Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[C:19]=2[CH:26]=1.Cl>O1CCCC1.C1C=CC=CC=1.CCCCCCC>[C:22]([NH:23][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:26][C:19]=1[C:20]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:25])(=[O:21])[CH3:24]
Reactant: Cc1nc2ccc(Cl)cc2c(=O)o1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reaction time: 0.83 h

Procedure:
To a solution of 114 g. (1.0 mole) of m-difluorobenzene in 800 ml. of dry tetrahydrofuran cooled to -50° C. and maintained under a nitrogen atmosphere was added, with stirring, 320 ml. of an n-heptane solution of n-butyl lithium containing 1.0 mole of the latter. The addition was carried out during 50 minutes and was followed by stirring 2 hours more at -50° C. The cold solution was then added with stirring during 50 minutes to a solution of 187.8 g. (0.97 mole) of 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one [J. Am. Chem. Soc. 70, 2423 (1948)] in 1400 ml. of benzene and 1000 ml. of tetrahydrofuran at 25° C. The mixture was stirred under a nitrogen atmosphere for 20 hours, at which time 1000 ml. of 2N hydrochloric acid was added. The aqueous layer was separated and discarded. The organic layer was filtered to remove suspended solid material and the filtrate was washed with cold, dilute aqueous sodium hydroxide solution. Three layers were present, a light colored aqueous phase, a dark brown aqueous phase, and an organic phase. The organic phase, after being dried with anhydrous sodium sulfate, was concentrated to give 101 g. of a semi-solid which was then extracted with 2100 ml. of hot Skellysolve B hexanes. Evaporation of the extract gave 39.9 g. of crude product of melting point 106°-116° C. Recrystallization of this material from Skellysolve B gave purified 2-acetamido-5-chloro-2',6'-difluorobenzophenone of melting point 118°-120° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:16])=[CH:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>[OH-].[Na+]>[C:17]([O:1][C@@H:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:16])=[CH:3]1)(=[O:19])[CH3:18]
Reactant: COC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@H]1C(C)=C[C@H](OC(C)=O)CC12CCCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A part of the crude trans-methyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate obtained (4.0 g) was treated with acetic anhydride (3.5 ml, 37.4 mmol) and sodium acetate (1.46 g, 17.8 mmol). The resulting mixture was stirred at 80° C. for 4 h, poured into cold 2N aqueous NaOH (20 ml), and extracted twice with MTBE (30 ml). The combined organic phases were washed with water (30 ml), with a saturated aqueous solution of NaCl (30 ml), dried (MgSO4), concentrated giving crude trans-methyl 9-acetoxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (4.4 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a room temperature mixture of 4-[(2-Fluoro-3-methoxy-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 14.2 mmol) in THF (50 mL) under nitrogen was added potassium tert-butoxide (15.0 mL of a 1M THF solution, 15.0 mmol) rapidly and the reaction refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (250 mL) and washed with water (100 mL) and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give a waxy solid. Recrystallization of the solid did not remove impurities so the crude product was chromatographed on silica using a step gradient elution of 10% ethyl acetate/dichloromethane to 40% ethyl acetate/dichloromethane to afford 3.04 g (64%) of the desired product as a white powder, mp: 130-132° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:25][O:26][CH3:27])=[C:13]([C:22]([OH:24])=[O:23])[N:14]=[CH:15][C:16]=1[NH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:29](=O)([O-])[O-].[Cs+].[Cs+].[CH2:35](O)[CH3:36]>>[CH:35]([O:23][C:22]([C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:18]3[C:10]([C:11]=2[C:12]=1[CH2:25][O:26][CH3:27])=[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:21]=[CH:20][CH:19]=3)=[O:24])([CH3:36])[CH3:29]
Reactant: CCO
Reactant: O=C([O-])[O-]
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [Cs+]
Solvent: O
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12

Procedure:
740 mg (2 mmol) of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid is stirred for 2 hours at 80° C. in 50 ml of ethanol and 20 ml of water with 977 mg of cesium carbonate. After concentration on a rotary evaporator and drying in a desiccator, the mixture is taken up in 50 ml of DMF, combined with 0.2 ml of 2-bromopropane, and heated for 8 hours to 60°-70° C. After concentration, the mixture is chromatographed over silica gel with hexane:acetone=1:1 as the eluent, thus obtaining 340 mg of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester having the above-mentioned melting point.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[S:61][C:60]([CH3:62])=[N:59][C:58]=2[C:63](O)=[O:64])=[CH:53][CH:52]=1>CN(C=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:63]([C:58]1[N:59]=[C:60]([CH3:62])[S:61][C:57]=1[C:54]1[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=1)=[O:64]
