Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:25]=O)=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:25][NH:6][CH3:5])=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1
Reactant: Cn1cc(C=O)c2ccc(Cl)cc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cc(Cl)ccc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 6-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:22]=[C:23]([CH3:27])[N:24]([CH3:26])[CH:25]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[N:47]=[CH:46][C:45]4=[CH:48][CH:49]=[C:50](B5OC(C)(C)C(C)(C)O5)[N:44]4[N:43]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][N:24]1[CH:25]=[C:21]([C:50]2[N:44]3[C:45]([CH:46]=[N:47][C:42]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:36][CH:37]=4)=[N:43]3)=[CH:48][CH:49]=2)[N:22]=[C:23]1[CH3:27]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(B5OC(C)(C)C(C)(C)O5)n4n3)cc2)CC1
Reactant: Cc1nc(Br)cn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)cn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
Palladium acetate (13.0 mg, 0.0580 mmol) and triphenylphosphine (19.0 mg, 0.0725 mmol) were placed in tetrahydrofuran (2.00 mL). The mixture was allowed to stir at room temperature for 10 minutes. 4-Bromo-1,2-dimethyl-1H-imidazole (102 mg, 0.580) was then added and the reaction was again allowed to stir for 10 minutes. [4-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (105 mg, 0.242 mmol) was added followed by 1.50 M sodium carbonate in water (0.645 mL, 0.967 mmol) and ethanol (2.00 mL). The reaction mixture was then heated at 80° C. overnight. The reaction was partitioned between DCM (50 mL) and water (50 mL). The organic layer was washed twice with water (50 mL) and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 10-45% AcN/water both containing 0.1% TFA as the eluting solvent. The product was then free based to obtain the title compound as a yellow solid (22 mg, 23%). m.p.=242-244° C.; LCMS (m/e) 403 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 7.84 (s, 1H), 7.57-7.50 (m, 2H), 7.24 (d, 1H, J=4.8 Hz), 7.02-6.95 (m, 2H), 6.80 (d, 1H, J=4.8 Hz), 6.55 (bs, 1H), 3.62 (s, 3H), 3.24-3.16 (m, 4H), 2.65-2.57 (m, 4H), 2.46 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:36][N:35]([CH2:34][C:33]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:31][N:32]=1)[CH3:37]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)Nc4ccc(F)cc4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3c2)n1
Yield: 50 %

Procedure:
Prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(4-fluorophenyl)carboxamide.2HCl (1.50 g, 3.15 mmol), N-amino-2-(dimethylamino) acetamide (1.2 g, 10.33 mmol) and sodium methoxide (1.8 mL of a 25% w/w in methanol) in anhydrous methanol (20.0 mL) with a reaction time of 1.5 days. Purification by flash chromatography on silica gel using 50% methanol in ethyl acetate afforded a solid which was dissolved in anhydrous methanol and treated with anhydrous hydrogen chloride gas for 10 min at 0° C. After stirring at ambient temperature for 5 min anhydrous ethyl acetate was added to precipitate the desired product which was collected on a sintered glass funnel, washed with methanol and ethyl acetate and dried under vacuum to give the title compound (267 mg, 50% yield) as a light yellow solid 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.5 (s, 1H), 8.5 (s, 1H), 8.2 (br d, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.84 (dd, 2H), 7.75–7.6 (m, 2H), 7.2 (t, 2H), 3.6 (bs, 2H), 2.2 (s, 6H), ES-MS (m/z) 456 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:7]/[C:2](=[CH:1]\[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:3]([O:5][CH3:6])=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(C)=COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C(C)=C/Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.2 %

