Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].CS(O[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:13]([O:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O=C1OCCC1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC1CCOC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of α-hydroxybutyrolactone (2.0 g, 19.6 mmol) and linoleyl methane sulfonate (5.4 g, 15.7 mmol) in anhydrous DMF (60 mL), was added cesium carbonate (8.0 g, 24.5 mmol). The solution was stirred overnight under nitrogen at 80° C. Upon completion, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (3×50 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with 10% ethyl acetate in hexanes) to afford 3-((9Z,12Z)-octadeca-9,12-dienyloxy)dihydrofuran-2(3H)-one as a pale yellow oil (3.5 g, 51%).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])=[CH:8][CH:9]=1)[CH3:14])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)C(F)F)cc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.95 g, a white solid) from 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.82 g, 3.46 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:2]>[Ni].CO>[NH2:2][CH2:1][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C#N
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CN

Procedure:
Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (2×) and charged into a parr shaker. A solution of tert-butyl 2-cyano-4,4-difluoro-piperidine-1-carboxylate, 13h, (1.33 g, 5.40 mmol) in methanol (50 mL). The reaction mixture was subject to hydrogenation conditions overnight on the parr shaker (46 PSI). The mixture was filtered through celite and washed thoroughly with CH2Cl2. All volatiles were removed at reduced pressure and the crude material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]([CH2:37][C:38](O)=[O:39])[C:33](=[O:41])[N:32]=1)=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])=[N:32][C:33]1=[O:41])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1ccn(CC(=O)O)c(=O)n1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCCSC)nc1=O
Yield: 84.9 %

Procedure:
The title compound (2.60 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(2-methylthioethoxycarbonyl)-cytosin-1-yl]-acetic acid (1.44 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.89 (t, 0.6H) 8.75 (t, 0.4H) 8.28 (dd, 1H) 8.19 (dd, 1H) 7.90 (d, 0.6H) 7.84 (d, 0.4H) 7.67 (m, 2H) 6.99 (m, 1H) 4.81 (s, 1.2H) 4.62 (s, 0.8H) 4.35 (s, 0.8H) 4.26 (t, 2H) 4.14 (q, 0.8H) 4.06 (s, 1.2H) 4.04 (q, 1.2H) 3.59 (t, 1.2H) 3.42 (m, 2.0H) 3.21 (q, 0.8H) 2.73 (t, 2H) 2.12 (s, 3H) 1.20 (t, 1.2H) 1.15 (t, 1.8H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(O)(=O)C>O1CCOCC1>[CH:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]3[CH:14]=[C:15]([C:20]4[S:24][C:23]([C:25]5([OH:29])[CH2:28][CH2:27][CH2:26]5)=[N:22][CH:21]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)[N:7]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Reactant: Clc1nccc(C2CCC2)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C3CCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
2-Chloro-4-cyclobutylpyrimidine (65 mg, 0.39 mmol), Intermediate 15 (100 mg, 0.39 mmol), and acetic acid (22 μL, 0.39 mmol) were combined in dioxane (1.9 mL) and the mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and directly purified by Combiflash chromatography on silica gel, eluting with ethyl acetate/isohexane to provide 66 mg (0.17 mmol, 44%) of 1-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol. MS ESI: [M+H]+ m/z 393.2. 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.33 (d, J=4.8, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 6.68 (d, J=5.4, 1H), 6.46 (s, 1H), 3.53-3.50 (m, 1H), 2.52-2.46 (m, 2H), 2.33-2.22 (m, 9H), 1.99 (m, 1H), 1.87-1.83 (m, 3H). rhSYK activity=+++
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:30][C:31]([OH:33])=[O:32])([C:14]([N:16]2[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:30][C:31]([O:33][CH3:34])=[O:32])([C:14]([N:16]2[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][C:20]([C:26]([F:28])([F:29])[F:27])=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC(=O)O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
To a solution of the product of Step A (436 mg, 0.84 mmol, 1 eq) in methanol (20 mL) at 0° C. was added trimethylsilyl diazomethane (5 mL of a 2 M solution in hexanes, 10 mmol, 11.9 eq) until the yellow color persisted. The yellow solution was concentrated. Purification by chromatography (24 g column) eluting with 40 to 80% EtOAc/heptane afforded the product of Step B. 1H NMR (CHLOROFORM-d) δ: 8.70 (s, 1H), 7.69 (s, 1H), 6.37 (d, J=5.4 Hz, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.98 (d, J=17.4 Hz, 1H), 4.63-4.83 (m, 3H), 4.07-4.20 (m, 1H), 3.79-3.93 (m, 1H), 3.64 (s, 3H), 3.08-3.19 (m, 2H), 3.04 (d, J=15.9 Hz, 1H), 2.62 (dd, J=13.4, 7.1 Hz, 1H), 2.46 (d, J=15.7 Hz, 1H), 2.01-2.12 (m, 1H), 1.43 (s, 9H). Calculated for C23H28F3N3O5: 506.2 (M+23). found: 506.2.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[K+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH:7]=1>CN(C)C=O.O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])[CH:7]=1
Reactant: ClCCCCCCc1cccnc1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCCCc1cccnc1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A mixture of 4.0 g of potassium cyanide, 0.85 g of potassium iodide and 10.1 g of 6-(3-pyridyl)hexyl chloride in 100 ml of dimethylformamide was heated at 100° C. overnight. The reaction mixture was diluted with 200 ml of water and was extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and were evaporated. The residue was distilled to give 8.1 g (84%) of 3-pyridine heptanenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[C:24]1([C:30]2[CH:39]=[CH:38][C:33]([C:34](=[O:37])[CH2:35]Br)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:35]=1[C:34](=[O:37])[C:33]1[CH:38]=[CH:39][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:31][CH:32]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3ccccc3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-phenylphenacyl bromide.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.CCOC(C(P(OCC)(OCC)=O)F)=O.[CH2:27]([N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH:42]([CH3:44])[CH3:43])=[CH:36][C:37]=2[C:39](=[O:41])[CH3:40])[C:32]([CH3:46])([CH3:45])[CH2:31][CH2:30]1)[CH3:28]>C1COCC1>[CH:42]([C:35]1[CH:34]=[C:33]2[C:38](=[C:37]([C:39](=[O:41])[CH3:40])[CH:36]=1)[N:29]([CH2:27][CH2:28][CH3:1])[CH2:30][CH2:31][C:32]2([CH3:45])[CH3:46])([CH3:43])[CH3:44]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Reactant: [Li]CCCC
Agent: CCOC(=O)C(F)P(=O)(OCC)OCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of a 1.6 M solution of n-butyl lithium in hexane (3.33 ml, 5.33 mmol) and 20 ml of anhydrous THF under argon at −78° C. was slowly added triethyl-2-fluoro-2-phosphonoacetate (1.29 g, 5.33 mmol). After 40 minutes at −78° C., a solution of 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethanone (Intermediate 12, 497 mg, 1.33 mmol) in 4 ml THF was added by cannula. The resulting mixture was stirred at −78° C. for 10 minutes, allowed to warm up to room temperature, and then heated to 80° C. for 12 hours. The reaction was quenched with saturated NH4Cl and product was extracted with ethyl ether. The extract was washed with water, and brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography using 2% ethyl acetate in hexane to yield the title compound as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: N#CCc1ccsc1
Product: N#CC(=C1CCCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cyclohexanone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 68 °C
Yield: 22.6 %

