Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]([OH:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccccc1-c1ccccc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2-c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and biphenyl-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C24H24O5 [M+Na]+: 415.4.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[OH:15])=[CH:6][CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:15])[N:12]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:13]=[CH:14]2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1nncn1-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncn(-c2ccc(Br)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dry NaH (360 mg, 15.0 mmol) under an Argon atmosphere was added dropwise a solution of compound 82a (1.92 g, 6.80 mmol; based on 85% purity) in anhydrous DMF (20 mL). After stirring at room temperature for 1 h, the mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (3.07 mL, 17.0 mmol) was added dropwise over 2 min. The mixture was stirred at room temperature for 1.5 h. The mixture was quenched carefully with 1 mL of saturated aqueous NH4Cl and poured into water (150 mL). After saturating the aqueous mixture with solid NaCl, the mixture was extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a pale brown solid which was purified by flash column chromatography on silica gel (0-40% EtOAc-heptane) to afford compound 82b as a white solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2Si, 392.1/3.94.1 (M+Na). found 392.2/3.94.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[N:23]1[C:28]2[NH:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[NH:32][CH2:33][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:32]1[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[NH:29][C:28]2[N:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:33]1)=[O:6]
Reactant: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under anhydrous conditions a mixture of the 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid of Example 13, Step E (1.9 g, 8.05 mmol) and oxalyl chloride (0.79 mL, 9.0 mmol) in 20 mL of dichloromethane containing a catalytic amount of dimethylformamide was stirred at ambient temperature for 1 hour. The solvent was evaporated and the solid acid chloride was dissolved in 5 mL of dimethylformamide and added directly to a mixture of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (1.59 g, 8.05 mmol) and potassium carbonate (1.25 g, 9.0 mmol). After stirring for 2 hours at ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to small volume. Flash chromatography of the residue (on silica Merck 60, ethyl acetate-hexane, gradient from 4:3 to 2:1) gave the product as a syrup which crystallized from diethyl ether (1.8 g, 61% yield1) as a white solid, m.p. 196-197° C. Another recrystallization from ethanol-diethyl ether provided a higher melting polymorph, m.p. 202° C. as determined by differential scanning calorimetry.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[CH:11][CH:10]=1)[C:6](O)=[O:7].Cl.[CH2:30]([N:32]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O.O.O1CCCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[CH:11][CH:10]=1)[C:6]([NH:32][CH3:30])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)CC(C(=O)O)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)C(CC(=O)OC)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.8 %

Procedure:
To a solution of 2-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinic acid 4-methyl ester (310 mg) obtained in Step 6 in N,N-dimethylformamide (4 mL) were added successively 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg), 1-hydroxybenzotriazole hydrate (115 mg) and a tetrahydrofuran solution of methylamine (2M, 0.53 mL), followed by stirring the reaction mixture at room temperature for 13 hours. Then, after addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give N-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succina mic acid methyl ester (278 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethoxyaniline (44 mg, 0.290 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried under vacuo to give a gray solid (36 mg, 50%). 1H NMR (CDCl3): 8.51–8.48 (m, 2H), 8.14 (s, 1H), 7.51–7.48 (m, 4H), 6.89 (s, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.66 (dd, J=3.0, 8.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: COC[O:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=[O:8].C[C:15]1[CH:22]=[CH:21][CH:20]=[C:19](C)[C:16]=1[CH:17]=O.Cl>O1CCCC1>[C:5]1([C:17]([C:16]2[CH:15]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([C:7]([C:6]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:5]=3[OH:4])=[O:8])=[CH:22][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:6]=1
Reactant: COCOc1ccc(C)cc1C=O
Reactant: Cc1cccc(C)c1C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C(=O)c2ccc(C=C(c3ccccc3)c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 211.5 %