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccc3s2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Piperidin-2-ylmethylbenzothiazole, D30 (0.135 g), HATU (0.228 g), diisopropylethylamine (0.300 ml) and 5-(4-fluorophenyl)-2-methylthiazol-4-carboxylic acid (0.144 g) were dissolved in dry DMF and shaken at room temperature for 16 hours. The solvent was then evaporated and the residue partitioned between dichloromethane and brine. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with diethyl ether provided the title compound as a foam (220 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([C:17]([CH3:29])([CH2:27][CH3:28])[CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)[NH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([C:17]([CH3:29])([CH2:27][CH3:28])[CH2:18][NH2:19])[CH:14]=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3[nH]nc(Cl)c23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CN)c1cccc(-c2ccnc3[nH]nc(Cl)c23)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
tert-butyl 2-(3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-methylbutylcarbamate (60 mg, 0.1446 mmol) was dissolved in dry DCM (2 mL) and cooled in an ice-bath. TFA (2 mL,) was added slowly dropwise and the resultant was stirred at 0° C. for ˜25 minutes and at RT for ˜45 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a slightly yellow gum. The resulting mixture was purified by column chromatography (9% MeOH/1% NH4OH in DCM, ˜50 mL silica) to give a white solid (25.2 mg, 55% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (4.2 g, 10.9 mmol) was dissolved in DMF (60 mL). tert-Butyldimethylsilyl chloride (4.92 g, 7.93 mmol) and imidazole (2.22 g, 32.6 mmol) were added and the reaction stirred at room temperature until completion. The reaction was submitted to aqueous workup to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)(=O)[C:11](Cl)=[O:12].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:25]=2)=[CH:19][CH:18]=1.O>ClCCCl.C1COCC1>[CH:33]1([C:31]([NH:30][C:26]2[CH:25]=[C:24]([O:23][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:11]([NH:9][C:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:8])=[O:12])=[N:22][CH:21]=3)[CH:29]=[CH:28][N:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: NC(=O)C1CCOCC1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(=O)C1CCOCC1)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of Example B5 (0.096 g, 0.740 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.081 mL, 0.925 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 3 h. The mixture was cooled to RT, treated with a solution of Example A7 (0.1 g, 0.370 mmol) and TEA (0.155 mL, 1.110 mmol) in THF (5 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was suspended in 30% MeCN/water (4 mL), sonicated and the resulting solid collected via filtration and dried to afford N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (61 mg, 39%). 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.88 (s, 1H), 10.86 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 3.88 (m, 2H), 3.31-3.29 (m, 2H), 2.68-2.66 (m, 1H), 1.96-1.95 (m, 1H), 1.73-1.72 (m, 2H), 1.62-1.60 (m, 2H), 0.75 (d, J=6.2 Hz, 4H); MS (ESI) m/z: 426.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:29]5[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl.CO>[CH3:37][O:36][C:16]1[CH:17]=[C:18]([C:21]2[S:25][C:24]3=[N:26][CH:27]=[C:28]([C:29]4[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=4)[N:23]3[N:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1.[ClH:38]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[5-(2-Amino-pyrimidin-5-yl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (9 mg; 0.017 mmol; 1 eq) was dissolved in anhydrous DCM (1 mL) and 4M HCl in 1,4-dioxane (0.042 ml, 0.17 mmol, 10 eq) was added. The reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was co-evaporated with DCM (×3). The residue was triturated in CH3CN and filtered. The oily-solid obtained was dissolved in MeOH and evaporated to give the desired product as HCl salt (6 mg, 77%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.29 min, [M+H]+ m/z 424.1; 1H NMR (300 MHz, DMSO) δ 8.93 (s, 3H), 7.77 (s, 1H), 7.55 (m, 2H), 7.29 (d, J=8.9 Hz, 1H), 4.76 (m, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.09 (m, 2H), 2.11 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7].CC(C)([O-])C.[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:4](=[N:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Reactant: ClCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2ccncc2)c1C
Temperature: 250 °C
Yield: 36.7 %

Procedure:
