Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)[S:32][C:33]=1[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.CC([O-])(C)C.[K+].O>C(Cl)(Cl)Cl.C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:49]=[CH:48][C:45](/[CH:46]=[CH:2]/[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:44][CH:43]=2)[S:32][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(-c2sc(-c3ccc(C=O)cc3)cc2Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2sc(-c3ccc(/C=C/c4ccccc4)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
A mixture of benzyltriphenylphosphonium bromide (23.7 g, 54.7 mmol) and (62) (17 g, 45.5 mmol) was dispersed in chloroform (300 mL) and stirred at RT under argon atmosphere for 15 min. A solution of t-BuOK (10.3 g, 91 mmol) in anhydrous THF (80 mL) was added dropwise. The reaction mixture was stirred at RT for 3 h. Then water was added, followed by extraction with chloroform. The combined extracts were dried over anhydrous MgSO4 and solvent evaporated to half of its initial volume by rotary evaporation; the resulting light yellow precipitation was filtered and dried (9.63 g; 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1cc(C2CC2)no1
Product: O=C(NCc1cc(C2CC2)no1)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and 3-cyclopropyl-5-isoxazolemethanamine (CAN 851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 99.6%, 452.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][S:38][C:33]1[N:32]=[C:31]([NH2:30])[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:34]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1nc(N)cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)n1
Yield: 27.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:19][C:18]4([CH2:28][CH2:27][C:22]5(OCC[O:23]5)[CH2:21][CH2:20]4)[O:17][C:16]3=[O:29])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]3[CH2:19][C:18]4([CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]4)[O:17][C:16]3=[O:29])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCC3(CC2)OCCO3)CN1Cc1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CN(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)O2
Temperature: 60 °C
Yield: 78.6 %

Procedure:
3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one (50 mg, 0.126 mmol) and 10% HCl (2 mL) were mixed in THF. The reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution until PH=8. THF was removed under reduced pressure, and the aqueous phase was extracted with DCM (3×3 mL). The combined organic phases were dried over anhydrous sodium sulfate and condensed in vacuo. The residue was purified on silica gel eluting with 10˜35% ethyl acetate in hexane to give the product as a white solid (35 mg, 78%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.57 (m, 4H), 7.36 (d, 2H), 7.14 (t, 2H), 4.84 (s, 2H), 3.96 (m, 2H), 3.18 (s, 2H), 2.01 (m, 4H), 1.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]=[N:15][NH:14][C:13](=[O:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CS(C)=O.BrN1C(=O)CCC1=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[N:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2C=NNC(=O)C2)cc1OC
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one (288 mg) was suspended in a mixed solvent of dimethyl sulfoxide (3 ml) and water (0.1 ml), to which N-bromosuccinimide (438 mg) was added under cooling on ice. After the addition was complete, the reaction temperature was raised to room temperature and stirred for 2 hours. The reaction mixture was poured into an ice-cold water and the deposit was filtered. The residue was purified with flash chromatography (SiO2: eluted with ethyl acetate) to obtain the title compound (185 mg, yield 64.7%).
Reaction SMILES: C(Cl)Cl.Br[C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[S:13][C:12]([C:18]4[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=4)=[N:11][C:10]=3[C:9]=2[CH:26]=1.[Br-].[CH:28]1([Zn+])[CH2:32][CH2:31][CH2:30][CH2:29]1>CC(N(C)C)=O.CCOC(C)=O.Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]I>[CH:28]1([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [Zn+]C1CCCC1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: [Cu]I
Agent: [Fe+2]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCCC3)cc1-2
Reaction time: 0.17 h
Yield: 10 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (1:1) (8.45 mg, 0.0104 mmol), copper(I) iodide (3.94 mg, 0.0207 mmol) and 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.081 g, 0.21 mmol) were mixed in DMA (2.5 mL) and stirred under argon for 10 min and cyclopentylzinc bromide (0.5 M in THF, 0.42 mL, 0.21 mmol) was transferred to this mixture via syringe. The reaction was carried out at 80° C. Subsequently cooled to room temp. and diluted with EtOAc and 1 N HCl and worked up. Purified via rp-HPLC to provide 251 (8 mg, 10% yield). LC/MS (ESI+): m/z 381 (M+H). 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=2.0, 1H), 8.08 (d, J=16.1, 1H), 7.16 (dd, J=8.2, 2.1, 1H), 6.98 (d, J=8.2, 1H), 5.83 (dt, J=13.2, 6.7, 1H), 4.34 (t, J=5.0, 2H), 3.42 (t, J=5.0, 2H), 3.05 (p, J=8.3, 1H), 2.19-1.98 (m, 2H), 1.73 (ddd, J=11.4, 6.9, 3.8, 4H), 1.61-1.48 (m, 8H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16](Cl)=[N:17][C:5]1=2)[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:25])=[CH:22][C:21]=3[O:36][CH3:37])=[N:17][C:5]1=2)[CH:2]=[CH2:3]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: C=CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: C=CCN1CC(C)C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Yield: 50.1 %

