Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](Cl)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]>N1C=CC=CC=1.O>[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a stirred solution of piperidine (0.36 mL, 3.6 mmol) in pyridine (50 mL) was added 2-(3-(2-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (1.53 g, 3.6 mmol), and the resulting solution stirred at room temperature for 18 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated copper sulfate solution (×3), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester (1.23 g, 2.60 mmol, 72%) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([CH3:16])([CH2:14]O)[CH3:13]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:10][CH2:11][C:12]([CH3:16])([CH3:14])[CH2:13][O:7]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (100 g, 0.54 mole), neopentyl glycol (115 g, 1.10 mole), and p-toluenesulfonic acid (800 mg, 4 mmole) in benzene (800 mL) was heated to reflux using a Dean Stark apparatus for 16h. The reaction mixture was cooled to room temperature and most of the benzene was removed. The residue was partitioned between ethyl acetate (500 mL) and cold water (150 mL). The organic phase was washed with water (2×150 mL) and brine (1×150 mL), then dried (Na2SO4) and concentrated to give the desired product (136 g, 93%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1>C(O)CCC.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:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[C:30]([CH3:32])[CH:31]=[C:26]([CH3:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: Cc1cc(C)cc(S)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1cc(C)cc(Sc2ccc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3c2)c1
Temperature: 110 °C
Yield: 65 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,5-dimethyl-thiophenol (180 mg, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.8:0.2→8:2) to give 380 mg of the title compound as colourless oil (yield 65%). 1H NMR (CDCl3) δ 8.05-8.10 (m, 1H), 7.80-7.85 (m. 1H), 7.60-7.75 (m, 1H), 7.17-7.25 (m, 1H), 7.10 (bs, 2H), 7.00 (bs, 1H), 3.40-3.50 (m, 4H), 3.10-3.20 (m, 4H), 2.25 (bs, 6H), 1.50 (s, 9H).
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22](=[S:25])[NH:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:27](N(C(C)C)CC)(C)C.O1CCCC1>C(O)C>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22]([S:25][CH3:27])=[N:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:5]
Reactant: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of iodomethane (0.7 mL, 11 mmoles), 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (2.5 g, 7 mmoles) and diisopropylethylamine (1.5 mL, 8.5 mmoles) in 25 mL of ethanol with enough tetrahydrofuran added to effect solution is stirred overnight under N2 at room temperature, then stirred into 250 mL of ice water. The precipitate is filtered off, rinsed with water, dried, and recrystallized from ethyl acetate to afford the product (1.6 g) 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one, mp 177°-178° C., retaining 0.25 equivalent of solvent of recrystallization.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=[CH:3]1.[C:12]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:8][C:7]1[N:2]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:32][CH:33]=2)[CH:3]=[N:4][C:5]2=[N:11][CH:10]=[CH:9][C:6]=12
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Reactant: Oc1c2ccnc-2ncn1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC
Reaction time: 2 h

Procedure:
To a mixture of 10 mmol of 3-iodo-4-hydroxypyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(4-ethynylbenzoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis(triphenylphosphine) palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride. There is obtained dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which is purified by chromatography over silica, m.p. 160° C. (dec.). 1NMR (d6 -DMSO) δ1.98-2.15 (m, 2H), 2.45 (t, J=7.5 Hz, 2H), 3.57 (s, 3H), 3.64 (s, 3H), 4.40-4.45 (m, 1H), 7.51 ((d, J=2.5 Hz, 1H), 7.55 (d, J=8.2 Hz), 2H), 7.87 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 11.97 ((d, J=3.7 Hz, 1H), 12.31 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:6][C:5]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>CO>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:5]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:4]([CH:9]=1)[C:3]([OH:37])=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Yield: 99.8 %

