Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([CH3:10])[CH2:8][NH2:9])[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([CH3:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]2[CH:32]=[C:24]([C:21]3[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=3)[CH:25]=[N:26][CH:27]=2)[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(CN)c1cn(C)c(-c2ccccc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1cn(C)c(-c2ccccc2)n1
Yield: 16 %

Procedure:
This compound was synthesized from 2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (10 mg, yield 16%). 1H NMR (400 MHz, CDCl3) δ 9.40 (d, J=2.1 Hz, 1H), 9.31 (d, J=2.1 Hz, 1H), 9.16-9.15 (m, 1H), 8.87-8.86 (t, J=2.1 Hz, 1H), 7.62-7.59 (m, 2H), 7.42-7.40 (m, 3H), 6.81 (s, 1H), 4.02-3.96 (ddd, J=12.9 Hz, 6.2 Hz, 4.3 Hz, 1H), 3.75 (s, 3H), 3.42-3.35 (ddd, J=12.9 Hz, 9.4 Hz, 3.2 Hz, 1H), 3.15-3.10 (m, 1H), 1.40-1.38 (d, J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20]
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Reactant: CCOc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOc1cncc(-c2ccc3c(c2Cl)CC(=O)N3C)c1
Temperature: 115 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (95 mg, 0.31 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 69 mg, 0.34 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.390 mL, 0.77 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (140 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 115° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3%) to furnish 4-chloro-5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0901 (M+H)1; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=6.9 Hz, 3H), 3.26 (a, 3H), 3.61 (a, 2H), 4.15 (q, J=6.9 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.28-7.33 (m, 2H), 8.26 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH:16]3[CH:14]([CH:15]3[NH:18][C:19]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[CH:24]=3)=[O:20])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH:16]3[CH:14]([CH:15]3[NH:18][C:19](=[O:20])[O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28](=[O:29])[NH:34][CH3:33])[CH:24]=3)[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CN
Reactant: CCOC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Solvent: CCO
Product: CNC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Yield: 60 %

Procedure:
The procedure described in Example 6, step 6.4. is followed. Starting from 0.30 g (0.68 mmol) of ethyl 5-[({[3-(6-fluoro-quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamoyl}oxy)-methyl]isoxazole-3-carboxylate and 8.50 ml of an 8M solution of methylamine in ethanol, and after high-temperature crystallization in diethyl ether, 0.17 g (60%) of product is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)n2nccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
To a solution of 2.0g (13.6 mmloes) 5,7-dimethyl pyrazolo[1,5-a]-pyrimidine [Y. Makisumi, Chem. Pharm. Bull. (Tokyo) 10, 612 (1962)] in CHCl3 (25 ml) was added N-bromosuccinimide (NBS) [2.42 g (13.6 mmloes)]. This mixture was heated on the steam bath for 10 minutes, and then allowed to cool to room temperature. The clear yellow solution was then added to an ice cold solution of potassium hydroxide (50 ml, 2N) with good stirring. The CHCl3 layer was dried over Na2SO4, then chromatographed on basic alumina. Evaporation on the CHCl3 eluant afforded a white solid which was further purified by recrystallization from petroleum ether (30°-60°) to give 1.7g (56%) of analytically pure product; mp 115°-6°.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[C:9]([C:23](=O)[NH:24][CH2:25][CH:26]=[CH2:27])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.[CH:29]([NH:31][NH2:32])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:23]2[N:24]([CH2:25][CH:26]=[CH2:27])[CH:29]=[N:31][N:32]=2)=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: C=CCNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: NNC=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCn1cnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Yield: 10.4 %

Procedure:
Phosphorus pentachloride (0.67 g, 3.22 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-(N-allylcarbamoyl)quinoxaline (Preparation 18, 1.0 g, 2.93 mmol) in toluene (40 mL) at room temperature and then heated under reflux for 1 hour. After being cooled, formylhydrazine (0.585 g, 8.79 mmol) and triethylamine (0.592 g, 8.79 mmol) were added and the mixture heated under reflux for 1 hour. After being cooled, the mixture was partitioned between ethyl acetate (60 mL) and 10% w/w aqueous potassium carbonate solution (60 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using toluene:ethyl acetate (1:0 changing to 1:1, by volume) to afford 6,7-dichloro-2,3-dimethoxy-5-(4-allyl-4H-1,2,4-triazol-3-yl)quinoxaline (0.112 g, 10%) as a white solid, mp 206-208° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: C1CCNCC1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (28 mg) was dissolved in acetonitrile (2 ml) and piperidine added (23 μl in 500 μl acetonitrile). The mixture was left to stir for 1.5 hr after which time the solvent was removed in vacuo. Purification using a short silica plug, eluting with a mixture of ethyl acetate and petroleum ether (1:1 v/v) furnished the title compound (25 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[O:9][CH:8]([C:18]([F:21])([F:20])[F:19])[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6]2.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>N1C=CC=CC=1.C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([CH3:16])([CH3:17])[CH2:14][NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[O:9][CH:8]([C:18]([F:21])([F:20])[F:19])[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6]2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CN)cc2OC1C(F)(F)F
Agent: Cl
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CNC(=O)c3ccc(Cl)cc3)cc2OC1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of the title product of Example 130 Step 1 (150 mg, 0.397 mmole) in 5 mL of pyridine was added a solution of 4-chlorobenzoyl chloride (90 mg, 0.51 mmole) in 1 mL of DCM. The mixture was stirred for 2 h, and 750 mg of Tris amine resin was added. After stirring overnight, the mixture was filtered and concentrated to give the title compound, which was used as is for the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([CH2:18][CH3:19])([CH2:14][CH2:15][CH2:16][CH3:17])[C:9](OCC)=[O:10].[OH-].[Na+].O>C(OCC)C>[NH2:7][C:8]([CH2:18][CH3:19])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][OH:10]
Reactant: CCCCC(N)(CC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCC(N)(CC)CO
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Lithium aluminium hydride (22.2 g) was added to anhydrous diethyl ether (450 ml) under nitrogen. The product from (d) (129.0 g) was diluted with diethyl ether (40 ml) and added dropwise. The reaction was refluxed for 1 hour then cooled to room temperature. 1M sodium hydroxide (23 ml) was added dropwise followed by deionised water. The resulting suspension was filtered and the filtrate concentrated to give the desired product as a colourless oil (87.9 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: O.Cl[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].P(Cl)(C(C)(C)C)C(C)(C)C>[C:11]1([C:3]2[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
The procedure from Example above was followed using 110 mg (0.609 mmol) of (Me3C)2P—Cl, 67 mg (0.299 mmol) of Pd(OAc)2, 60 mg (3.3 mmol) of H2O, and 3-chloroanisole (1.43 g, 10.0 mm), C6H5B(OH)2 (1.83 g, 15.0 mm) and CsF (4.56 mg, 30.0 mmol) in 15 mL of 1,4-dioxane. After the mixture was refluxed for 42 h, the reaction mixture was then cooled to room temperature, quenched with 50 mL of H2O, and extracted with 300 mL of diethyl ether. The organic extracts were washed with H2O (2×50 mL), brine (50 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.49 g (81% yield) of 3-phenylanisole. It was >95% pure by 1H NMR and GC/MS.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:25]1([CH:32]=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:24][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:32][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=CC1CCCCCC1
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OC1CCN(CC2CCCCCC2)CC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reaction time: 0.5 h

