Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)O1.[NH2:23][C@@:24]1([CH3:45])[CH2:28][CH2:27][C@@H:26]([NH:29][C:30]2[C:31]3[N:32]([CH:39]=[C:40](Br)[CH:41]=3)[N:33]=[CH:34][C:35]=2[C:36]([NH2:38])=[O:37])[C:25]1([CH3:44])[CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>CN(C=O)C.CO.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:23][C@@:24]1([CH3:45])[CH2:28][CH2:27][C@@H:26]([NH:29][C:30]2[C:31]3[N:32]([CH:39]=[C:40]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:13][CH:14]=4)[CH:41]=3)[N:33]=[CH:34][C:35]=2[C:36]([NH2:38])=[O:37])[C:25]1([CH3:44])[CH3:43]
Reactant: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)N
Reactant: CC1(C)OB(c2ccc(N3CCOCC3=O)cc2)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccc(N5CCOCC5=O)cc4)cc23)CC[C@]1(C)N
Temperature: 93 °C

Procedure:
A solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (31.9 mg, 0.105 mmol), 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 48, 20 mg, 0.053 mmol), 1,1′-bis(di-t-butyl/diphenylphosphino) ferrocene (2.495 mg, 5.26 μmol), palladium (II) acetate (1.181 mg, 5.26 μmol) and dibasic potassium phosphate (0.079 mL, 0.158 mmol) in DMF (0.5 mL) was purged with N2 for 5 min. The reaction mixture was sealed and heated at 93° C. for 120 min. The reaction mixture was cooled and diluted with methanol and filtered. The filtrate was purified by prep HPLC [Column: YMC 20×100; Mobil phase: B in A: 20%-100% (A: 10% MeOH in H2O with 0.1% TFA, B: 90% MeOH in H2O with 0.1% TFA; gradient time: 15 min., hold time: 5 min] to afford the title compound, assumed to be TFA salt (7.2 mg, 0.012 mmol, 23.18% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.19 (1 H, s), 8.02 (1 H, d, J=1.54 Hz), 7.73-7.87 (2 H, m), 7.42 (2 H, d, J=8.58 Hz), 7.25 (1 H, d, J=1.54 Hz), 4.72 (1 H, t, J=9.02 Hz), 4.31 (2 H, s), 4.00-4.13 (2 H, m), 3.76-3.86 (2 H, m), 2.42-2.65 (1 H, m), 2.11-2.24 (1 H, m), 2.00-2.10 (1 H, m), 1.77-1.92 (1 H, m), 1.50 (3 H, s), 1.18 (3H, s), 1.08 (3H, s). HPLC (condition F): ret. Time 3.143 min.; LC/MS [m/z, (M+H)] 477.1.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]>[Pd].CCO>[CH:2]([C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cccc2c1oc1ccccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc2c1oc1ccccc12
Reaction time: 2 h
Yield: 74.5 %

Procedure:
4-(Prop-1-en-2-yl)dibenzo[b,d]furan (14.5 g, 69.6 mmol) was added to a hydrogenator bottle with EtOH (100 mL). The reaction mixture was degassed by bubbling N2 for 10 minutes. Pd/C (1.14 g, 1.39 mmol) and PVC (2.72 g, 0.7 mmol) was added. The reaction mixture was placed on a Parr hydrogenator for 2 hours (H2˜72 psi, based on calculations). The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane. GC/MS confirmed complete conversion. The crude product was chromatographed on silica gel with 2% DCM in hexane (v/v) to yield 10.9 g (74%) of the desired product. The product was confirmed by GC/MS.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[NH:23])[S:22][CH3:25])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCCCC1
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCCCC2)c1
Yield: 70 %

Procedure:
Using the compound obtained in Example 140 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 85 mg of the titled compound (yield, 70%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:28]([O:27][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[CH2:23][CH2:22]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Yield: 107 %