Procedure:
A suspension of 2.4 g (4.7 mmol) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid methyl ester in 70 ml of methanol and 23 ml (23 mmol) of 1.0N NaOH was stirred at reflux for 4 hours when a clear solution was obtained. The solvent was removed at reduced pressure and the residue was treated with water, acidified to pH 1 with 3N HCl and the product was extracted with chloroform. The dried extract was concentrated to a solid which was recrystallized from ether-hexane to give 2.33 g (99% yield, mp 80°-81°) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11][CH:10]=1)([OH:8])=[O:7].N>S(=O)(=O)(O)O>[C:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:1]([O-:4])=[O:2])[CH:12]=[N:11][CH:10]=1)([OH:8])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cncc2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cncc2cccc([N+](=O)[O-])c12
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A nitrating mixture obtained by dissolving potassium nitrate (94 g.) in concentrated sulphuric acid (d= 1.83) (750 cc.) is added dropwise, over the course of 1 hour, to a solution of 4-carboxy-isoquinoline (146.8 g.) in concentrated sulphuric acid (d= 1.83) (880 cc.). The solution obtained is kept at a temperature of about 20° C. for 16 hours and is then poured onto ice (18 kg.). Ammonia (11 N) (5.5 liters) is added gradually, whilst stirring and keeping the temperature of the mixture at between 15° and 20° C. The yellow precipitate which has appeared is filtered off, washed with water (800 cc. in total) and then dried. 4-Carboxy-5-nitro-isoquinoline (144 g.) melting at 285° is thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[CH:59]1([C:62](Cl)=[O:63])[CH2:61][CH2:60]1>ClCCl>[Br:13][C:11]1[C:10]([CH2:14][O:15][CH:16]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][CH2:2][NH:1][C:62]([CH:59]1[CH2:61][CH2:60]1)=[O:63])[CH:5]=[C:6]2[CH3:52]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(=O)C4CC4)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of 0.400 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 76b) in 2.5 ml of dichloromethane is admixed successively with 0.74 ml of pyridine and 0.43 ml of cyclopropanecarbonyl chloride, and stirred at room temperature over 30 minutes. The reaction mixture is poured onto water (50 ml) and extracted with dichloromethane (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.[NH2:11][C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:20][C:12]1([N:11]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: O=C1OC(=O)c2cscc21
Reactant: CC1(N)CCC(=O)NC1=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cscc3C2=O)CCC(=O)NC1=O
Yield: 79.1 %

Procedure:
1.54 g of thieno(3,4-c)furan-1,3-dione was dissolved in 20 mL of anhydrous THF, and 1.42 g of 3-amino-3-methylpiperidin-2,6-dione was added. The reaction mixture was allowed to react at room temperature for 4 h, and 2 g of CDI and a catalytic quantity of DMAP were added. The reaction mixture was allowed to reflux for 6 h during which time a solid precipitated. The reaction solution was cooled and filtered to obtain a white solid (2.2 g). MS (m/z): 278 (M)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].CN(C=O)C.Cl[CH2:41][C:42](=[O:44])[CH3:43]>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:26]=1)[C:6]1[CH:7]=[C:8]([C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:41][C:42](=[O:44])[CH3:43])=[CH:15][CH:14]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 0.33 h

Procedure:
A vial was charged with (S)-2-amino-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (192.0 mg, 554 μmol), cesium carbonate (271 mg, 832 μmol), and potassium iodide (92.0 mg, 554 μmol). DMF (2217 μl, 554 μmol) was added, the vial was sonicated for about 30 seconds, and the mixture was stirred vigorously for 20 min, at which time some white solid still remained. The vial was cooled in an ice-bath for 10 min, and to it chloroacetone (48.6 μl, 610 μmol) was added dropwise. The cooling bath was removed after 5 h, and the mixture was stirred for an additional 10 h. The reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 2.5%-10% MeOH/DCM to afford (S)-1-(2-amino-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)propan-2-one as a white solid. MS m/z=403.2 [M+H]+. Calc'd for C22H19N4O4: 403.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][C:9]1(C(OC)=O)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[C-]#N.[Na+]>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: COC(=O)C1(CCC2OCCCO2)CCCCC1=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1CCCCC1CCC1OCCCO1

Procedure:
The product of Example 108 is reacted with sodium cyanide in DMSO at 160° C. by the method of Example 103 to generate the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:30])[CH2:15][CH:16]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
A solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (100 mg, 0.25 mmol) and 2-chlorobenzoxazole (38.3 mg, 0.25 mmol) in toluene (1.0 mL) was heated at reflux for 16 h. Solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, solvent was again removed under reduced pressure, and the residue was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). A 1 N aqueous solution of sodium hydroxide (0.77 mL, 0.77 mmol) was added, and the mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]-4-oxo-2-(2-phenylethyl)butanoic acid (40 mg, 33% yield). LC-MS ret. time 4.14 min, m/z 519.5 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.82-1.90 (m, 2H), 2.68 (m, 2H), 2.80-2.85 (m, 1H), 3.16 (dd, 1H), 3.41 (m, 1H), 7.10-7.30 (m, 8H), 7.48 (t, 2H), 7.78-7.86 (m, 4H), 7.89 (d, 2H), 8.02 (d, 2H), 10.83 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:34](OCC)[O:35]CC)=[C:5]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:34]=[O:35])=[C:5]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 102.4 %

