Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C.O>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Reactant: NCCCc1ccccn1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cn2c3c(c(NCCCc4ccccn4)c(F)c(N)c3c1=O)OCC21CC1
Yield: 17.2 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile (320 mg, 1.1 mmol) and 3-(pyridine-2-yl)propan-1-amine (270 mg, 2 mmol) and triethylamine (221 μL, 2.7 mmol) in DMSO (8 mL) was stirred at 120° C. for 15 hr. The reaction mixture was added portion wise to water and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The dry residue was purified by column chromatograph (ethylacetate, to ethylacetate-MeOH 10:1) to yield the title compound (76.9 mg) as a yellow solid. MS (EP) m/z: 406.2 (M++1). (Calcd for C22H20FN5O2, 405.42). 1H NMR (400 MHz, CD3OD) δ 1.15 (2H, t), 1.59 (2H, t), 2.03 (2H, t), 2.88 (2H, t), 3.54 (2H, m), 4.15 (2H, s), 7.23 (1H, m), 7.33 (1H, m), 7.74 (1H, m), 8.04 (1H, s), 8.42 (1H, m)
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[N:25]1([C:2]2[N:7]=[C:6](/[CH:8]=[C:9]3/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/3)[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1NC(=O)/C(=C/c2cccc(N3CCCCC3)n2)S1
Temperature: 110 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
A 2 dram round-bottomed vial was charged with (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (60 mg, 0.210 mmol, 1 equiv.), DMSO (1 mL, 0.08 M), diisopropylethylamine (34 μL, 0.2 mmol, 1 equiv.), and piperidine (21 μL, 0.21 mmol, 1 equiv.), and the reaction was heated with shaking at 110° C. for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (7.9 mg, 60.9 mg theoretical, 12.9%). LC-MS m/z 290.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][NH:25][CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:43]=1.I[CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][N:25]([CH2:45][CH2:46][C:47]4[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=4)[CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:41][CH:42]=3)=[N:7][C:6]=2[CH:43]=1
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 375 mg (0.63 mmol) of ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]-oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 117A), 272 mg (0.94 mmol) of methyl 4-(2-iodoethyl)benzoate and 99 mg (0.94 mmol) of anhydrous sodium carbonate in 10 ml of dry acetonitrile was stirred overnight at a bath temperature of 110° C. A further 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was once more heated under reflux overnight. Another 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was again heated under reflux overnight. After cooling of the reaction mixture, ethyl acetate and water were added, the organic phase was separated off and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1→2:1). This gave 324 mg (0.42 mmol, 68% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[C:17](Br)Br)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.CCCCCC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[CH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC1CCN(Cc2cccnc2OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2.9 g of 1-[(2-methoxy-3-piridyl)methyl]-4-(2,2-dibromovinyl)piperidine was dissolved in 25 ml of tetrahydrofuran, and 12.3 ml of a 1.50 M n-butyllithium hexane solution was added dropwise at −78° C. After completing the dropwise addition, the mixture was further stirred at −78° C. for one hour. An aqueous saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then the dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([SH:21])=[CH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(Cl)Cl.II>C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:21][N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:12](=[O:13])[CH:11]=2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(C=C(S)c1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cc(=O)n(-c3ccccc3)s2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of 0.30 g (1.00 mmol)3-(4-carboxyphenyl)-3-mercapto-N-phenylpropenamide and 50 mL methylene chloride was stirred at room temperature. Added was 0.25 g (1.00 mmol) iodine followed by 0.2 mL (excess) triethylamine and the mixture stirred for one hour. Solvent was evaporated and 250 mL ethyl acetate added. The mixture was washed with three 100 mL portions of water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was triturated in absolute ethanol and filtered to dryness to provide 0.16 g (0.54 mmol, 54%)5-(4-carboxyphenyl)-N-phenyl-4-isothiazolin-3-one as a pale, yellow powder, mp=260-261° C. NMR (d6 -DMSO/TMS): 7.08 (s, 1H), 7.39-8.07 (m, 9H), 13.30 (bs, 1H). IR (KBr): 1678, 1652. Mass spectrum (CI): M/z=298.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14](OC)=[O:15])[CH2:9]1>C1COCC1>[F:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][OH:15])[CH2:9]1
Reactant: COC(=O)CN1CC[C@@H](F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1CC[C@@H](F)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2-[(3R)-3-fluoropyrrolidin-1-yl]ethanol was synthesized as followed: a suspension of (3R)-3-fluoropyrrolidine hydrochloride (1 g, 8 mmol) in CH2Cl2 was cooled to 0° C. Triethylamine (2.79 mL, 20 mmol) and methyl bromoacetate (0.83 mL, 8.8 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo, yielding methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]acetate, which was used in the next step without further purification (1.29 g). A solution of lithium aluminium hydride in THF (2 M, 8 mL, 6 mmol) was slowly added to a solution of methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]acetate (1.29 g, 8 mmol) in THF (72 mL). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to 0° C. and ice-cold 10% KOH aqueous solution was added slowly. The reaction mixture was filtered and the solid was washed with 10% KOH aqueous solution and hot ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo, yielding 2-[(3R)-3-fluoropyrrolidin-1-yl]ethanol as an oil (779 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].Cl[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCN(CC)CCCl
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OCCN(CC)CC)cn2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.6 g) was reacted with 1-chloro-2-(diethylamino)ethane (2.7 g) and anhydrous K2CO3 (2.8 g) in dimethylformamide (40 ml) under stirring at 50° C. for 8 hours. After dilution with water, the precipitate was filtered off and washed with water until neutral: crystallization from isopropyl ether gave 2.1 g of 2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, 2-diethylamino-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[S:13]([NH:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[C@H:25]([CH3:37])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[O:38][CH3:39])(=[O:15])=[O:14]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[S:13]([NH:16][C:17]1[C:18]([O:38][CH3:39])=[CH:19][CH:20]=[C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:37])[CH2:24]2)[N:22]=1)(=[O:14])=[O:15]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1Cl
Temperature: 35 °C
Reaction time: 2 h
Yield: 157.4 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-({[2-chloro-4-(3-furanyl)phenyl]sulfonyl}amino)-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D15) (0.170 g) was dissolved in 4N HCl/dioxane (6 mL) and the reaction stirred at 35° C. for 2 hours. The reaction mixture was evaporated and triturated with ethyl acetate/ether (×3) to give a white solid which was dried at 50° C. under high vac to give the compound as a white solid (E7)(0.119 g). MS (ES+) m/e 477/479 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1.N>[Ni].C(O)C>[NH2:10][CH2:9][C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:12])([F:1])[F:11]
Reactant: N#Cc1cnccc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cnccc1C(F)(F)F
Temperature: 40 °C
Yield: 54.8 %