Procedure:
To a solution of 1-(1-benzyloxycarbonyl-4-piperidinylmethyl)-4-(t-butoxycarbonylamino)piperidine (5.6 g) in ethanol (100 ml) is added 5% palladium-on-carbon (0.6 g), and the mixture is hydrogenated at 30° C. under atmospheric pressure. After a theoretical amount of hydrogen is consumed, the catalyst is removed by filtration, and the ethanol in the filtrate is evaporated under reduced pressure to give crude 4-(t-butoxycarbonylamino)-1-(4-piperidinylmethyl)piperidine (4.13 g).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:18]([F:21])([F:20])[F:19])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1OCCOCCOCCOCCOCCOC1.CC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:6]([C:5]#[C:4][CH:1]3[CH2:3][CH2:2]3)([C:18]([F:20])([F:21])[F:19])[C:7]=2[CH:16]=1)[CH3:36]
Reactant: O=C1Nc2ccc(O)cc2C(C#CC2CC2)(C(F)(F)F)O1
Reactant: CCOC(=O)CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Temperature: 56 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To 120 mg (0.40 mmol) of 9 were added 12 mL of anhydrous acetone, 120 mg (0.86 mmol) of anhydrous potassium carbonate, 2 mg of 18-crown-6 and 40 μL (0.28 mmol) of ethyl 4-bromobutyrate. The reaction mixture was allowed to stir at 56° C. for 3 hours and was concentrated under reduced pressure. To the residue 20 mL of water were added followed by 1 mL of 1N HCl. The aqueous layer was extracted with 4×20 mL of dichloromethane. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 2 mm thickness, E. Merck) using 1% methanol in dichloromethane to give 45 mg (0.11 mmol, 27%) of 10 as a colorless thick oil [LC-MS; M+H 412.1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:13]1([CH:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClC(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(OC(Oc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Inside a nitrogen purged glove box, to a solution of 4-bromophenol (12.0 grams, 69.4 millimoles, 2.5 equivalents) dissolved in anhydrous 1-methyl-2-pyrrolidinone (100 milliliters), was added 95% sodium hydride (1.82 grams, 72.1 millimoles, 2.6 equivalents) in small portions over a 30 minute period. The reaction was stirred for an additional 90 minutes at room temperature. α,α-dichlorotoluene (4.13 milliliters, 27.7 millimoles, 1.0 equivalent) was added and the reaction was heated to 70° C. overnight. The reaction was quenched addition to water (200 milliliters). The aqueous phase was extracted with a 1:1 mixture of diethyl ether and ethyl acetate (3×120 mL). The combined organic phases were then washed with de-ionized water (5×100 milliliters), brine (1×100 milliliters) and dried over magnesium sulfate. After filtration and concentration on the rotary evaporator, the residue was taken up in diethyl ether (60 milliliters) and filtered through a plug of basic alumina. The product was fully eluted with additional diethyl ether (700 milliliters) and concentrated on the rotary evaporator. Further drying under high vacuum for several days yielded the product quantitatively in form of a yellow oil that crystallizes over time to give an off-white solid (12.0 grams, 27.7 millimoles, 100%). m.p.: 50.8; 1H-NMR (400 MHz, CDCl3) δ 7.59-7.51 (m, 2H), 7.44-7.37 (m, 3H), 7.37-7.29 (m, 4H), 6.93-6.82 (m, 4H), 6.59 (s, 1H); 13C-NMR (101 MHz, CDCl3) δ 155.07, 136.58, 132.59, 129.65, 128.86, 126.78, 119.60, 115.42, 100.77; FTIR: 605, 658, 674, 694, 741, 792, 816, 848, 886, 928, 984, 1031, 1060, 1100, 1115, 1167, 1178, 1210, 1242, 1280, 1304, 1363, 1449, 1483, 1584, 1689, 3033, 3065 cm−1; UV/Vis 223 (shoulder), 237, 278 nm; GC/MS/EI+: 432, 434, 436 [M+] (2×Br isotope pattern); 261, 263 [Br—C6H4—O—CHPh]+ (1×Br isotope pattern); 182 [C6H4—O—CHPh]+; HRMS (ESL): calc. for C19H13Br2O2− [M+Na]+ 430.9288, found 430.9287.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)N2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) dissolved in methylene chloride (10 ml) under an argon atmosphere were treated with DMAP (0.673 g) at RT, the mixture was cooled to 0° C. and morpholine-4-sulfonylchloride (0613 g) in methylene chloride (2 ml) was added dropwise. The mixture was stirred for 12 h at RT then partitioned between methylen chloride and 1 M HCl. The layers were separated, the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 50%) to give 4-(2-methoxy-ethyl)-1-(morpholine-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester, (0.68 g) as a light yellow solid. MS (ESI): 365.17 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C(F)(F)F)=O>C1COCC1>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCN1CCS(=O)(=O)CC1)CCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 119.2 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.500 g, 1.38 mmol) was combined with 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (0.296 g, 1.65 mmol) in THF (10 mL). To this mixture was added triphenylphosphine (0.541 g, 2.06 mmol) and diethyl azodicarboxylate (0.359 g, 2.06 mmol). The resulting mixture was stirred at rt for 72 h. The mixture was concentrated in vacuo, then redissolved in acetonitrile. Purification by reverse phase preparative HPLC gave the title compound as a pale yellow solid (0.863 g, 83% yield) bis-TFA salt. LCMS: m/z 525 (M+H+), retention time 1.25 min (method 11). 1H NMR (500 MHz, MeOD) δ ppm 2.85 (t, J=6.71 Hz, 4H) 3.14 (d, J=5.49 Hz, 8H) 3.18 (d, J=5.80 Hz, 8H) 3.51 (t, J=6.71 Hz, 4H) 7.71-7.75 (m, 1H) 7.75-7.84 (m, 2H) 8.05 (d, J=7.63 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][C:18](=[O:21])[N:17](CC3C=CC(OC)=CC=3)[C@H:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C@H:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: COc1ccc(CN2C(=O)CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)N1

