Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH:15]=O.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:15]([C:14]4[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:12]([F:11])[CH:13]=4)[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cc(F)cc(C(F)(F)F)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 3-fluoro-5-(trifluoromethyl)benzaldehyde (0.768 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.558 mL, 4 mmol), di-(imidazol-1-yl)methanone (0.648, 4 mmol) as described in method 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].CN(C)C=O.CS(O[CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1)(=O)=O>C(OCC)(=O)C>[O:29]1[CH2:30][CH2:31][CH:27]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:28]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL, 10 mmol) was stirred at r.t. for 10 min, then, tetrahydrofuran-3-yl methanesulfonate (86 mg, 0.52 mmol) was added. The resulting mixture was stirred at 110° C. for 2 hours. After cooling it was diluted with ethyl acetate, washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 95 mg of product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][OH:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([CH2:25][O:26][Si:27]([C:40]([CH3:42])([CH3:43])[CH3:41])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[O:24])=[C:15]([Cl:52])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CO)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C=O)(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.7 %

Procedure:
The compound of Example 191 (940 mg) was dissolved in DMF (10 mL). To this solution, pyridinium dichromate (800 mg) was added and the mixture was stirred for 48 hours at room temperature. Following addition of water, the mixture was extracted with ethyl acetate. The extract was then washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel chlomatography (hexane:ethyl acetate=3:1) to give the desired product as a colorless oil (710 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:3]=[N:2]1.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[O:22])[CH2:19][CH2:20]2)=[O:12])[N:3]=[N:2]1
Reactant: O=C(O)CCCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5-(1H-1,2,3-Triazol-4-yl)entanoic acid (step 3) (50 mg, 0.294 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (Example 17, step 2) (100 mg, 0.294 mmol) were dissolved in DMF (1 ml). DIPEA (257 μl, 1.472 mmol) was added followed by 50% T3P® solution in DMF (344 μl, 0.589 mmol). The reaction mixture was stirred at RT for 96 hrs and concentrated under reduced pressure. The crude product was dissolved in DCM and washed with 10% citric acid. The organic portion was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. Purification by preparative HPLC afforded product fractions that were concentrated to afford a residue. The residue was dissolved in DCM and washed with a minimal volume of water, dried over MgSO4 (anh) filtered and evaporated under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[C:22]1([N:28]2[C:32](=[O:33])[CH2:31][C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[NH2:13][C:12]1[O:33][C:32]2[N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:29]=[C:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:31]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Reactant: N#CCC#N
Reactant: O=Cc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC1=C(N)Oc2c(c(-c3ccccc3)nn2-c2ccccc2)C1c1ccc(F)cc1
Reaction time: 0.02 h
Yield: 20.5 %

Procedure:
A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1,3-diphenyl-1H-pyrazol-5(4H)-one (678 mg, 2.87 mmol, 1 equ.). The precipitate formed was filtered out and washed with ethanol and hexanes, and re-crystallized from ethanol to afford 6-amino-4-(4-fluorophenyl)-1,3-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (240 mg, 0.588 mmol, 20%) as a white powder. 1H-NMR (400 MHz) DMSO: 7.94-7.92 (d, 2H), 7.61-7.55 (m, 4H), 7.42-7.38 (t, 1H), 7.28-7.24 (m, 7H), 7.06-7.02 (t, 2H), 5.15 (s, 1H), 13C-NMR (100 MHz) DMSO: 162.6, 159.0, 146.8, 145.6, 140.6, 137.8, 132.5, 130.0, 129.9, 129.8, 128.6, 128.6, 127.3, 127.0, 121.3, 120.2, 115.6, 115.4, 97.9, 59.6, 37.0; LC/MS-MS: 410.4→242.2 m/z; GS1 and GS2 at 30, DP=21, CE=47, CXP=16, tR=4.63 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][O:15][S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1oc(-c2ccc(Cl)nc2)nc1CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Reaction time: 8 h

Procedure:
The crude 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanol from step C is dissolved in methylene chloride (50 mL), then TsCl, DMAP and triethyl amine are added and stirred overnight. The reaction mixture is washed with water, brine and concentrated. Column chromatography on silica gel gave the title compound (0.5 g).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@H:9]2[C@@H:14]([N:15]([CH3:17])[CH3:16])[CH2:13][C@H:12]([O:18][C@@H:19]3[C:24]4[C:25]([OH:40])=[C:26]5[C:33](=[O:34])[C:32]6[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=6[C:29](=[O:30])[C:27]5=[CH:28][C:23]=4[C@@H:22]([C:41]([O:43][CH3:44])=[O:42])[C@@:21]([OH:46])([CH3:45])[CH2:20]3)[O:11][C@H:10]2[CH3:47])C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3.Cl.[OH-].[Na+].O>CC(C)=O>[CH3:47][CH:10]1[O:11][CH:12]([O:18][CH:19]2[C:24]3[C:25]([OH:40])=[C:26]4[C:33](=[O:34])[C:32]5[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=5[C:29](=[O:30])[C:27]4=[CH:28][C:23]=3[CH:22]([C:41]([O:43][CH3:44])=[O:42])[C:21]([OH:46])([CH3:45])[CH2:20]2)[CH2:13][CH:14]([N:15]([CH3:17])[CH3:16])[CH:9]1[OH:8]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of 100 mg of auramycin B in 15 ml of acetone was added 0.3 ml of concentrated hydrochloric acid and hydrolysed at room temperature for 120 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution and 20 ml of water was added and extracted with 20 ml of chloroform twice. The extracts were combined and concentrated to a small volume in vacuo. The concentrate was chromatographed by a column packed with silica gel (chloroform:methanol, 95:5). The fractions containing auramycin D were concentrated in vacuo to give 38 mg of auramycin D.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][N:12]([C:10]2[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[N:11]=2)[CH2:17][CH2:16]1
Reactant: CCCc1nc(N)nc(N2CCOCC2)n1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc(NC(C)=O)nc(N2CCOCC2)n1
Reaction time: 6 h
Yield: 43.3 %