Procedure:
Add 4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) and ethanol wet Raney® activated nickel (0.2 g) to a Parr pressure vessel. Immediately add, at ambient temperature, 2B-ethanol (25 mL) previously saturated with ammonia gas and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 KPa), seal the vessel, agitate the reaction and heat to 40° C. Continue the reaction for 20 h then turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel, wash with ethanol and concentrate in vacuo. Purify by SCX chromatography to give the title compound (560 mg, 55%). MS (ES+) m/z: 177 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:49])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:49][CH2:23][C:3]1[C:2]([F:1])=[C:11]2[C:6]([C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C)c(F)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)c(F)c2n1
Yield: 84.7 %

Procedure:
Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate 7-9 (991 mg, 3.16 mmol), Benzoyl peroxide (102 mg, 0.316 mmol), and NBS (591 mg, 3.32 mmol) were heated at reflux in CCl4 for 5 hours. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-50%) to afford Methyl 7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10 (1.05 g, 85% yield) as a white solid, LCMS shows the compound is 67% pure, LRMS m/z (M+H)+ 392.0 found, 392.1 required.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]4[N:27](C5CCCCO5)[N:28]=[CH:29][C:24]4=[C:23]([C:36]4[CH:37]=[C:38]([NH:42][C:43](=[O:46])[CH:44]=[CH2:45])[CH:39]=[CH:40][CH:41]=4)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:26]=[C:25]4[NH:27][N:28]=[CH:29][C:24]4=[C:23]([C:36]4[CH:37]=[C:38]([NH:42][C:43](=[O:46])[CH:44]=[CH2:45])[CH:39]=[CH:40][CH:41]=4)[N:22]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3c2cnn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoroacetic acid (0.220 mL, 2.85 mmol) was added to a solution of N-(3-(6-((4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (15 mg, 0.029 mmol) in CH2Cl2 (5 mL) and the reaction mixture was stirred overnight at room temperature, after which the solvent was removed in vacuo. The residue was purified by flash column chromatography (5% CH3OH/CH2Cl2) to yield the title compound as a solid. 1H NMR (400 MHz, CD3OD): δ 8.71 (s, 1H), 7.32 (s, 1H), 7.99 (m, 1H), 7.74 (m, 3H), 7.54 (m, 1H), 7.00 (m, 2H), 6.48-6.43 (m, 2H), 5.82 (dd, 1H, J=2.4 and 9.6 Hz), 3.85 (m, 4H), 3.12 (m, 4H): ESI-MS: 442.27 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.NC1C=C(Cl)C=C(Br)C=1[OH:22].ClCC(Cl)=O>>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:22])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: Nc1cc(Cl)cc(Br)c1O
Reactant: Clc1cc(Br)c2c(c1)NCCO2
Agent: O=C(Cl)CCl
Product: O=C1COc2c(Br)cc(Cl)cc2N1

