Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[N:15])[C:7]=1[O:19][CH3:20])(C)(C)C.FC(F)(F)C(O)=O.[Cl:28]CCl>>[Cl:28][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[N:15])[C:7]=1[O:19][CH3:20]
Reactant: COc1c(C(C#N)C2CC2)ncc(F)c1OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C#N)C2CC2)ncc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of (4-tert-butoxy-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetonitrile (0.9 g, 3 mmol) [Example 8] and trifluoroacetic acid (2 mL) in dichloromethane was stirred at room temperature for 25 minutes. The solvent was removed in vacuo and the oily residue dissolved in 15 mL of dichloromethane and 2 mL of dimethylformamide. The resulting solution was cooled in an ice-bath and treated dropwise with phosphoryl chloride (2.4 mL). The solution was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured onto ice and extracted with dichloromethane (2×20 mL). The combined extracts were washed with water, saturated sodium bicarbonate, water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexane (1:4) to provide the title compound (0.4 g, 60%). 1H NMR (400 MHz, CDCl3) δ 8.32 (s. 1H), 4.05 (s, 3H), 3.77 (d, 1H), 1.58-1.49 (m 1H), 0.80-0.71 (m, 1H), 0.68-0.55 (m, 2H), 0.52-0.43 (m, 1H). MSCI: m/z=241 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]1>>[C:10]([CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:3]1=[O:13])([OH:12])=[O:11]
Reactant: CCOC(=O)C(=O)CCc1c[nH]c2ccccc12
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Product: CCOC(=O)C(CCc1c[nH]c2ccccc12)N[C@H]1CCCCN(CC(=O)O)C1=O

Procedure:
In the same manner react the 3-(S)-amino-1-carboxymethylperhydroazepin-2-one with ethyl 4-(3-indolyl)-2-oxobutyrate to obtain 1-carboxymethyl-3-(S)-[(1-ethoxycarbonyl-3-(3-indolyl)propyl)amino]perhydroazepin-2-one. Standard alkaline hydrolysis (as in Example 3) of this material yields 1-carboxymethyl-3-(s)-[(1-carboxy-3-(3-indolyl)propyl)amino]perhydroazepin-2-one. Alternatively, esterification in HCl-ethanol affords 1-ethoxycarbonylmethyl-3-(S)-1-(1-ethoxycarbonyl-3-(3-indolyl)lpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38](C4C(C#N)=CSC=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].OC1C=CC([N:55]2[CH2:60][CH2:59][N:58]([C:61](=[O:63])[CH3:62])[CH2:57][CH2:56]2)=CC=1>>[C:61]([N:58]1[CH2:59][CH2:60][N:55]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][C:25]3[S:24][C:23]([N:20]4[CH2:19][CH2:18][C:17]5[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]6[S:1][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=7[N:3]=6)[CH:14]=[CH:15][CH:16]=5)[CH2:21]4)=[N:27][C:26]=3[C:28]([OH:30])=[O:29])=[CH:40][CH:39]=2)[CH2:56][CH2:57]1)(=[O:63])[CH3:62]
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: CC(=O)N1CCN(c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 61 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.36 Hz, 1H), 7.78 (d, J=8.29 Hz, 1H), 7.66 (d, J=7.06 Hz, 1H), 7.33-7.49 (m, 4H), 6.90-6.92 (m, 2H), 6.80-6.82 (m, 2H), 4.82 (s, 2H), 3.90 (t, J=6.29 Hz, 2H), 3.71 (t, J=6.29 Hz, 2H), 3.53-3.56 (m, 2H), 3.13-3.17 (m, 2H), 3.02 (t, J=5.37 Hz, 4H), 2.94-2.96 (m, 2H), 2.02 (s, 3H), 1.92-1.99 (m, 2H). ESI (+)/MS: 697 (M+H)+.