Procedure:
4 g (0.05 mole) of acetyl chloride are added dropwise into a solution of 11.2 g (0.05 mole) of 2-amino-4-morpholino-6-propyl-1,3,5-triazine in 100 ml of anhydrous pyridine at room temperature. The mixture is stirred for 6 hours and then allowed to stand for 48 hours. The pyridine hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is taken up once in toluene, and the mixture is evaporated again. The residue is then taken up in dichloromethane and the solution is washed with water and dried over sodium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography over silica (eluent: 90:10 v/v) dichloromethane-ethanol) and the product is finally recrystallized from ethyl acetate. 5.75 g of N-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-acetamide are obtained. Yield: 43.4%. M.P.: 141°-142° C. (Compound 21a). Hydrochloride: M.P.: 145°-146° C. (isopropyl alcohol-ether). (Compound 21b).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]=[C:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C:9]2([O:19][CH2:18][CH2:17][O:12]2)[CH2:8][C@H:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCCCC1=CC(=O)CCC1C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCC[C@@H]1CC2(CC[C@@H]1C(=O)OCC)OCCO2

Procedure:
2-Butyl-4-oxocyclohex-2-ene carboxylic acid ethyl ester (9.05 g; 40 mmole), ethyleneglycol (2.73 g; 44 mmole) and p-toluenesulphonic acid (100 mg) were refluxed in benzene (80 ml) using a Dean-Stark water trap. After 12 hours the mixture was cooled, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate followed by water. Drying over MgSO4 and evaporation gave a liquid (10.80 g 100%) which was pure enough to use directly. Found: C,66.71; H,9.79, C15H26O4 requires C,66.64; H,9.69%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and pivaloyl chloride (0.025 g, 0.283 mmol) was added and stirred for 3 h at RT. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford of the crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.28-4.30 (d, J=6 Hz, 2H), 7.39-7.42 (d, J=8. Hz, 1H), 7.59-7.61 (d, J=6.4 Hz, 2H), 7.84-7.86 (d, J=8.8 Hz, 2H), 8.14-8.19 (m, 3H), 12.59 (br s, 1H); MS (m/z): 451.29 (M−H−).
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O.CS(C)=O>[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 6 mL of a tetrahydrofuran solution containing 1.0 g of trans-4-(tert-butoxycarbonylamino)cyclohexanol and 873 mg of benzylbromide was gradually added 204 mg of 60% sodium hydride, 0.5 mL of dimethyl sulfoxide was then further added thereto, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent: hexane-ethyl acetate (4:1)), and the obtained powdery crystals were suspended in an ethyl acetate-hexane mixed solvent, and collected by filtration to obtain trans-1-tert-butoxycarbonylamino-4-(benzyloxy)cyclohexane.
Reaction SMILES: CN(C=O)C.FC(F)(F)C(O)=O.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]4[O:36][C:35](=[O:37])[NH:34][C:33]=4[CH:38]=3)[C:25]([CH3:39])=[CH:24][N:23]=2)=[CH:16][C:15]=1[O:40][CH3:41].C([O-])([O-])=O.[Cs+].[Cs+].[P:48]([O:60][CH2:61]Cl)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>O>[P:48]([O:60][CH2:61][N:34]1[C:33]2[CH:38]=[C:29]([NH:28][C:26]3[C:25]([CH3:39])=[CH:24][N:23]=[C:22]([NH:21][C:17]4[CH:18]=[C:19]([CH3:20])[C:14]([F:13])=[C:15]([O:40][CH3:41])[CH:16]=4)[N:27]=3)[CH:30]=[CH:31][C:32]=2[O:36][C:35]1=[O:37])([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:49]
Reactant: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)[nH]c4c3)n2)cc(C)c1F
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(OC(C)(C)C)OC(C)(C)C)c4c3)n2)cc(C)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
With reference to Scheme (XI), A DMF (300 mL) suspension of 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate (prepared as described in Example 3)(40.38 g, 79 mmol) and Cs2CO3 (78.3 g, 238 mmol) was stirred at rt under Nitrogen atmosphere, after 2.5 h, di-tert-butyl chloromethyl phosphate (26.6 g, 103 mmol) was added and stirring was continued at room temperature. After 49 h, by LC-MS, the reaction was >90% complete (note: due to relatively poor quality of alkylating agent of this batch, additional ˜7 g of di-tert-butyl chloromethyl phosphate was added). With stirring, the reaction mixture was poured into 1.2 L of H2O, ppt formed and was a bit lumpy, additional 500 mL of H2O was added to ensure the formation of non-sticky solid. Precipitate was collected by filtration, washed with water, and was further dried under high vac. Compound di-tert-butyl (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate was obtained as a light brown solid and was used directly in the next reaction.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O>C(#N)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:34][CH:35]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(8-(4-(diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (5 mL), stirred for 30 min, Then the mixture was evaporated under reduced pressure to get the title compound (140 mg, yield 91%). LC-MS (ESI) m/z: 439 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[C:14](O)=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[C:14]([Cl:3])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Temperature: 85 °C