Procedure:
cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-6-keto-1-(4-methoxybenzyl)-2-phenyl piperidine (0.17 g, Example 27) was dissolved in acetonitrile (3 ml) and water (1 ml) then cooled to 0° C. and cerium ammonium nitrate (173 mg) was added. The mixture was stirred at 23° C. for 18h, then poured into water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (1×10 ml) then dried (MgSO4) and concentrated to leave a pale yellow oil. Purification on silica gel (hexanes/ethyl acetate 1:1 then ethyl acetate then methanol/ethyl acetate 1:9) provided cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-6-keto-2-phenyl piperidine as an oil. 1H NMR (360 MHz, CDCl3) δ7.72 (1H, s), 7.44 (2H, s), 7.37 (5H, m), 5.86 (1H, s), 4.75 (1H, d, J=3.2 Hz), 4.52 (1H, d, J=12.5 Hz), 4.14 (1H, d, J=12.5 Hz), 3.98 (1H, m), 2.65 (1H, ddd, J=6.4, 12.2, 18.2 Hz), 2.48 (1H, m), 2.30 (1H, m), 2.06 (1H, m). m/z (CI+) 418 (MH).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16]/[C:17](=[C:22](\[CH:27]([CH3:29])[CH3:28])/[C:23]([O:25][CH3:26])=[O:24])/[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.ClCCl.CO>CO>[CH3:21][O:20][C:18](=[O:19])/[C:17](/[CH2:16][C:15]1[CH:30]=[CH:31][C:12]([O:11][CH2:10][CH2:9][NH2:8])=[CH:13][CH:14]=1)=[C:22](/[CH:27]([CH3:28])[CH3:29])\[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)/C(Cc1ccc(OCCN)cc1)=C(\C(=O)OC)C(C)C
Reaction time: 20 h
Yield: 100.4 %

Procedure:
To a solution of dimethyl 2-{4-[2-(t-butoxycarbonylamino)ethoxy]benzyl}-3-isopropylmaleate (287 mg, 0.659 mmol) in methanol (6 mL) was added 5 M hydrochloric acid (5.9 mL) at room temperature, and the mixture was left standing at room temperature for 20 h. The residue obtained by concentrating the mixture under reduced pressure was dissolved in ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added. After separating the phases, the organic layer was concentrated and the residue thus obtained was subjected to LH-20 (dichloromethane-methanol 1:1) to give 222 mg of the title compound as oil (quantitative).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]3[CH:27]=[C:26]([CH2:28]Cl)[CH:25]=[N:24][C:18]=3[N:19]([CH2:22][CH3:23])[C:20]=2[N:21]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]3[CH:27]=[C:26]([CH2:28][S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:25]=[N:24][C:18]=3[N:19]([CH2:22][CH3:23])[C:20]=2[N:21]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncc(CSc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of thiophenol (0.16 mL, 1.6 mmol) in N,N-dimethylformamide (15 mL) was treated with sodium hydride (60% wt, 62 mg, 1.6 mmol). After stirring 15 minutes the 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.50 g, 1.5 mmol) was added and the mixture was stirred for 18 hours more. The excess thiolate was quenched with methanol and the mixture was diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organics were dried over sodium sulfate, filtered, concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate) and recrystallization from hexanes/ethyl acetate to give the title compound (0.378 g, 62%), m.p. 92°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)CCl.[C:16]1([NH2:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A mixture of 4-Bromophenylacetic acid (1.5 g, 7.0 mmol, 1 eq.), EDC (2.67 g, 14.0 mmol, 2 eq.), DMAP (846 mg, 7.0 mmol, 1 eq.), and phenylamine (0.765 mL, 8.4 mmol, 1.2 eq.) in 15 mL of DMF was stirred under nitrogen at room temperature for 3.5 hrs. After aqueous workup and recrystallization, 2-(4-Bromophenyl)-N-phenyl-acetamide was obtained in 69% yield (1.4 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.6 (s, 2 H) 7.0 (m, 1 H) 7.3 (m, 4 H) 7.5 (m, 2 H) 7.6 (dd, J=8.7, 1.1 Hz, 2 H) 10.2 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[N:14]=2)[CH:3]=1.[NH3:21].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:21])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[N:14]=2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccc(Cl)c(C)n1
Solvent: CO
Product: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 116 %

