mg) were suspended in dioxane (1 ml) and water (0.5 ml) and heated to 130° C. in the microwave for 15 min. The reaction mixture was quenched with 2 ml of water and 3 ml of DCM and the organic phase separated using a hydrophobic fritted tube. The organic phase was concentrated and the residue purified by prep basic HPLC to give 3-cyclopropyl-1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)imidazolidine-2,4-dione (Example 7a) 21.3 mg (53%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H) 7.63 (d, 1H) 7.58 (m, 3H) 7.35 (d, 2H) 4.59 (s, 2H) 4.37 (s, 2H) 3.71 (s, 2H) 2.96 (m, 1H) 2.64 (m, 1H) 1.01-0.86 (m, 8H) LCMS m/z (M+H) 402.2.
Reaction SMILES: [S:1]([N:11]1[CH2:17][CH2:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H][H]>CO.[Pd]>[S:1]([N:11]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)=Cc3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)Cc3ccccc32)cc1
Yield: 840.3 %

Procedure:
To a solution of tert-butyl 1-tosyl-2,3-dihydro-1H-benzo[b]azepin-4-ylcarbamate (4.5 g, 0.001 mol) in methanol (120 mL), 10% palladium on carbon (0.5 g) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen for 4 days. The reaction mixture was filtered and concentrated to dryness to give a residue which was purified by silica gel column chromatography eluting with (0-10% ethyl actetae in hexane) to afford tert-butyl 1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (3.5 g). 1H NMR: (400 MHz, CDCl3) δ: 7.54 (d, 1H), 7.40 (d, 2H), 7.18-7.08 (m, 4H), 7.06 (d, 1H), 6.38 (s, 1H), 5.65 (s, 1H), 3.86-3.82 (m, 2H), 2.78-2.74 (m, 2H), 2.18 (bs, 3H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].CN(C1C=CC=CN=1)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 4.0 mL, 40.0 mmol) in methylene chloride (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and dimethylaminopyridine (0.20 g, 1.64 mmol) under an atmosphere of nitrogen. The reaction was stirred at 45° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography 3% methanol in methylene chloride to give a white solid (59, 8.0 g, 85%). MS (ESI) [M−H+]−=234.0.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C(O)C>[ClH:4].[Cl:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[N:8]=[CH:7][N:6]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cl
Product: NNc1cc(Cl)ncn1
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (0.89 ml, 0.92 g, 1.8 mmol) was added to 4,6-dichloropyrimidine (2.5 g, 1.7 mmol) in ethanol (25 ml) at 0° C. After stirring the reaction mixture at this temperature for 0.5 h, the precipitate which formed was collected and washed with ethanol to afford the title compound as a white solid; yield 1.5 g.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16](=[O:20])[CH:17]=NO)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>O>[S:6]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]3[C:11]=2[C:17](=[O:2])[C:16](=[O:20])[NH:15]3)[N:8]=[CH:7]1
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc2ncsc2c1
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1 N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxylamine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids dissappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipatated from solution. The precipatate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): δ12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)−. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for ˜1 h, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): 11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MS m/z 203 (M−H)−.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[N:13]([O-])=O.[Na+].[N-:17]=[N+:18]=[N-:19].[Na+]>O>[NH2:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:3]=1[CH2:2][CH2:1][CH2:11][C:9]2=[O:10].[N:17]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:3]=1[CH2:2][CH2:1][CH2:11][C:9]2=[O:10])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=N[O-]
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1cccc2c1CCCC2=O
Product: [N-]=[N+]=Nc1cccc2c1CCCC2=O
Temperature: 25 °C

Procedure:
5-Amino-1-tetralone was prepared from α-tetralone according to the literature (J. Am. Chem. Soc. 1994, p4852). To a cold solution of 5-amino-1-tetratone (415 mg) in water (2 mL) and concentrated hydrochloric acid (5 mL) was added a solution of sodium nitrite (186 mg) in water (1.2 mL), maintaining low temperature. After 40 minutes a solution of sodium azide (184 mg) in water (1.2 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature. After one further hour the reaction was quenched with water, extracted into ether, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield crude material which was purified using flash chromatography to yield 5-azido-1-tetralone (77 mg).