Procedure:
To a solution of 6.98 g (25.8 mmol) of methyl 2-methyl-3-(p-toluenesulfonyloxy)-2-propenoate in 30 ml of DMF was added 2.67 g (28.3 mmol) of phenol and 10 g (30.6 mmol) of cesium carbonate and stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with tert-butyl methyl ether (twice). The combined organic layer was washed sequentially with a 1N aqueous NaOH solution, water, and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 657 mg of (E)-methyl 2-methyl-3-phenoxy-2-propenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC(OC)=CC=1.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[OH:9][C:8]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a suspension of 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol (25 mg, 0.055 mmol) in 1.5 ml of dichloromethane was added 78 mg of PS-thiophenol resin (Argonaut Technologies, 1.41 mmol·g−1), followed by TFA (0.3 ml). The clear suspension was stirred at room temperature for 1 hour, then the resin was filtered off, washed with ethyl acetate, then methanol. The filtrate was evaporated and the residue was taken up in 2 ml of ethyl acetate and saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered off, washed with water, then ethyl acetate and dried in vacuo to afford 5-(5-(4-hydroxy-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ol as a light beige solid (15 mg, 80% yield). 1H NMR (DMSO-d6): δ 11.83 (broad s, 1H), 11.67 (broad s, 1H), 9.05 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.88 (dd, J=3.0, 9.5 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (dd, J=2.0, 8.5 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.44 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); HPLC/MS m/z: 334.1 [MH]+.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>C(O)C>[C:5]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:29]=3[O:28][CH3:27])[C:33]([OH:35])=[O:34])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, are placed 1 g of 1-acetoxyadamantane and 50 ml of n-heptane. After dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop at a temperature of approximately 22° C. and 0.783 g of 4-methoxybenzoic acid is poured in slowly. After leaving the mixture well agitated for 48 hours, 50 ml of denatured ethanol are added and the insoluble material is filtered Concentration of the filtrate volume to three quarters yields a solid white precipitate which is filtered with sintered glass. It is dried in a vacuum oven for 24 hours at 30° C. and 0.680 g of expected raw product was collected (Melting point: 245°-246° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14]4=[C:15]([CH2:17][CH2:18][CH2:19][N:13]4[CH2:12][C@@H:11]4[CH2:20][NH:21][CH2:22][C@H:10]34)[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:23].Cl.[C:25]1(C2C=C3C4=C(CCCN4C[C@@H]4CNC[C@H]34)C=2)C=CC=CC=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C(O)(=O)C.CCOCC>[ClH:23].[ClH:23].[CH3:25][N:21]1[CH2:22][C@H:10]2[C@H:11]([CH2:12][N:13]3[CH2:19][CH2:18][CH2:17][C:15]4[CH:16]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=[C:9]2[C:14]3=4)[CH2:20]1
Reactant: c1ccc(-c2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1C[C@H]2CN3CCCc4cc(-c5ccccc5)cc(c43)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of (±)-cis-2-phenyl-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline, the free base of EXAMPLE 15, (20 mg, 0.07 mmol) in 2 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.010 mL, 0.11 mmol), sodium triacetoxyborohydride (37 mg, 0.17 mmol) and glacial acetic acid (1 drop). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.07 mL, 0.14 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 20 mg (77%) of the title compound of EXAMPLE 16 as an off white powder. 1H NMR (d6-dmso): δ 7.55-7.50 (m, 2H), 71.35 (app t, 2H, J=7.5 Hz), 7.24-7.17 (m, 2H), 7.14 (s, 1H), 4.07-3.98 (m, 1H), 3.82-3.73 (m, 1H), 3.44-3.32 (m, 1H), 3.10-3.03 (m, 2H), 3.02-2.97 (m, 1H), 2.94-2.70 (m, 9H), 1.97-1.85 (m, 2H). LRMS (ES)+: 305.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[Br:6][C:7]1[N:12]=[C:11]([C:13]([O:15]CC)=O)[CH:10]=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[N:12]=[C:11]([C:13](=[O:15])[CH2:4][C:3]#[N:5])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a suspension of sodium hydride (0.6 g, 60% in oil, 15.7 mmol) in anhydrous THF (70 mL) was added dropwise anhydrous acetonitrile (1.02 mL, 19.6 mmol). The mixture was stirred for about 30 min at rt and then ethyl 6-bromopyridine-2-carboxylate (3.00 g, 13.0 mmol, Apollo Scientific) was added. Subsequently, the resulting mixture was heated under reflux, for about 2 h. After cooling to rt, the volatiles were removed in vacuo and to the residue was added saturated aqueous ammonium chloride (150 mL) and ethyl acetate (600 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (2×125 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:3) to give crude 3-(6-bromo-2-pyridyl)-3-oxo-propanenitrile (1.71 g, 7.6 mmol, 58%), as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.38 (2 H, s); 7.74-7.84 (2 H, m); 8.08 (1 H, dd, J=2 Hz, 6.5 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1)=[O:37]
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.22 g, 0.53 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (77%, 0.12 g, 0.53 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.17 g, 86%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[NH:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>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>[NH:42]1[CH:43]=[C:44]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)[CH:45]=[N:41]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cn[nH]c3)cc2)CCCC1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate, 4.5 equivalents 4-pyrazoleboronic acid pinacol ester and 0.2 equivalents Pd(PPh3)4 in Step A. MS (ESI): mass calcd. for C34H31N5O3, 557.24; m/z found, 558.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=8.5, 1H), 8.10 (d, J=8.4, 1H), 7.84 (d, J=7.6, 1H), 7.78 (s, 2H), 7.77-7.73 (m, 1H), 7.71 (d, J=8.5, 1H), 7.59-7.54 (m, 1H), 7.43 (d, J=8.2, 2H), 7.36-7.34 (m, 1H), 7.18 (d, J=8.9, 1H), 7.07-7.04 (m, 1H), 7.02 (d, J=8.1, 2H), 5.42 (s, 2H), 5.34 (s, 2H), 3.43-3.41 (m, 1H), 3.13 (s, 2H), 1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.30-1.24 (m, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:19][C:18](=[O:31])[C:13]([C:14]([O:16]C)=[O:15])=[CH:12]2)=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:19][C:18](=[O:31])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cn(-c2ccc(NC(C)=O)cc2)c(-c2ccc3ccccc3c2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
In a mixed solvent of 10 ml of ethanol and 10 ml of a 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 1-(4-acetaminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinate, and the solution was refluxed for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and diluted with 20 ml of water. This solution was then adjusted to a pH of 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.38 g of 1-(4-aminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 148°-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(C(C)(C)C)(C)C>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.C1(C)C=CC=CC=1>[OH:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:3]=2)=[CH:34][CH:33]=1
Reactant: NC(=O)Nc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(-c2cccc(NC(N)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
Prepared according to the method described in Example 12b) from 3-bromophenylurea (0.215 g), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.2 g, Example 11)), and tetrakis(triphenylphosphine)palladium (0) (0.02 g) with heating at 120° C. for 4 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-25% ethanol in dichloromethane to give the title compound as a solid (0.116 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.Cl[C:16]1[CH:29]=[C:28]2[C:23](N=CC=C2)=[C:22]2[C:17]=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].IC1C=CC=CC=1.[OH-].[NH4+].O>CN1CCCC1=O>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])/[N:4]([C:16]2[CH:29]=[CH:28][CH:23]=[CH:22][CH:17]=2)[CH:3]=1
Reactant: Clc1cc2cccnc2c2ncccc12
Reactant: Cc1cnc(NC(=O)N2CCCC2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: Ic1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2ccccc2)/c(=N/C(=O)N2CCCC2)s1
Temperature: 120 °C