Procedure:
Starting from a mixture of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (1.24 g) in acetone (12 ml) and 6N hydrochloric acid (1.2 ml) was obtained an oil (1.1 g) of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate, in a substantially similar manner to that of Example 2-(6).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:6]=[C:7]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=2)[S:8][C:9]=1[C:10]([OH:12])=O)=[O:4].C1C=C[C:29]2N(O)N=[N:32][C:30]=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C(N)C>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([NH:32][C:10]([C:9]1[S:8][C:7]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=2)=[N:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:25])=[O:4])=[O:12])[CH3:29]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)O)s2)cn1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)NCC)s2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.4 %

Procedure:
To a stirred solution of 4-[(dimethylamino)carbonyl]-2-(6-{[(ethylamino)carbonyl]amino}pyridin-3-yl)-1,3-thiazole-5-carboxylic acid (Example 53, 0.12 g, 3.3 mmol) in dry dimethylformamide (2 mL), HOBT (0.101 g, 6.6 mmol), N-methylmorpholine (0.108 mL, 9.9 mmol), EDC hydrochloride (0.126 g, 6.6 mmol), ethylamine (2 M in tetrahydrofuran, 0.13 mL, 3.3 mmol) were added at 0° C. and stirred overnight at room temperature. After completion of the reaction, reaction mixture was diluted with ethyl acetate (20 mL) and was washed with water (1×20 mL), 2 N hydrochloric acid (1×20 mL), and sodium bicarbonate solution (1×20 mL). The organic layer was dried, concentrated under reduced pressure and the residue was triturated with acetonitrile (1 mL). The obtained solid was filtered and dried to afford 0.018 g (20%) of the title compound as white solid. MS (APCI): 391 (M+H+) for C18H23N5O3S; NMR: δ 1.06 (t, 3H), 2.86 (s, 3H), 2.99 (s, 3H), 3.17 (q, 4H), 7.60 (d, 1H), 7.76 (br s, 1H), 8.22 (dd, 1H), 8.72 (br t, 1H), 8.78 (s, 1H), 9.52 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:27][C@H:26]([O:28][CH3:29])[C@@H:25]([NH2:30])[CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][C@@H:25]2[C@@H:26]([O:28][CH3:29])[CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCN1C[C@H](OC)[C@@H](N)C1
Product: CCN1C[C@H](NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)[C@@H](OC)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (3S,4S)-1-ethyl-4-methoxypyrrolidin-3-amine (14.4 mg, 0.1 mmol). The title compound was obtained as a solid (7.9 mg, 17% yield). MS m/z: 476.86, 478.86 [M+H]+.
Reaction SMILES: B(O)(O)C1C=CC(F)=NC=1.O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57](OC)=[O:58])=[N:54][CH:55]=3)=[CH:46][CH:45]=2)[CH2:37][CH2:36]1.FC1N=CC(C2C=CC(OCCN3CCOCC3)=CC=2)=CC=1.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>>[O:35]1[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][O:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:51]=[CH:52][C:53]([CH2:56][C:57]([NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)=[O:58])=[N:54][CH:55]=3)=[CH:48][CH:49]=2)[CH2:39][CH2:40]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: OB(O)c1ccc(F)nc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In one aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of: reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:25].[Na+].C(#N)C>C(Cl)(Cl)(Cl)Cl.O.C(Cl)Cl.[Ru](Cl)(Cl)Cl>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([OH:25])=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)N1CCC(CO)CC1Cc1ccc(C(C)(C)C)cc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of methyl 2-(4-tert-butylbenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.9 g, 9.08 mmol) in carbon tetrachloride (18 mL) was added sodium periodate (5.83 g, 27.24 mmol) and water (27 mL). Acetonitrile (18 mL) was added to this mixture, followed by ruthenium(III) chloride (0.041 g, 0.20 mmol). The resulting biphasic mixture was stirred vigorously at room temperature for 2 h. The reaction mixture was diluted with water and DCM, the aqueous layer was extracted with DCM (×3). The combined organic layers were dried over MgSO4 and evaporated to give the product as an oil (3.0 g, 98%) MS m/z 332 (M−H)−.