Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2)(O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:31]=[C:27]1[NH:26][C:21]2([CH2:20][CH2:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:13]([NH:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)=[O:14])[CH:17]=3)[CH2:22]2)[C:29](=[O:30])[NH:28]1
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Reactant: NCc1cccc2cccnc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCc3cc(C(=O)NCc4cccc5cccnc45)ccc3C2)N1

Procedure:
A mixture of 8-(aminomethyl)quinoline (14 mg, 0.088 mmol), (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (15 mg, 0.058 mmol), EDC (22 mg, 0.115 mmol), and HOBT (13 mg, 0.088 mmol) was stirred in DMF (0.8 mL) at ambient temperature for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a tan solid. MS: m/z=401 (M+1). HRMS: m/z=401.1584; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].N1C=CC=CC=1.[C:46](Cl)(=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50]>ClCCl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]([N:34]1[CH2:39][CH2:38][N:37]([C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:24][CH2:25][CH2:26]2)=[O:15])[N:9]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:8]=1)=[O:6]
Reactant: CCCCC(=O)Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 50 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 4 ml dichloromethane were added at 0° C. 15 l pyridine, 13 l valeryl chloride and a catalytic amount of DMAP. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([O:26][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 30 °C
Reaction time: 15 h

Procedure:
To the product of Example 68 (250 mg, 0.575 mmol) was added NaH (73.6 mg, 1.84 mmol, 60%) and ethyl 2-bromoacetate (0.23 mL 2.07 mmol) in DMF (3 mL). The reaction was stirred 3 h at 30° C. and 15 h at rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-33% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 520.1 (M+1), 522.0 (M+3); Rt=4.43 min.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][CH3:24].O>Br>[CH2:21]([CH:20]1[O:25][C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4](=[O:18])[C:3]=2[CH2:19]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(O)Cc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: Br
Solvent: O
Product: CCCCC1Cc2c(c3cccnc3n(-c3ccccc3)c2=O)O1
Temperature: 80 °C