Procedure:
A pressure tube was charged with methyl 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (600 mg, 1.92 mmol) and an ammonia solution in methanol (7M, 20 mL, 140 mmol). The reaction mixture was heated to 50° C. and was stirred for 18 h. The mixture was cooled and concentrated in vacuo to give 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (665 mg crude, 116%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 11.69 (br. s., 1H), 9.18 (s, 1H), 8.20 (br. s., 1H), 7.61 (d, J=8.59 Hz, 1H), 6.77 (d, J=8.59 Hz, 1H), 5.71 (br. s., 1H), 2.65 (s, 3H). LC-MS 298 [M+H]+. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1

Procedure:
3,5-dichloro-4-fluorobenzoic acid was refluxed with >1 equivalent of thionyl chloride and one drop of DMF neat or as a solution in CHCl3. The solvent and volatile by-products were removed in vacuo to provide 3,5-dichloro-4-fluorbenzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1I.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1c(I)ccc2cnsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2ccc3cnsc3c2Br)c1
Yield: 60.4 %

Procedure:
A suspension of 7-bromo-6-iodo-1,2-benzothiazole (29.6 mg, 0.0871 mmol), 3-fluorobenzeneboronic acid (12.8 mg, 0.0915 mmol), potassium carbonate (39.2 mg, 0.284 mmol), and Pd(PPh3)4 (12.2 mg, 0.0106 mmol) in 4:1 1,4-dioxane:water (1 mL) was heated to 80° C. for 15 h. The reaction mixture was concentrated in vacuo. Purification of the residue by ISCO chromatography (0 to 100% dichloromethane:heptane) to afford 16.2 mg (59%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.73 (d, J=7.58 Hz, 1H), 7.52 (dt, J=5.81, 7.96 Hz, 1H), 7.37 (qd, J=0.88, 7.71 Hz, 1H), 7.33 (d, J=7.58 Hz, 1H), 7.28-7.31 (m, 1H), 7.20 (ddt, J=1.01, 2.59, 8.43 Hz, 1H); MS (ESI): 307.87, 309.86 [M+H]+; HPLC tR=4.33 min (ZQ3: nonpolar—5 min).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[N:27]=[C:28]([NH:34][C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:42][CH2:41]3)[CH:39]=2)[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1)(=O)C.C1COCC1.CC(O)C.O[Li].O>O>[CH:40]1([N:38]2[CH:39]=[C:35]([NH:34][C:28]3[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=[C:26]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[CH:9][CH:8]=4)[N:27]=3)[CH:36]=[N:37]2)[CH2:42][CH2:41]1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(C4CC4)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2cccc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)nc(Nc2cnn(C3CC3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask equipped with a stirring bar, 114c THF (1.25 mL), i-PrOH (1.25 mL), H2O (1.25 mL), LiOH H2O (135 mg) were added. The resulting mixture was stirred at RT for 1 hr. Removed all the solvent in vacuo and silica gel column chromatography (MeOH:DCM=10:90) gave 38.6 mg 2-(3-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)-phenyl)-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-1(2H)-one 114 as a yellow solid. MS (ESI+) m/z 526.3 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:33]4[S:29][C:30](=[O:35])[NH:31][C:32]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(-c4ccnc(F)c4)nc23)S1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
To 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 30 mg, 0.1 mmol) in EtOH (1 mL) was added piperidine (13 μL, 0.1 mmol), and thiazolidine-2,4-dione (12 mg, 0.1 mmol). The reaction was stirred at 80° C. for 2 hours. The solid formed was isolated by filtration, washed with water then ethanol. The recovered solid was further purified by washing with 20% methanol/dichloromethan to provide 9 mg of 5-((7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (23%). LCMS (M+1=397)