Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.[OH-].[Na+]>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][CH2:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCc1ccccc1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)c1cccc(C(=NOCc2cccc(NCCCc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (125.0 mg, 0.35 mmol) in dry 1,2-dichloroethane (10 mL), under argon atmosphere, were added 3-phenylpropionaldehyde (66.6 mg, 0.49 mmol) and sodium triacetoxyborohydride (135 mg, 0.63 mmol) at room temperature. After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane (50 mL) and aq. NaOH (1 M, 30 mL) was added. After phase separation, the organic layer was washed with water (40 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-N-(3-phenylpropyl)pyridin-2-amine as an oil [82 mg, yield 47%; HPLC/MS: m/z=471 (M+H); logP(HCOOH)=2.57].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27].[ClH:33]>O1CCOCC1>[ClH:33].[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCCCC3)S(C)(=O)=O)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 100 °C
Yield: 94 %

Procedure:
To a stirred solution of tert-butyl 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetate (450 mg, 0.967 mmol) in dioxane (7 ml), 4 M HCl in dioxane (2.5 ml, 10.00 mmol) was added. The reaction was heated at 100° C. under microwave irradiation for 4 hours. The volatiles were removed under vacuum and the resulting solid was triturated with Et2O and recovered by filtration affording 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetic acid hydrochloride (407 mg, 0.913 mmol, 94% yield, MS/ESI+ 409.8 [MH]+).
Reaction SMILES: [C:1](=[O:33])([O:7][C:8]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Cl-].[Li+].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1.C(Cl)(Cl)Cl.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>[C:1](=[O:33])([O:7][C:8]1[C:13]([CH:36]=[CH2:37])=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C=Cc1c(C)nc(C)c(CCCCCCCCCCCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 4.6 %

Procedure:
To a solution of 8 (85 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-hexadecyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (10) (19 mg, 27%). 1H NMR (CDCl3) δ 0.02-0.03 (m, 3H), 1.20-1.27 (m, 28H), 1.46 (s, 9H), 2.45 (s, 3H), 2.48 (s, 3H), 2.54-2.56 (m, 2H), 5.55 (dd, 2H, J=17.6 Hz, 11.6 Hz) and 6.50 (dd, 1H, J=11.2 Hz, 11.2 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])[CH3:9]>C(OCC)C>[CH3:21][C:18]([C:15]1[CH:14]=[C:13]([CH2:22][CH2:23][CH2:24][OH:25])[CH:12]=[C:11]([C:8]([CH3:9])([CH3:7])[CH3:10])[C:16]=1[OH:17])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1cc(CCCO)cc(C(C)(C)C)c1O
Yield: 92.7 %

Procedure:
To a suspension lithium aluminum hydride (11.2 g) in diethyl ether (500 mL) is added over a period of 30 minutes ethyl 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]propionate (60.0 g) in diethyl ether (100 mL). The mixture is heated at reflux for 3 hours and then quenched by the sequential addition of water (11 mL), 10% aqueous sodium hydroxide (11 mL) and water (66 mL). The resulting suspension is washed with tetrahydrofuran and the filtrate is concentrated to give 48 g of 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl]propanol. Trituration of the residue with heptane gave 46 g of light yellow crystals. The 1H NMR spectrum and field desorption mass spectrum are consistent with the above-specified product.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:26]([O:29][C:30]([N:32]1[C@H:36]([CH:37]([C:43]2[S:47][C:46]3=[CH:48][N:49]=[C:50]([Cl:51])[N:45]3[CH:44]=2)OC(SC)=S)[CH2:35][C@@H:34]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:33]1)=[O:31])[CH:27]=[CH2:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:26]([O:29][C:30]([N:32]1[C@H:36]([CH2:37][C:43]2[S:47][C:46]3=[CH:48][N:49]=[C:50]([Cl:51])[N:45]3[CH:44]=2)[CH2:35][C@@H:34]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:54])[CH3:55])[CH2:33]1)=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(OC(=S)SC)c1cn2c(Cl)ncc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(Cl)ncc2s1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
Tri-n-butyltin hydride (1.8 ml) and 147 mg of 2,2′-azobisisobutyronitrile are added to a solution of 2.520 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-(5-chloroimidazo[5,1-b]thiazol-2-yl)-1-(methylthiothiocarbonyloxy)methyl]pyrrolidine (a diastereomer mixture) in 22.5 ml of dry toluene, and the mixture is stirred in an argon atmosphere at an external temperature of 80° C. for 90 min. The reaction solution is diluted with 200 ml of ethyl acetate, washed with semi-saturated saline and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 1.467 g of (3R,5s)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(Cl)c32)ccc1C(C)(C)C#N
Yield: 159.6 %