Procedure:
A solution of 4-hydroxy-3-(2-hydroxyhexyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (2g.) in 47% HBr was stirred in an atmosphere of nitrogen and heated to 80° C. for 4 1/2 hrs. after which time it was cooled and poured into water. The precipitate was filtered off, washed with water, dried in air, recrystallized from ethanol/charcoal to yield the product m.p. 179°-180° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[SH2:21].[Na]>CN(C)C=O>[CH:7]1[N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:18]2[C:5](=[C:4]([NH2:20])[NH:3][C:2]([N:19]=2)=[S:21])[N:6]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
The starting material, the 2-thioadenosine of the formula (IV), used in the above Process 2 can be obtained in high yield from 2-chloroadenosine of the formula (II) by the procedure disclosed in Japanese Patent Application OPI No. 52,795/1973. That is, 2-chloroadenosine is reacted with sodium hydrogen sulfide in a solvent such as dimethylformamide at a temperature of about 50°C to 100°C to obtain the desired 2-thioadenosine of the formula (IV) in about 100% yield. The preparation of the starting material of the formula (IV) will be hereinafter described in greater detail in Reference Example 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C1C=CC2N(O)N=NC=2C=1.[CH3:18][C:19]1[CH:20]=[C:21]([C:36]2[CH:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=2)[CH:22]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:24]=1>CN(C=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([C:36]2[CH:37]=[CH:38][C:39]([C:42]([N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)=[O:43])=[N:40][CH:41]=2)[CH:22]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:24]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Reactant: O=C1CNCCN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)N3CCNC(=O)C3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperazin-2-one (80.0 mg, 0.801 mmol), silica-bound carbodiimide (1.08 mmol/g load, 989 mg, 1.07 mmol), and HOBT (123 mg, 0.801 mmol) were added to a solution of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid (200 mg, 0.534 mmol) in DMF (5.30 mL) and the reaction mixture was stirred at room temperature overnight. Macroporous-carbonate (3.17 mmol/g load, 1.01 g, 3.21 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was filtered, washed with DMF and was concentrated under reduced pressure. The residue was triturated with dichloromethane and was isolated by filtration (cold ether wash) to yield 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]carbonyl}piperazin-2-one. MS APCI calc'd for C22H20F3N6O2 [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.84 (d, J=5.5 Hz, 2H), 8.14 (s, 2H), 8.00 (s, 1H), 7.76 (t, 1H), 7.60 (s, 1H), 7.32-7.13 (m, 2H), 4.16 (d, J=12.2 Hz, 2H), 3.92-3.77 (m, 1H), 3.72 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]2[CH2:17][CH2:18][C:19](O)=[O:20].[C:22](OC(=O)C)(=[O:24])C.O>C(O)=O>[CH:22]([N:9]1[C:10]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]3[C:19](=[O:20])[CH2:18][CH2:17][CH:7]([C:6]=23)[CH:8]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24]
Reactant: Cc1cccc2c1NC(c1ccccc1)C2CCC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: Cc1ccc2c3c1N(C=O)C(c1ccccc1)C3CCC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
7-methyl-2-phenyl-2,3-dihydroindole-3-propionic acid (13.47 g) synthesized as in Example 1, steps 1 and 2 was dissolved in formic acid (50 ml) and to the solution was added acetic anhydride (4.53 ml) under cooling with ice. The mixture was stirred for 3 days at room temperature. After adding water, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 13.07 g (97%) of the titled compound as pale brown crystals.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21]C)[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:24]#[CH:25])[OH:23])[CH3:2].Cl.O>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([C@@H:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:24]#[CH:25])[OH:23])=[CH:16][C:15](=[O:21])[CH2:14][CH2:13]4)[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(C)C4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CC
Agent: Cl
Solvent: CO
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene (3.5 g) in methanol (90 ml) containing concentrated hydrochloric acid (6.0 ml) and water (4.0 ml). Stir the solution under nitrogen for one hour. Work up in the usual fashion. Chromatograph on Florex (150 g), then recrystallize from ether-hexane to obtain dl-13-ethyl-17α-ethynyl-17-hydroxy-6α-methylgon-4-en-3-one (0.60 g) m.p. 148°-151°; ultraviolet absorption peak at 240 mμ (ε15,300), infrared maxima (chloroform) at 2.55 μ, 3.05 μ, 6.01 μ.
Reaction SMILES: BrCCBr.Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:28][C:27]([C:29](OC)=[O:30])=[N:26][N:25]=1>C1COCC1>[C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:29]([C:27]2[O:28][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:25][N:26]=2)=[O:30])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A dry vial was charged with freshly activated Mg turnings (115 mg, 5 mmol), 100 μL of anhydrous THF and a drop of 1,2-dibromoethane under Ar. This mixture was treated dropwise with a solution of 6-bromohexylbenzene (240 mg, 1 mmol) in THF (1 mL) at 23° C. The mixture was warmed and sonicated repeatedly until Grignard formation occurred. The gray solution of the Grignard reagent was added to a solution of methyl 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate (S7, 40 mg, 0.17 mmol) in THF (2 mL) at −40° C. Stirring was continued for 2 h before the reaction was quenched by the addition of MeOH at −40° C. The mixture was extracted with EtOAc and washed with water, saturated NaHCO3 and saturated aqueous NaCl followed by separation and evaporation. Flash chromatography (SiO2, 1×4 cm, 40% EtOAc-hexanes) afforded the title compound (30 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.85 (d, 1H, J=4.7 Hz), 8.30 (d, 1H, J=7.9 Hz), 7.93 (td, 1H, J=1.5, 7.8 Hz), 7.54 (ddd, 1H, J=0.9 4.7, 7.6 Hz), 7.26-7.30 (m, 2H), 7.16-7.19 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.6 Hz), 1.82 (quintet, 2H, J=7.3 Hz), 1.66 (quintet, 2H, J=7.5 Hz), 1.43 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 187.1, 165.0, 161.2, 150.8, 142.6 (2C), 137.3, 128.3, 128.2, 126.7, 125.6, 124.0, 40.0, 35.8, 31.2, 28.9, 28.8, 23.5; IR (film) νmax 2927, 2856, 1709, 1589, 1442, 1398, 1038, 986, 798, 754, 710 cm−1; HRMS-ESI-TOF m/z 336.1717 ([M+H]+, C20H21N3O2 requires 336.1706).
Reaction SMILES: ClCCl.[CH2:4]([C@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:5][CH2:4][C@@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O[C@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (173 mg, 0.532 mmol) and dichloromethane (13 ml) was added (±) camphorsulfonic acid (148 mg, 0.638 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (5 ml) to disperse the crude cobalt (III) complex and then thereto were added (S)-epichlorohydrin (2.50 ml, 31.9 mmol, optical purity 99% e.e.) and phenol (2.50 g, 26.6 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (S)-1-chloro-3-phenoxy-2-propanol (5.75 g). This crude compound (5.75 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (6.64 g, 39.8 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (20 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 mm) in order. The organic layer was condensed under reduced pressure to give (R)-glycidylphenyl ether (3.96 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (R)-glycidylphenyl ether (3.80 g, 95.4%) was produced with optical purity at 99% e.e.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[CH:13]=1.[N+:16]([O-])([OH:18])=[O:17]>C(OCC)(=O)C.ClCCl>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[C:13]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COc1cc2cc(C(=O)O)sc2cc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2cc(C(=O)O)sc2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Hydroxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid (3.2 g) was dissolved in ethyl acetate (200 ml) and a solution of nitric acid in dichloromethane (2M, 7.7 ml) was gradually added at 0° C. into. The solution was stirred 30 min at room temperature and then it was poured into ice-cold water and filtered. The solid was washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=2[F:30])[CH2:17][CH:16]1[CH3:31])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH:16]2[CH3:31])=[O:14])[N:2]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)C(C)C2)c(F)cc1Cl
Reactant: Nc1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 80 °C