Reaction SMILES: [H-].[Na+].[S:3]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(OCC)(=O)C>CN(C)C=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][N:13]([S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:4])=[O:5])[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N(CCCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To 0.892 g (0.0372 mol) of sodium hydride resulting from washing 1.11-1.12 g of an 80% oil dispersion with hexanes under nitrogen was added 26 mL of dry dimethylformamide. To the stirred mixture was added dropwise over a 21 min period through an addition funnel a solution of 10.00 g (0.0313 mol) of ethyl 4-tosylaminobenzoate (Baker, B. R.; Santi, D. V.; Shapiro, H. S. J. Pharm. Sci.. 1964, 53, 1317) in 52 mL of dry dimethylformamide and then 3 mL of rinse dimethylformamide. When the stirred mixture had cooled to room temperature, to it was added at one time 27.74 g (0.128 mol) of 1,4-dibromobutane. The stirred mixture was heated for 4 h 45 min with a bath maintained near 80° C. and was allowed to cool to room temperature and stand under nitrogen overnight. The mixture was concentrated under vacuum at 40° C. to an oil/solid mixture; yield, 22.37 g. To the mixture was added 100 mL of ethyl acetate, and undissolved solid was collected by suction filtration. The filtrate was purified by a flash chromatography column consisting of 700 g of Silica Gel 60 with 6:1 hexane/ethyl acetate as the eluting solvent. The major fractions of clean product were combined and concentrated under vacuum to a colorless oil that solidified to a white solid; yield, 10.91 g (77%): NMR (Me2SOd6) δ 1.29 (t, 3H), 1.3-1.5 (m, 2H), 1.7-1.9 (m, 2H), 2.37 (s, 3H), 3.47 (t, 2H), 3.60 (t, 2H), 4.29 (q, 2H), 7.23 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.91 (d, 2H). An additional 5% yield was obtained from later column fractions.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([C:18]2[N:23]=[C:22]([N:24]3[C@@H:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][O:26][C:25]3=[O:32])[CH:21]=[CH:20][N:19]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)(O)[O-].[Na+].N#N>O1CCOCC1.CCOC(C)=O>[CH:29]([C@H:28]1[CH2:27][O:26][C:25](=[O:32])[N:24]1[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:23]=1)([CH3:31])[CH3:30]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(Br)cc2)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
In a 5 mL microwave vial a solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate (101 mg, 0.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL) was bubbled N2 for 3 min then Cl2Pd(dppf)CH2Cl2 (16 mg, 0.02 mmol) was added. The capped tube was heated to 100° C. for 16 h. After cooling the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (50 mg, 49.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].[CH2:37]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH3:37])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C=O
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
(Method C) 4-(6-Chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (90 mg) was dissolved in a 37% aqueous solution of formaldehyde (2.9 ml) and formic acid (1.4 ml) and refluxed for 15 hours. The reaction mixture was cooled, made alkaline by adding a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (38 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88%): 1H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH:11]=1)[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCCNC(=O)c1ccccc1)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 10.1 g benzoyl chloride in 15 ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0° and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2 N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title compound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73°-74° after crystallization from methanol/water/ethyl acetate (1:1:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[F:29])[N:16]=1.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[F:29])[N:16]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: Brc1ccc([C@H]2CCCNC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC[C@H](c3ccc(Br)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of (3R)-3-(4-bromophenyl)piperidine obtained in Reference Example 15 (0.21 g, 0.9 mmol), 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidine-4-one (0.21 g, 0.9 mmol), and triethylamine (0.30 g, 3.0 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford 2-((3R)-3-(4-bromophenyl)piperidin-1-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidine-4-one (0.24 g, 62%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:31]1.C(OCC)(=O)C>C1COCC1>[C:6]([C:5]1[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:10][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31]2)=[N:3][C:4]=1[O:26][CH2:27][CH2:28][CH3:29])(=[O:7])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCCOc1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide (500 mg, 1.194 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (956 mg, 4.77 mmol) in THF (3 mL) was sealed in a vial and heated at 100° C. for 24 hrs. The reaction mixture was dissolved into ethyl acetate, washed with water, and concentrated. The solid material was chromatographed on an ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH:NH4OH)/CH2Cl2 gradient (10-100%) to give 530 mg of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)-6-propoxypyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=583.46.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[Br:25])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1Br