Procedure:
Stirring thionyl chloride (20 mL) is treated portionwise with 3-cyclopentyloxy-4-methoxybenzoic acid (5.0 g; that is prepared as described hereinbefore in Reference Example 2) and the solution is then heated at 85° C. for 3 hours. Toluene (50 mL) is added and the mixture is concentrated to give 3-cyclopentyloxy-4-methoxybenzoyl chloride (4.12 g) in the form of an oil which slowly crystallized. [NMR(CDCl3): 1.6-1.7 (m,2H),1.8-1.95(m,4H),1.94-2.05(m,2H),3.94(s,3H),4.85 (m,1H),6.9(d,1H),7.55(d,1H),7.8(q,1H); Elemental analysis: C,61.3; H,5.94; Cl,13.9%; Calculated: C,61.3; H,5.94; Cl,13.92%].
Reaction SMILES: [CH3:1][N:2](OCC1C=CC=CC=1)[C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][C:4]1=2.B.O1CCCC1.O>O1CCCC1>[CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CN(OCc1ccccc1)C1(C)CCCc2nc(OCc3ccccc3)ccc21
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 70.5 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-N,2-bis(phenylmethoxy)-5-quinolinamine (12.3 g) in tetrahydrofuran (160 ml) at 0° C. was treated dropwise with borane-tetrahydrofuran complex (1M in tetrahydrofuran, 63.4 ml). The solution was heated under reflux for 3 hrs., cooled to 0° C., and water (30 ml) was added. The reaction mixture was concentrated in vacuo, 20% potassium hydroxide solution (60 ml) was added, and the mixture was heated at reflux for 2 hrs. The mixture was cooled, acidified with conc hydrochloric acid, and washed with diethyl ether. The aqueous phase was basified with 20% potassium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated to afford 6.3 g (92%) of product.
Reaction SMILES: [F:1][C:2]1[C@H:3](O)[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]2[N:39]=[CH:40][NH:41][C:37]=2[C:36]([F:42])=[CH:35][N:34]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:32][C:33]1[C:38]2[N:39]=[CH:40][N:41]([C@H:3]3[C@H:4]4[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[O:8]4)[CH:11]=[C:2]3[F:1])[C:37]=2[C:36]([F:42])=[CH:35][N:34]=1.[F:32][C:33]1[C:38]2[N:39]([C@H:3]3[C@H:4]4[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[O:8]4)[CH:11]=[C:2]3[F:1])[CH:40]=[N:41][C:37]=2[C:36]([F:42])=[CH:35][N:34]=1
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O)O1
Reactant: Fc1ncc(F)c2[nH]cnc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)C(F)=C[C@H]2O1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)C(F)=C[C@H]2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-6) (290 mg, 1.6 mmol, 1 equiv) was dissolved in dry THF (15 mL). Triphenylphosphine (620 mg, 2.4 mmol, 1.5 equiv) was added followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4) (370 mg, 2.4 mmol, 1.5 equiv). The mixture was cooled to 0° C. and DIAD (0.46 mL, 2.4 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 2 hours. Upon disappearance of the starting material, the solvent was removed at reduced pressure and the yellow residue was purified by flash chromatography (40 g SiO2, 15-100% EtOAc in hexanes) to yield 4,7-difluoro-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridine (5-7) and 4,7-difluoro-3-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridine (5-8) as a 1:1 regioisomeric mixture. 1H NMR (5-7) (500 MHz, CDCl3): δ 7.91 (s, 1H); 7.86 (t, J=2.0 Hz, 1H); 5.80 (s, 1H); 5.66 (s, 1H); 5.38 (m, 1H); 4.75 (q, J=5 Hz, 1H); 1.56 (s, 3H); 1.37 (s, 3H). LRMS m/z (M+H) 311.9 found, 312.1 required. 1H NMR (5-8) (500 MHz, CDCl3): δ 7.99 (s, 1H); 7.89 (t, J=2.0 Hz, 1H); 5.80 (s, 1H); 5.66 (s, 1H); 5.38 (m, 1H); 4.75 (q, J=5 Hz, 1H); 1.56 (s, 3H); 1.37 (s, 3H). LRMS m/z (M+H) 311.9 found, 312.1 required.