Procedure:
An intermediate compound was prepared by the same method described in Example 6 except that 2-methoxymethoxy-5-methylbenzaldehyde (1.3 g) synthesized in the above-described Synthesis Example 3 was used instead of 2,6-dimethylbenzaldehyde (0.65 g). A 6 N hydrochloric acid solution (1 mL) was added to a tetrahydrofuran solution (30 mL) of the intermediate compound, and the mixture was stirred at 25° C. for 12 hours. After confirmation of the degree of reaction progress by TLC, the reaction was quenched with an aqueous solution of sodium hydrogen carbonate, and the organic phase was extracted with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated, and recrystallized to obtain 2.0 g (yield: 84%) of [4-(2,2-diphenylvinyl)phenyl]-(2-hydroxy-5-methylphenyl)methanone (12) as white crystals. The structure of Product 12 was confirmed by 1H-NMR. Table 1 shows optical characteristics and practical utility of Product 12.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][F:9])(=O)=O.[CH2:12]([O:15][C:16]([N:18]1[C@H:22](/[CH:23]=[CH:24]\[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:21][C@H:20]([S:33][C:34]2[C@H:35]([CH3:51])[C@@H:36]3[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:37]3[C:38]=2[C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].[Cl:52]C(Cl)C>>[Cl-:52].[CH2:12]([O:15][C:16]([N:18]1[C@H:22](/[CH:23]=[CH:24]\[C:25]2[N+:26]3[C:27](=[CH:30][N:31]([CH2:7][CH2:8][F:9])[CH:32]=3)[S:28][CH:29]=2)[CH2:21][C@H:20]([S:33][C:34]2[C@H:35]([CH3:51])[C@@H:36]3[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:37]3[C:38]=2[C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C\c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: O=S(=O)(OCCF)C(F)(F)F
Reactant: CC(Cl)Cl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C\c3csc4cn(CCF)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoroethyl trifluoromethanesulfonate (198.9 mg) is added to a solution of 53.1 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[2(Z)-(imidazo[5,1-b]thiazol-3-yl)ethenyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 38-a), in 0.8 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 24 hr. The solvent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and ion-exchanged using Amberlyst A-26 (Cl− form) (water) to give 63.7 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[2(Z)-(6-(2-fluoroethyl)imidazo[5,1-b]thiazolium-3-yl)ethenyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate chloride as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Yield: 113 %

Procedure:
A mixture of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzaldehyde (1.56 mmol), potassium carbonate (7.8 mmol) and methyl iodide (7.8 mmol), in acetone (25 ml) was stirred for 18 h at 23° under nitrogen. Water (150 ml) was added and the mixture extracted with diethyl ether (3×50 ml). The combined organic extracts were washed with saturated brine, dried (Na2SO4) and evaporated to give the title compound as a yellow solid (0.48 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:18][CH2:19]3)[CH:25]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: NCc1cccc(Br)c1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Temperature: 150 °C
Yield: 83.7 %

Procedure:
To a solution of [(3-bromophenyl)methyl]amine hydrochloric salt (0.556 g, 2.5 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.041 g, 3.25 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), K2CO3 (1.382 g, 10 mmol) and was heated in a microwave at 150° C. for 15 min. The organic layer was separated, dried with a Glas-Col evaporator, then was purified by CombiFlash chromatograph to afford 0.798 g (84%) of the title compound. LC-MS m/z 382 (M+H)+.
Reaction SMILES: [C:1]([C:5]1C=C(C2C=CC=C(C3N=C(C=O)C4C(C=3)=C[C:23]([O:27]C)=[C:22](OC)C=4)C=2)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[BH4-].[Na+].C[C:36]([CH3:38])=[O:37]>C(O)C>[CH3:22][CH2:23][O:27][C:36]([CH3:38])=[O:37].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: CC(C)=O
Reactant: COc1cc2cc(-c3cccc(-c4cccc(C(C)(C)C)c4)c3)nc(C=O)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 1 h
Yield: 52 %