Procedure:
1H-Pyrazolo[3,4-b]pyridin-3-ylamine (67 mg), 2-Chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (167 mg) and K2CO3 (414 mg) were combined in DMF (1 mL) and heated at 80° C. for 2 hr, then cooled to room temperature. The resultant mixture was purified by preparative HPLC to provide 2-(3-Aminopyrazolo[3,4-b]pyridin-1-yl)-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]ethanone as a yellow powder. LCMS (ES) M+H 433.5, Rf 2.06 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:4].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([CH3:24])=[O:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:23])[CH3:24])=[CH:19][CH:20]=2)[CH3:13])=[CH:7][CH:8]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CC(Br)C(=O)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OC(C)C(=O)Nc2ccc(Br)cc2)cc1
Yield: 71.7 %

Procedure:
A solution of 2-bromo-N-(4-bromophenyl)propanamide (3.00 g, 10.2 mmol), 1-(4-hydroxyphenyl)acetone (1.54 g, 10.2 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in DMF (20 ml) was stirred at room temperature for 4 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine. The solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from isopropyl ether-ethyl acetate to give the title compound (2.75 g).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[CH2:16]([O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: C#CCCCCC#C
Reactant: BrCCCCCCCOC1CCCCO1
Product: C#CCCCCC#CCCCCCCCOC1CCCCO1
Yield: 64.9 %

Procedure:
Oct-1,7-diyne (6.3 g, 59.3 mmol) was alkylated with 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (11 g, 39.56 mmol) as described above to give 2-(pentadeca-8,14-diynyloxy)tetrahydro-2H-pyran (7.82 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.57 (t, J=2.5 Hz, 1H), 3.82-3.87 (m, 1H), 3.70-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.36-3.42 (m, 1H), 2.14-2.20 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.46-1.72 (m, 20 H)
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:10]([CH3:17])[CH2:11][C:12](OCC)=[O:13]>C(O)C>[CH3:17][C:10]1[CH:11]=[C:12]([OH:13])[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Product: Cc1cc(O)n(-c2ccccn2)n1

Procedure:
In a 1.0-liter egg plant-type flask, an ethanol solution (300 mL) of 2-hydrazinopyridine (16.3 g, 0.15 mol) and ethyl 3-oxobutanoate (20.5 g, 0.16 mol) was stirred overnight with heating under reflux. Ethanol was removed from the reaction solution under reduced pressure to obtain the title compound as a brown oily crude product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:16](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:17][CH3:18])=[CH:11][CH:10]=1>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:9]1[N:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[C:16](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:17][CH3:18])=[CH:11][CH:10]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirred solution of 2-(methylamino)ethanol (672 mg, 10 eq) in 20 mL anhydrous THF was added NaH (373 mg, 8.0 eq) at 0° C. The mixture was stirred at rt for 1 h, then to the mixture was added (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (300 mg, 1 eq, made from example 1). The reaction was heated at reflux for 16 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (200 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.18-7.20 (m, 2H), 7.08-7.16 (m, 3H), 7.01-7.06 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 2.93 (t, J=5.2 Hz, 2H), 2.46-2.55 (m, 5H), 0.92 (t, J=7.6 Hz, 3H); m/z=375 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2].[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:26])[CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=4)[CH2:21]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCOC(=O)Cc1ccc(C2CCC(=O)CC2)cc1
Product: CCOC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of [4-(4-oxo-cyclohexyl)-phenyl]-acetic acid ethyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[N:9]([CH2:29][O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[N:17]([CH2:26][O:27][CH3:28])[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])=O)C.O.[NH2:33]N.C(O)(=O)C>O>[CH3:28][O:27][CH2:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]([CH2:29][O:30][CH3:31])[C:8]([C:6]1[N:5]=[CH:4][NH:2][N:33]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19]
Reactant: NN
Reactant: COCN(c1cccc2cc(C(=O)/N=C/N(C)C)n(COC)c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)O
Product: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylene]-1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.06 g), hydrazine monohydrate (0.22 mL) and acetic acid (10 mL) was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.99 g, quantitative) as colorless crystals. melting point 97-99° C.