Procedure:
Titanium (IV) chloride (179.4 g, 0.94 mol) was added drop wise to a suspension of zinc powder (123.6 g, 1.89 mol) in THF (1200 ml). This solution was heated at 68° C. for one hour, then cooled to RT before rac-(3R,4S)-1-benzyl-3-(4-fluoro-phenyl)-4-nitro-pyrrolidine (94 g, 0.31 mol) in THF (400 ml) was added. The reaction mixture was then stirred at reflux over night. The reaction was cooled to RT, diluted with 3000 ml of Et2O, washed with an aqueous solution of NaHCO3 and the organic phases were dried over Na2SO4. Flash chromatography (SiO2, CH2Cl2/MeOH, 9:1) yielded 18.9 g (22%) of rac-(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylamine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C[C@H](NC)[C@@H](O)C1C=CC=CC=1.O.Cl>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of racemic 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (100 g; 0.37M) in ethyl acetate (1.5L) and methanol (75mL) was added solid (1S,2S)-(+)-pseudoephedrine (61.1 g; 0.37M). With efficient agitation the mixture was warmed to reflux, held for 30 minutes and slowly cooled to 25° C. After a minimum of 2 h the slurry was filtered and washed with ethyl acetate to yield enriched diastereomeric salt (88.6 g; 0.20M; 55%; diastereomeric ratio 80:20, as determined by HPLC). The enriched salt was slurried in 3% methanolic ethyl acetate (2.74 L),warmed to reflux,held 30 minutes,cooled to 25 C. slowly, held 2 h and then filtered and washed with ethyl acetate to provide further enriched salt (70 g; 0.16M; 79%; diastereomeric ratio 95:5, as determined by HPLC). Treatment of the further enriched salt with 5% methanolic ethyl acetate using the same procedure yielded highly enriched salt (60.0 g; 0.14M; 85%; diastereomeric ratio 99:1, as determined by HPLC). This salt (60 g; 0.14M) was added to water (1L) and the consequent suspension acidified to pH 2-3 with concentrated hydrochloric acid (15 mL) and then extracted with diethyl ether (3×500 mL). The combined organic extracts were washed with brine,dried (MgSO4) and evaporated to an oil. Hexane was added and evaporated to afford enantiomerically enriched acid (36 g; 0.13M; 98% recovery; enantiomeric ratio 99:1, as determined by HPLC) as a white solid. Crystallisation from a mixture of hexane (360 mL) and cyclohexane (720 mL) afforded enantiomerically pure (9S,10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracene-carboxylic acid as a white solid (30 g, 0.11 mol, 81%) mp 172°-173° C. αD =+101° (c=2.0,CHCl3).
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([NH:36][S:37]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)(=[O:39])=[O:38])[CH:35]=1)[NH:32][C:31]([C:45](O)=[O:46])=[CH:30]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([NH:36][S:37]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)(=[O:39])=[O:38])[CH:35]=1)[NH:32][C:31]([C:45]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:46])=[CH:30]2
Reactant: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.32 g), triethylamine (0.126 mL) and N,N-dimethylformamide (10 mL) were added 5-methoxy-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (265 mg), 1H-1,2,3-benzotriazol-1-ol (0.15 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (188 mg) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from dichloromethane-hexane to give the title compound (465 mg, yield 95%) as pale-yellow crystals. melting point 128-129° C.
Reaction SMILES: [CH2:1]([O:4][P:5]([CH2:11][C:12]([OH:14])=O)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[CH2:8]([O:7][P:5]([CH2:11][C:12]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:32]([O:31][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:38])=[O:14])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C=CCOP(=O)(CC(=O)O)OCC=C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: C=CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)OCC=C
Reaction time: 0.75 h