Procedure:
3-(3′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxyisoquinoline-1-carbaldehyde (52 mg) in 4 mL ethanol was treated slowly with NaBH4 (14 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H2O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a yellow oil (27 mg, 52% yield). 1H NMR (400 MHz) (CDCl3) δ 8.24 (t, J=4 Hz, 1H), 8.03-8.01 (m, 1H), 7.88 (s, 1H), 7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.51 (t, J=12 Hz, 1H), 7.45-7.42 (m, 1H), 7.36-7.35 (m, 2H), 7.12 (s, 1H), 6.98 (s, 1H), 5.39 (bs, 1H), 5.12 (s, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.33 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 154.60, 153.16, 151.69, 150.40, 147.62, 142.51, 141.06, 139.64, 133.80, 129.14, 128.55, 127.49, 125.67, 125.47, 124.61, 124.52, 124.46, 119.79, 115.38, 105.87, 101.22, 61.39, 56.13, 34.88, 31.47.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.[Pd]>[CH:1](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])[P:22](=[O:29])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCC/C=C\c1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 3 h
Yield: 30.5 %

Procedure:
Tetraethyl [2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (1.5 g, 2.7 mmol) prepared according to Example 9 was dissolved in ethanol (17 ml), and quinoline (0.043 ml) and 5% palladium on calcium carbonate poisoned with lead (13 mg) was added. A balloon filled with hydrogen was attached to the flask after purging with hydrogen. After stirring for 3 hours the hydrogen pressure was released, and the reaction mixture was filtered through Celite. The filtrate was stripped. 1H NMR showed that only small amount of starting material had been converted to product. The hydrogenation was repeated using twice the amount of catalyst and quinoline for 4.5 hours, then workup as before. 1H NMR showed that a considerable amount of starting material remained. Three additional hydrogenations totaling 47 hours were done before the conversion was greater than 90%. Chromatography on silica eluting with 5% ethanol in petroleum ether (90°-110° C. boiling range) gave the product, 0.459 g, 0.825 mmol, 30.5% yield; 1H NMR (CDCl3) ∂0.88 (t, J=6.7 Hz, 3H), 1.03 to 1.45 (several m, 30H), 2.09 (m, 2H), 3.96 (m, 4H), 4.20 (m, 4H), 5.79 (dt, J=11.5, 7.4 Hz, 1H), 6.37 (d, J=11.4 Hz, 1H), 7.28 (m, 3H), 7.78 (d, J=7.3 Hz, 1H), 8.31 (dd, J=47.8, 28.4 Hz, 1H); CI mass spectrum m/z 557 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: NCc1ccccc1
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11])[CH3:45]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg) and ethyl 3-bromopropanoate (181 mg) in N,N-dimethylacetamide (5 ml) was added cesium carbonate (489 mg), and the mixture was stirred at 70° C. for 15 hr. Ethyl 3-bromopropanoate (181 mg) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:36][CH:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Reactant: CN1CCC(N)CC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(Nc2cccc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)n2)CC1
Temperature: 160 °C
Yield: 43 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.14 mmol) and 1-methyl-4-piperidinamine (30.7 mg, 0.27 mmol) were dissolved in DMSO (0.5 ml) in a microwave vial. DIPEA (0.141 ml) was added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The reaction mixture was diluted with MeOH (0.5 ml) and was purified by Mass Directed Automated Preparative HPLC (Method C). Fractions containing product were blown to dryness and the residue dissolved in methanol. This solution was loaded onto a 1 g aminopropyl column which was eluted with MeOH (1 column volume). The solvent removed under a stream of nitrogen to give the title compound (28 mg) as a cream solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (5 mL), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (153 mg, 1.00 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The crude product was purified by applying onto a C18 Column (water/acetonitrile) to afford 150 mg (41%) of 148 as a white solid. LC-MS (ES, m/z): 355 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.97 (s, 1H), 7.69 (d, 1H), 7.48 (m, 5H), 7.25 (m, 2H), 7.11 (m, 2H), 6.58 (d, 1H), 5.65 (q, 1H), 1.71 (d, 3H)