Procedure:
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine used in this Example was prepared by first reacting 2-amino-6-bromo-4-chloro-phenol with chloroacetyl chloride to provide 8-bromo-6-chloro-4H-benzo[1,4]oxazin-3-one using the procedure reported by Combs et al.; J. Med. Chem.; 33; 380-386 1990. This benzoxazinone was then reduced to 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine using borane in THF according to the procedure described in Tetrahedron; 53(26); 8853-8870 1997.
Reaction SMILES: [CH:1]([CH:4]([S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:9])[C:5](O)=[O:6])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>>[CH:1]([CH:4]([S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:9])[C:5]([Cl:24])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1ccccc1OS(=O)(=O)C(C(=O)O)C(C)C
Product: CC(C)c1ccccc1OS(=O)(=O)C(C(=O)Cl)C(C)C

Procedure:
2,6-Diisopropylphenoxysulfonyl acetic acid (prepared as described in Example 3) was reacted with oxalyl chloride to provide 2,6-diisopropylphenoxysulfonyl acetyl chloride. The acid chloride was reacted with 2,6-diisopropylphenol in dichloromethane to provide, following evaporation of the reaction solvent, 2,6-diisopropylphenyl (2,6-diisopropylphenoxycarbonyl)methyl sulfonate, mp 90°-92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([CH3:33])([CH3:32])[CH3:22])=[CH:31][CH:30]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: C[Si](C)(C)Oc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(O[Si](C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 1.4 g, 5 mmol) and 4-trimethylsiloxyaniline (8, 906 mg, 5 mmol) were dissolved in 50 ml of toluene. To this solution 4 Å molecular sieves were added. After standing at room temperature for 4 days with addition of more molecular sieves the reaction mixture was filtered and the solvent was removed in vacuo. The product was washed with a small amount of methanol. Yield 1.4 g (63%) of mixed diimine (9). 1H NMR (CDCl3) δ 8.42 (dd, 1H), 8.33 (dd, 1H), 7.86 (t, 1H), 6.88 (s, 2H), 6.86 (d, 2H), 6.74 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.00 (s, 6H), 0.27 (s, 9H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:30][C:31]1[CH:57]=[CH:56][C:34]2[N:35]3[C:39]([CH2:40][NH:41][CH2:42][C:33]=2[CH:32]=1)=[N:38][N:37]=[C:36]3[C@H:43]1[CH2:48][CH2:47][C@H:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH2:45][CH2:44]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O.CO>[Cl:30][C:31]1[CH:57]=[CH:56][C:34]2[N:35]3[C:39]([CH2:40][N:41]([C:1](=[O:5])[CH2:2][OH:3])[CH2:42][C:33]=2[CH:32]=1)=[N:38][N:37]=[C:36]3[C@H:43]1[CH2:48][CH2:47][C@H:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH2:45][CH2:44]1
Reactant: O=C(O)CO
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(CO)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 1 h

Procedure:
A solution of glycolic acid (11.5 mg, 0.151 mmol) and HATU (57.3 mg, 0.151 mmol) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 5 minutes. trans-8-Chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and N-ethyldiisopropylamine (0.053 ml, 0.30 mmol) were added consecutively. The reaction mixture was stirred for 1 h. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (41 mg, 71%) as white solid. MS m/e: 456 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23]O)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH:6]=1.Cl[C:44]1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(COC(=O)C)=O)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:44])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:8]=2)[CH:6]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(N)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP), by substituting N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1).
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9]Br)[CH2:2][CH3:3].[SH:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:22]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:16]([C:13]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][S:19][CH2:20][CH:21]2[CH2:25][O:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[S:22]2)=[C:4]([CH2:1][CH2:2][CH3:3])[C:14]=1[OH:15])(=[O:18])[CH3:17]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
3-(2-n-Propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (2.0 g, 0.006 mol), prepared by the method described in U.S. Pat. No. 4,565,882, Example 14, incorporated herein by reference, was dissolved in methyl ethyl ketone (20 ml). To this solution was added the thiol of Example 1 (2.0 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g) and the reaction mixture was refluxed with stirring under a nitrogen atmosphere for 24 hrs. The reaction was cooled to room temperature, filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 25% ethyl acetate/hexane as eluent to give 3.3 g (95%) of the title compound as an oil.