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1Br)S(=O)(=O)c1ccc(OC)cc1
Yield: 73.4 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 mmol) of 2-bromobenzyl bromide provided 0.761 g (73%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 518.1(M+H).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][S:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[O:12]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:13]#[N:14])=[CH:3][CH:4]=2)[CH2:9][S:8][CH2:7]1
Reactant: O=C1CSCc2cc(I)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CSCC2=O
Temperature: 95 °C

Procedure:
To a solution of 7-iodo-isothiochroman-4-one (290 mg, 1.0 mmol) in DMF (5 mL) is added Zn(CN)2 (117 mg, 1.0 mmol) and Pd(PPh3)4 (124 mg, 0.1 mmol). The reaction is then heated to 95° C. for 3 hours, at which time it is cooled to room temperature and concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:10 to 3:10) to furnish 4-oxo-isothiochroman-7-carbonitrile; MS: (ESI) m/z 188.2 (M−H)−.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[OH:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1)[O:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: OCc1cc(O)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a stirred mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (1.504 g, 3.85 mmol) and (5-hydroxy-1,3-phenylene)dimethanol (21) (0.54 g, 3.50 mmol) in anhydrous DMF (7.8 ml) was added potassium carbonate (0.726 g, 5.25 mmol). The reaction was stirred at room temperature for 18 hours at 75° C. The mixture was allowed to cool to room temperature, quenched with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% MeOH/CH2Cl2) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b)(340 mg, 26%). 1H NMR (400 Hz, CDCl3): δ 6.83 (s, 1H), 6.75 (s, 2H), 4.52 (s, 4H), 4.05 (t, J=4.8 Hz, 2H), 3.79 (t, J=4.8 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.70-3.56 (m, 8H), 3.26 (s, 2H), 2.55 (t, J=6.4 Hz, 2H); 13C NMR (400 Hz, CDCl3): δ 172.31, 159.1, 143.0, 117.7, 112.1, 70.8, 70.7, 70.5, 70.4, 69.8, 67.5, 66.6, 64.7, 51.8, 34.9; MS (m/z), found 395.2 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=O)[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>N1C=CC=CC=1>[OH:8][C:6]1[N:5]=[C:4]([SH:11])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(S)nc(O)n1
Temperature: 50 °C
Yield: 136.5 %

Procedure:
6-Methyluracil (25.0 g) was suspended in 1 liter of distilled pyridine with stirring and heated at 50° C. into solution. Phosphorus pentasulfide (12.6 g) was then added, and the mixture was refluxed for 20 hours. The solution was concentrated under reduced pressure, then the residue was refluxed with 500 ml of ethanol for one hour. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol, affording 5.5 g of the objective compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3].OS(O)(=O)=O.O>CC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10](=[O:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)N1CC(=O)C[C@H]1C(=O)O
Reaction time: 0.75 h

Procedure:
The alloc protected hydroxy proline (13) (18 g, 83.72 mmol) was dissolved in acetone (1260 ml). The Jone's reagent [Cro3:26.6 g/H2SO4:21.3 ml and the solution was made up to 100 ml with water] (87 ml) was added over 10 min. The resulting mixture was stirred for a further 45 minutes when the excess oxidant was quenched with methanol (15 ml). The green chromium salts were removed by filtration through Celite and the filtrate was diluted in CHCl3(1000 ml). The combined organic phase was washed with brine several times (5×500 ml) and the solvent was evaporated under reduced pressure, to yield the ketone 14 which was used without any purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[N:16]1[CH:1]([CH:3]2[CH2:8][O:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:2]=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOCC1C1N=NN=N1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of tert-butyl 3-cyanomorpholine-4-carboxylate (5 g, 23.6 mmol, the compound was synthesized according to the procedure as described in J. Med. Chem. 2007, 50(20), 4953-4975), sodium azide (1.53 g, 23.6 mmol) and ammonium chloride (0.63 g, 11.8 mmol) in anhydrous DMF (30 mL) was stirred at 100° C. for 72 hours and cooled to 25° C. The reaction mixture was diluted with EtOAc (300 mL), then washed with brine (150 mL×6). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=1/1) to give the title compound as a brownish solid (2.5 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([NH2:36])[C@H:32]([F:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[C@H:32]([F:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@H](F)C1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A stirred solution of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (173 mg, 0.513 mmol), trans-4-Amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.513 mmol), diisopropylethylamine (211 μl, 1.16 mmol) in propan-2-ol (2 ml) were stirred at 82° C. overnight then cooled to room temperature. The precipitated solid was then collected by filtration to yield 231 mg (87%) of trans-4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester that was used without further purification. LCMS (Method F): RT=1.22 min, m+H=520.0; 1H NMR (400 MHz, DMSO) 6=8.91 (s, 2H), 8.13 (d, J=7.4, 2H), 7.86-7.83 (m, 1H), 7.81-7.72 (m, 1H), 7.65 (s, 2H), 7.20-7.15 (m, 1H), 4.88-4.69 (m, 1H), 4.57-4.41 (m, 1H), 4.33 (d, J=4.2, 1H), 4.23-4.02 (m, 1H), 3.26-3.02 (m, 2H), 2.08-1.96 (m, 1H), 1.81-1.69 (m, 1H), 1.42 (s, 9H).