Procedure:
To a solution of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 16 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3H) 1.76 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.19-5.36 (m, 2H) 7.13-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.59 (dd, J=8.98, 4.30 Hz, 1H) 8.14 (s, 1H), MS [M+H], calcd: 413.2, found: 413.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.03 g) in acetone (50 ml) was added 6N-hydrochloric acid (5 ml), and the mixture was stirred for 2 hours at room temperature. After adding water (30 ml), the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant oily precipitates were extracted with ethyl acetate. The ethyl acetate extracts were washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give reddish oil of crude diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.26 g), which was used in a succeeding reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]1([CH3:75])[CH:57]=[CH:56][C:55]([S:58]([O:61][CH2:62][CH2:63]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:14]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:24]1)=[O:22])[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:63][CH2:62][O:61][S:58]([C:55]3[CH:56]=[CH:57][C:52]([CH3:75])=[CH:53][CH:54]=3)(=[O:60])=[O:59])[CH:3]=2)[CH:9]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCOS(=O)(=O)c3ccc(C)cc3)c2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 53.3 %

Procedure:
98.0 mg (0.16 mmol) Tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 6a) were dissolved in 6.1 ml N,N-dimethylformamide. 154 mg (0.47 mmol) cesium carbonate and 87.4 mg (0.24 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 68 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 70 mg (49%) tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C(OC([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[NH2:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[(benzyloxycarbonyl)amino]-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (7.00 g, 18.2 mmol) in glacial acetic acid (200 mL), prepared as in Intermediate 6, is saturated with HBr gas. The reaction is warmed to 70° C. and held for 20 min. The temperature is raised to 80° C. and maintained for an additional 20 min. The resulting slurry is cooled to ambient temperature, diluted with anhydrous diethyl ether (200 ml), agitated for 0.5 hrs., filtered and washed with diethyl ether. The hydrobromide salt is dried at 60° C. under vacuum to provide the dihydrobromide salt (6.836 g, 16.5 mmol) of the title compound. The free base is obtained by partitioning the dihydrobromide (6.100 g, 14.3 mmol) between aqueous potassium carbonate (5% w/v, 50 mL) and a mixture of ethyl acetate, isopropanol and DCM. After separating the phases, the organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a solid. The product is dried under high vacuum to provide the title compound as a crystalline solid (3.69 g, 14.3 mmol). 1H NMR (300 MHz, d6-DMSO) δ=4.21 (s, 1H); 7.15-7.60 (m, 9H); 10.66 (s, 1H). TLC: Rf =0.33 (95:5 chloroform: methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:30][CH2:31][CH3:32])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)OC)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.747 g, 2.00 mmol) and 1-iodopropane (0.585 mL, 6.00 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.415 g, 3.00 mmol), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 8 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (0.740 g, yield 89%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1.O>[Cl:1][C:2]1[S:3][C:4]([C:15](=[O:17])[CH3:16])=[CH:5][N:6]=1