Procedure:
[Bis(2-propenyloxy)phosphinyl]acetic acid (7.0 g., 0.032 mol.) is dissolved in 200 ml. of acetonitrile and stirred in an ice bath under a drying tube. 1,1'-Carbonyldiimidazole (5.5 g., 0.032 mol.) is then added and the mixture is stirred for 45 minutes. L-Proline t-butyl ester (5.5 g., 0.032 mol.) is then added, the ice bath removed, and the mixture stirred overnight. The solution is then evaporated in vacuo and the residue taken up in ethyl acetate and washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, then dried (MgSO4) and evaporated to a viscous liquid (10.7 g., 89%). The product [Bis(2-propenyloxy)phosphinyl]acetyl-L-proline, tert-butyl ester is substantially pure by tlc (Rf =0.35, silica gel, ethyl acetate; several trace impurities).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C@@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:22][C@@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: CC[C@H](N)CC#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC[C@@H](CC#N)NC(=O)[C@@H](C(C)C)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 25 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), (S)-3-aminopentanenitrile (3.19 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.1 mg, 24.6%). 1H NMR (400 MHz, CD3OD) δ 0.93 (d, J=6.57 Hz, 3 H) 0.97 (t, J=7.33 Hz, 3 H) 1.07 (d, J=6.57 Hz, 3 H) 1.51-1.69 (m, 2 H) 2.44-2.58 (m, 2 H) 2.58-2.72 (m, 1 H) 4.07 (br. s., 1 H) 4.86-4.97 (m, 1 H) 5.08 (d, J=11.12 Hz, 1 H) 5.31 (d, J=19.71 Hz, 1 H) 7.84 (s, 1 H) 8.23 (s, 1 H). [M+H] calc'd for C19H22ClN5O2, 388; found, 388.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:11][C:12]([F:39])([F:38])[C:13]([N:15]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][N:28]=1)[CH2:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:14]>>[F:38][C:12]([F:11])([F:39])[C:13]([N:15]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][N:28]=1)[CH2:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:21][CH2:20]1)=[O:14]
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)NC2CCNCC2)C(=O)C(F)(F)F)c1
Reactant: COc1ccccc1C=O
Product: CCOC(=O)c1ccnc(CN(CC(=O)NC2CCN(Cc3ccccc3OC)CC2)C(=O)C(F)(F)F)c1

Procedure:
Prepared by General Procedure A from 2-methoxybenzaldehyde and ethyl 2-[(2,2,2-trifluoro-N-{[(piperidin-4-yl)carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate. 1H-NMR (300 MHz, CDCl3): δ 8.75 & 8.71 (2d, 1H; rotamer), 7.91-7.78 (m, 2H), 7.36 (m, 1H), 7.25 (m, 1H), 7.99-7.86 (m, 2H), 4.95 & 4.72 (2s, 2H, rotamer), 4.45 (q, 2H), 4.30 & 4.08 (2s, 2H; rotamer), 3.83 (m, 4H), 3.60 (m, 2H) 2.95 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=O)[CH2:18][CH2:17]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: Cn1c(OC2CCN(c3ccccc3C=O)CC2)nc(-c2ccncn2)cc1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(OC2CCN(c3ccccc3CN3CCOCC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzaldehyde (80 mg, 0.20 mmol), morpholine (27 mg 0.31 mmol) and acetic acid (one drop) in 1,2-dichloroethane (1.0 ml) was added sodium triacetoxyborohydride (110 mg, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=95/5) to afford 1-methyl-2-[1-(2-morpholin-4-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (63 mg, 0.14 mmol, 67%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:29][CH2:30][CH2:31][OH:32])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 34 %

Procedure:
According to Example 34, the compound (147 mg) produced in Example 70 was reacted with 3-bromopropanol (42 μl) to obtain the title compound (57 mg; 34%).