Procedure:
A solution of 0.050 g (0.00019 mole) of (rac)-9-allyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-65), 0.049 g (0.00019 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00025 mole) of p-toluene-sulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.047 g of (rac)-4-(9-allyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-65) as white solid. HRMS (ES+) m/z Calcd for C26H35N7O3+H [(M+H)+]: 494.2874. Found: 494.2878.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[O:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1)[O:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][O:15][C:24]2[CH:25]=[C:26]3[N:33]([CH3:34])[CH2:32][CH2:31][N:27]3[C:28](=[O:30])[N:29]=2)=[CH:10][CH:9]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)nc1
Agent: [H-]
Agent: [Na+]
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)nc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (4.85 mg, 0.121 mmol), (6-(3-chloro-5-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol (60 mg, 0.198 mmol) in THEF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (36.7 mg, 0.198 mmol).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[C:20]([C:25](=[O:37])[NH:26][C:27]2[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=2)[CH:19]=3)=[C:11]([Cl:38])[CH:10]=1)(C)(C)C.Cl>C(Cl)Cl>[ClH:15].[Cl:38][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][C:6]([OH:39])=[O:5])[CH:14]=[C:13]([Cl:15])[C:12]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25](=[O:37])[NH:26][C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=1)[CH:19]=2
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)CCc1cc(Cl)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 3-{3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-indol-2-yl]-phenyl}-propionic acid tert-butyl ester (139 mg, 0.25 mmol) in DCM (1 mL) was added HCl (4M in 1,4-dioxane, 1 mL) and the solution was stirred for 2 h, after which more HCl (4M in 1,4-dioxane, 2 mL) was added. The mixture was stirred for 18 h then the solvent was removed under reduced pressure and the remaining solid was triturated with ether to obtain the title compound as a yellow solid. MS (m/z) 504.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.83 (s, 1H), 11.14 (s, broad, 1H), 8.44 (d, J=9.17 Hz, 1H), 8.36 (d, J=8.98 Hz, 1H), 7.97 (dd, J=8.21, 0.88 Hz, 1H) 8.21 (s, 1H), 7.92 (d, J=8.34 Hz, 1H), 7.80 (dd, J=8.40, 1.58 Hz, 1H), 7.76 (td, J=7.71, 1.39 Hz, 1H), 7.69 (d, J=8.34 Hz, 1H), 7.53 (m, 1H) 7.56 (s, 2H), 6.59 (dd, J=1.89, 0.76 Hz, 1H), 2.91 (t, J=7.39 Hz, 2H), 2.63-2.68 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[NH2:25][C@H:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12]([NH:25][C@H:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Reactant: N[C@@H](CO)CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)N[C@@H](CO)CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 70 mg (0.20 mmol) of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxylic acid were dissolved in 0.63 ml of dry dimethylformamide, 33.1 mg (0.28 mmol, 1.4 equivalents) of (2R)-2-aminopentan-1,5-diol, 98 μl of diisopropylethylamine (0.60 mmol, 3 equivalents) and 98 mg of HATU (0.26 mmol, 1.3 equivalents) were added and the mixture was stirred at room temperature overnight. A little water was then added, and the mixture was purified directly by preparative HPLC (Method 10). This gave 31.4 mg of the target compound (35% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:15])[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
300 mg (1.61 mmol) of 2-oxo-pyrrolidin-1-carboxylic acid t-butyl ester was dissolved in tetrahydrofuran and then cooled to −78° C. To the resulting solution, was dropwise added a solution of 1.7 mL (1.7 mmol) of 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran, followed by stirring for 1 hour. 0.19 mL (3.05 mmol) of iodomethane was dropwise added thereto. Thereafter, the temperature was gradually raised to −30° C. for 2 hours. 50 mL of ethyl acetate was added to the solution, and the reaction solution was washed with aqueous ammonium chloride, and an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 130 mg (0.65 mmol) of the title compound in a yield of 40%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[N-:12]=[N+:13]=[N-:14].[Na+].[I-].[K+].CCOCC.O>CN(C=O)C>[N:12]([CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCCOC1CCCCO1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(3-chloro-propoxy)-tetrahydro-pyran (6.28 g, 35.2 mmol), NaN3 (11.4 g, 176 mmol) and potassium iodide (584 mg, 3.52 mmol) in DMF (50 mL) was stirred at RT for 18 h. The reaction mixture was poured into a mixture of Et2O/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 15:85 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27].C(O)C.C>CO>[ClH:23].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1ccc(N)cc1Cl
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c(Cl)c2)c2c(ccc3nc[nH]c32)n1
Reaction time: 8 h