Reactant: Clc1nccs1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 2-chlorothiazole (2.5 g, 21 mmol) in THF (10 mL) was added dropwise to a chilled (−75° C.) 2.5 M hexanes solution of n-BuLi (9.2 mL, 23 mmol) in THF (70 mL). After the addition was complete the reaction mixture was stirred for 1 hr. Then a solution of N-methoxy-N-methylacetamide (2.4 g, 23 mmol) in THF (5 mL) was added. The reaction was allowed to stir overnight while warming to 25° C. The reaction was diluted with H2O and thrice extracted with ethyl ether. The organic portions were combined, washed with brine and then dried (Na2SO4). Filtration and removal of solvent gave a residue that was purified by flash chromatography on silica eluting with 5 percent Et2O in pentane, affording product as a white solid, 2.5 g, 15.5 mmol, 73 percent yield.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](=[O:16])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:46])([F:45])[F:44])[CH:37]=3)=[CH:34][N:35]=2)[N:32]=1.[F-].[Cs+]>CS(C)=O.O.C(Cl)Cl>[O:16]=[C:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:44])([F:46])[F:45])[CH:37]=4)=[CH:34][N:35]=3)[N:32]=2)[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1=O
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of compound tert-butyl 4-(aminomethyl)-2-oxopiperidine-1-carboxylate (37 mg, 0.16 mmol), DIEA (0.6 mL, 3.5 mmol), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (50 mg) and CsF (17 mg, 0.11 mmol) in DMSO (2 mL) was stirred at 120° C. overnight. The mixture was diluted with H2O (20 mL) and CH2Cl2 (20 mL). The organic phase was separated and condensed to give crude compound tert-butyl 2-oxo-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidine-1-carboxylate (60 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(O)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]3)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-Bromo-1H-indole-2-carboxylic acid (5 g, 20.8 mmol) and 4-methoxy-phenyl-boronic acid (3.2 g, 20.8 mmol) are dissolved in 1-propanol (100 ml) and the mixture is flushed with argon for 30 min. Then bis(triphenylphosphin)palladium(II)chloride (200 mg, 1 mmol) and Na2CO3 (4.4 g, 40.2 mmol) are added and the reaction mixture is stirred at 85° C. for 3 h. After cooling down to room temperature, ethyl acetate and 2M HCl are added. The organic layers are dried over sodium sulphate. Evaporation gave 6 g of an beige solide, which is further purified by crystallisation from ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12]CC)=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[OH-].[Li+].C(O)C>C1COCC1>[CH3:1][CH:2]1[C:6]2[NH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1CCc2cc(C(=O)O)[nH]c21
Yield: 9.9 %

Procedure:
The title compound was synthesized from ethyl 6-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0208 g, 0.11 mmol, 1 equiv) and lithium hydroxide (0.12 mL, 1 M aqueous, 0.12 mmol, 1.1 equiv), according to General Procedure 7. A 1:1 mixture of ethanol (EtOH) and THF (2 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (1.8 mg) with purity by HPLC of 100% (UV). LCMS m/e 164.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.23 (d, J=6.83 Hz, 3H), 1.81-2.04 (m, 1H), 2.42-2.71 (m, 3H), 3.10 (dd, J=6.69, 1.88 Hz, 1H), 6.55 (s, 1H), 8.48 (br. s, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[N:11]=[CH:10][N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][CH2:6][O:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[C:13]=1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OCCOc1ncnc(NS(=O)(=O)c2ccc(C)cc2)c1CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2CCc2ccccc2)cc1
Yield: 55.1 %

Procedure:
80 mg of 2-[(5-phenethyl-6-p-toluenesulphonamido-4-pyrimidinyl)oxy]ethyl acetate in 5 ml of methanol were stirred with 53 mg of finely powdered potassium carbonate at 20° C. for 15 hours. Thereafter, the methanol was removed under reduced pressure, the residue was taken up in ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, dried and evaporated. The residue was chromatographed over silica gel with methylene chloride/ethyl acetate(1:1) and ethyl acetate. There were obtained 40 mg of N-[6-(2-hydroxyethoxy)-5-phenethyl-4-pyrimidinyl]-p-toluenesulfonamide as a white resin.