To a solution of Example 97A (145 mg, 0.50 mmol) in DMF (5 mL) was added potassium tert-butoxide (120 mg, 1.10 mmol) and the hydrochloride salt of 4-chloromethyl-pyridine (82 mg, 0.5 mmol). The mixture was heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with ethyl acetate, washed with 1M NaHCO3, and layers were separated. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound (70 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.72 (m, 6H), 1.75 (d, J=2.4 Hz, 6H), 1.91 (s, 3H), 2.09 (d, J=0.7 Hz, 3H), 2.17 (d, J=0.7 Hz, 3H), 5.44 (s, 2H), 7.06-7.20 (m, 2H), 8.50-8.56 (m, J=6.1 Hz, 2H); MS (ESI+) m/z 382 (M+H)+; Anal. Calculated for C22H27N3OS.0.2H2O: C, 68.61; H, 7.17; N, 10.91. Found: C, 68.56; H, 7.12; N, 10.76.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH:9]([CH2:10][C:11](=[O:21])[N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O>[ClH:34].[ClH:34].[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[CH:9]([CH2:10][C:11](=[O:21])[N:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:13]=4)[CH2:8][CH2:7][C:6]=3[CH:22]=2)[CH2:39][CH2:40]1
Reactant: ClCCCN1CCOCC1
Reactant: O=C1CC2CCc3cc(O)ccc3C2=NN1c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=C1CC2CCc3cc(OCCCN4CCOCC4)ccc3C2=NN1c1ccccn1
Temperature: 55 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
To a mixture of 1.4 g of 8-hydroxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, 1.4 g of potassium carbonate and 30 ml of dimethylformamide is added 1.3 g of N-(3-chloropropyl)morpholine, and the mixture is stirred at 55° C. for 3 hours. After the completion of the reaction, water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained oily substance is purified by silica gel column chromatography (chloroform : methanol =10 : 1) and converted into the hydrochloride in methanol, which is recrystallized from methanol to give 0.6 g of 8-(3-morpholinopropoxy)-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one. dihydrochloride.dihydrate as white crystals, m.p. 201°-202° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:27])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH:40]1[CH:41]=[CH:42]C2N(O)N=[N:46][C:44]=2[CH:45]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:27])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](=[O:23])[N:46]3[CH2:42][CH2:41][CH2:40][CH2:45][CH2:44]3)[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.020 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.011 g), HOBT (0.007 g) and triethylamine (0.020 ml) and the mixture was stirred at room temperature for 30 min. Piperidine (0.006 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.002 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41]CC)=[O:40].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (30 mg, 0.075 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (48 mg, 65 μL, 0.375 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (27.6 mg, 19 μL, 0.165 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. After 2 h, a 5 M solution of sodium hydroxide (0.5 mL, 2.5 mmol, 33 equiv; [CAS RN 1310-73-2]) was added and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.5 mg (22%) of the title compound as a light yellow powder. MS (ISP): 458.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][CH3:46]>CN(C=O)C>[CH3:46][O:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccc(C)cc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (18 mg, 0.130 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with 1-bromo-2-methoxyethane (14 mg, 0.098 mmol). The mixture was heated at 90° C. for 4 h, cooled to rt and concentrated under vacuum. The residue was purified by preparative HPLC to provide 7-(2-methoxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (12.5 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1 H, s), 8.17 (1 H, br. s.), 7.95 (1 H, d, J=7.9 Hz), 7.54-7.64 (3 H, m), 7.49 (3 H, t, J=8.0 Hz), 7.27-7.38 (2 H, m), 7.00 (1 H, d, J=7.9 Hz), 6.91 (1 H, d, J=8.8 Hz), 6.59 (1 H, dd, J=8.8, 2.4 Hz), 4.91 (2 H, d, J=3.3 Hz), 4.12 (2 H, dd, J=5.5, 3.1 Hz), 3.63-3.75 (2 H, m), 3.33 (3 H, s), 2.44 (3 H, s), 1.83 (3 H, s). Mass spectrum m/z 520.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=3)[CH:32]=[N:31][CH:30]=2)[CH2:24][C:23]1=[O:44])C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[H][H]>CO.CCOC(C)=O.[Pd]>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=3)[CH:32]=[N:31][CH:30]=2)[CH2:24][C:23]1=[O:44]
Reactant: [H][H]
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3ccccc3OCc3ccccc3)C(=O)C2)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3ccccc3O)C(=O)C2)cc1F
Reaction time: 16 h

Procedure:
To a solution of the benzyl ether from Step F (402 mg, 0.647 mmol) in 5 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (200 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 16 hours, the solution was filtered through celite, and the filter pad was rinsed with 1:1 MeOH/EtOAc. Concentration in vacuo provided the titled product as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.S(Cl)(Cl)=O.Cl>CO>[CH2:17]([O:16][C:14]([N:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C1CN(C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C=C1CNN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of crude 4-methylenepyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 8, (30 g) in methanol (300 mL) is added thionyl chloride dropwise at 0° C. The reaction is warmed to room temperature and stirred an additional 18 hours. Concentration of the reaction in vacuo affords a yellow oil which crystallizes upon standing to provide 23 g (97% yield) of the desired product as the HCl salt.