Procedure:
To a 4 mL vial equipped with a septum cap and stir bar was added N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide (21 mg, 0.1 mmol), copper(I) trifluoromethanesulfonate benzene complex (10 mg, 0.02 mmol), 5-chloro-1,10-phenanthroline (8.5 mg, 0.04 mmol) and cesium carbonate (38.9 mg, 0.12 mmol). The mixture was placed under a nitrogen atmosphere. Iodobenzene (0.12 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the mixture. The reaction mixture was heated at 120° C. for overnight. A solution of concentrated ammonium hydroxide/water (1:2, 1 mL) was added and the mixture was filtered and solvent removed under reduced pressure. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:34][CH3:35])[NH:5][CH2:6][CH2:7][CH2:8][C@:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]([C:14](=[O:19])[C@@H:15]([O:17][CH3:18])[CH3:16])[N:12]=[C:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]1)#[N:2].[ClH:36].[OH2:37]>CO.O1CCOCC1>[ClH:36].[F:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[C:11]1[S:10][C@@:9]([CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:34][CH3:35])=[N:3][C:1]([NH2:2])=[O:37])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]([C:14](=[O:19])[C@@H:15]([O:17][CH3:18])[CH3:16])[N:12]=1
Reactant: O
Reactant: CNC(=NC#N)NCCC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=NC(N)=O)NCCC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of 2-cyano-1-(3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)-3-methylguanidine (Example 10; 130 mg, 0.26 mmol) in methanol (3 mL) was added HCl (0.65 mL of a 4 M solution in dioxane) and water (0.05 mL, 2.6 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was triturated with ether to provide the product as a pale pink solid (135 mg, 94% yield). MS ESI (+) m/z 541 (M+Na) detected: 1H NMR (400 MHz, CD3OD) δ 7.66-7.61 (m, 1H), 7.49-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.28 (m, 3H), 4.79 (q, 1H, J=6.4 Hz), 3.53-3.43 (m, 2H), 3.36 (s, 3H), 3.30-3.20 (m, 1H), 2.95 (s, 3H), 2.67-2.55 (m, 1H), 2.23-2.11 (m, 1H), 1.75-1.63 (m, 1H), 1.43 (d, 3H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)NC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 107 %

Procedure:
4-(4-Nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid benzyl ester (0.98 g, 2.4 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.34 g, 6.1 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1 g, 100% yield) as a brown solid. Tr=1.80 min, m/z (ES+) (M+H)+ 390.
Reaction SMILES: BrC1C=CC(F)=C(C2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])N=2)C=1.[F:17][C:18]([F:28])([F:27])[C:19]1[N:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][CH:20]=1>>[F:28][C:18]([F:27])([F:17])[C:19]1[N:24]=[C:23]([C:25]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:26]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1csc(-c2cc(Br)ccc2F)n1
Reactant: N#Cc1cccc(C(F)(F)F)n1
Product: O=C(O)c1csc(-c2cccc(C(F)(F)F)n2)n1

Procedure:
Following the procedure of Intermediate 129, replacing 5-bromo-2-fluoro-benzonitrile with 6-(trifluoromethyl)picolinonitrile gave the title compound.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[C:3][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: C#CCOC1CCCCO1
Reactant: CCCCCCCCCCCCBr
Product: CCCCCCCCCCCCC#CCOC1CCCCO1
Yield: 79.6 %

Procedure:
Alkylation of 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (15.5 g, 110.71 mmol) with 1-bromododecane (34.0 g, 132.04 mmol) as described above gave 2-(pentadec-2-ynyloxy)tetrahydro-2H-pyran (27.2 g, 80%) which was used without further purification. TLC: 10% EtOAc/hexanes, Rf≈0.5.