Procedure:
A 500 ml., 3-neck, r.b. flask fitted with stirrer, condenser, and thermometer was charged with a mixture of the compound of Example I, C. (21.7 g., 0.1 mole), 3-chloro-4-methylaniline (14.2 g., 0.1 mole) and ethanol (300 ml.). The mixture was heated at reflux, while stirring, overnight. The near solution was concentrated to dryness by rotary evaporator and the residue was collected and dried to yield 35 g. (97.5%), m.p. 352°-364°C (dec). A 10 g. sample was dissolved in methanol (200 ml.), treated with charcoal and filtered while hot. Ether (ca 750 ml.) was added until the filtrate remained turbid and was then chilled. The crystals were collected by filtration and dried to yield 3.4 g. yellow crystals, m.p. 362°-370°C (dec). After two recrystallizations a m.p. 368°-372°C (dec) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH:12][CH3:13]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]([N:12]([CH3:13])[CH3:11])=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cnnc(Cl)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cnnc(Cl)c1
Reaction time: 1 h

Procedure:
The 6-chloropyridazine-4-carbonyl chloride (0.18 g, 1.04 mmol was dissolved in methylene chloride (12.0 mL) and a 2.0 M dimethylamine in THF (1.4 mL) was added at room temperature. The reaction was stirred for 1 h and was complete. The reaction was partitioned between EtOAc and water. The organic layer was washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give 6-chloro-N,N-dimethylpyridazine-4-carboxamide as a colorless viscous oil, (0.16 gm, 60%). LCMS calculated for C7H9ClN3O (M+H)+: m/z=186.0. found: 185.9.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:22]([NH:23][CH3:24])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 66 %

Procedure:
A solution of 1-benzyl-3-butyl-6-hydrazinouracil (4.0 g, 13.9 mM) and methyl isothiocyanate (2.85 ml, 41.7 mM) in DMF (50 ml) was stirred at 120° C. for 20 hours. To the solution was added methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (3.0 g, 66%), m.p. 282°-284° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24](=[S:26])[NH2:25])[CH2:7]1)(=[O:4])=[O:3].CO[CH:29](OC)[N:30](C)C>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]2[S:26][N:30]=[CH:29][N:25]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(OC)N(C)C
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2ncns2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (1.5 g) was added N,N-dimethylformamide dimethylacetal (1.5 ml) and the mixture was stirred at room temperature for 1.5 hours. After the solvent was removed, the residue was dissolved in dichloromethane (30 ml). To the solution was added dropwise O-(mesitylenesulfonyl)hydroxylamine (1.5 g) in dichloromethane (20 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was washed with saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the residue was subjected to a column chromatography on silica gel (30 g) eluting with a mixture of n-hexane and ethyl acetate (1:2 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(1,2,4-thiadiazol-5-yl)pyrrolidine (850 mg).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3]1>CCO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][C@@H:2]2[F:1])=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2C(F)(F)F)[C@@H](F)C1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of tert-butyl (3S,4S)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.6 g, 1.0 eq, 1.5 mmol) and Pd—C (10%, 0.15 g) in EtOH (20 mL) was hydrogenated at 30 psi for 1 hour. The mixture was filtered through celite and the filter cake washed with EtOH (2×10 mL). The filtrate was concentrated under vacuum to give the desired product in 64% yield. This product was taken to next step with out further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccc(F)cc3)CC1)O2

Procedure:
Compound 164 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure X. M.p.=163-167° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 6.95 (t, 2H), 6.85 (m, 2H), 4.15 (m, 1H), 3.95 (d, 2H), 3.0-2.9 (m, 3H), 2.8 (d, 2H), 2.7-2.6 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.95-1.85 (m, 2H); LCMS: 470 [M+H].