Procedure:
To a solution of 9.3 mg of piperidin-4-yl (2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 1 ml of methanol, 10 mg of cycloheptanecarbaldehyde and then 0.5 ml of advancedly prepared 0.3 M methanol solution of sodium cyanoborohydride and zinc chloride (1:0.5) were added at room temperature, followed by 30 minutes' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated sodium hydrogenecarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on preparative thin layer chromatography (Kieselgel™60F254, Art5744 (Merck), chloroform/methanol=10/1) to provide the title compound.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:53][C:52]3[C:47](=[C:48]([O:60]C)[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51]=3[O:54]C)[CH2:46]2)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:46][C:47]3[C:48](=[O:60])[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51](=[O:54])[C:52]=3[CH2:53]2)=[CH:43][CH:44]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A water (1.0 ml) solution of CAN (976 mg, 1.78 mmols) was dropwise added to an acetonitrile (7.0 ml) solution of ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (350 mg, 0.711 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) followed by recrystallization from hexane-ethyl acetate to obtain the entitled compound (178 mg) as crystals.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11](=[O:16])[NH:12][CH:13]([CH3:15])[CH3:14])=[O:8].[CH3:21][N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:13]([NH:12][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:3]=[CH:4][C:5]=1[N+:18]([O-:20])=[O:19])=[O:16])([CH3:15])[CH3:14]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A mixture of 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (INTERMEDIATE IV.1) (400 mg, 1.4 mmol), 1-methylhomopiperazine (0.20 mL, 1.6 mmol) and potassium carbonate (1 g) in acetonitrile (20 mL) were heated at reflux temperature under an Argon atmosphere for 16 h. The mixture was cooled, filtered, the residue washed with DCM (2×1 mL) and the volatiles evaporated under reduced pressure. The red coloured residue was dissolved in DCM (15 mL), washed with 1 N NaOH (aq.) (2×5 mL) and brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford N-(isopropylcarbamoylmethyl)-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrobenzamide (510 mg, 1.4 mmol, 100%) as an orange-red solid. This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([Cl:18])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([Cl:18])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Treat a 0° C. mixture of 2,6-dichloro-4-benzyloxy-benzaldehyde (245 g, 0.871 mol) in ethanol (3 L) with sodium borohydride (32.97 g, 0.897 mol). Warm the reaction to room temperature and stir for 2 hours. Add the reaction mixture to saturated ammonium chloride (8 L). Extract the mixture with CH2Cl2 and dry the organic layer with Na2SO4. Remove the solvent in vacuo to afford 247 g (100%) of the titled product. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (m, 4H), 7.33 (m, 1H), 7.12 (s, 2H), 5.14 (s, 2H), 5.05 (t, 1H), 4.59 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]1)[CH2:6][C:5]2=[O:20].[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:14]1([CH3:19])[CH2:13][CH:12]([CH:7]2[CH2:6][C:5](=[O:20])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]#[N:22])[CH:3]=3)[O:8]2)[CH2:17][CH2:16][O:15]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)CC(C2CC(=O)c3cc(Br)ccc3O2)CCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(C2CC(=O)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
To a solution of crude 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one (460 mg, 1.36 mmol), 3-cyanophenylboronic acid (299 mg, 2.0 mmol) and Cs2CO3 (866 mg, 2.72 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) charged in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (50 mg), then the system was degassed by sweeping N2 and capped. Then the mixture was heated to 100° C. for 10 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel give (3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg). MS ESI+ve m/z 362 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(OCCBr)c(Cl)c1
Yield: 61.4 %

Procedure:
A mixture of 2,4-dichlorophenol (105 g, 0.64 mol), 1,2-dibromoethane (157 g, 0.84 mol) and water (500 mL) was heated at reflux, during which time a solution of sodium hydroxide (28.0 g, 0.70 mol) in water (125 mL) was added to the mixture over a period of one hour. The solution was allowed to reflux for 10 hours, cooled and the separated organic layer was distilled to give 1-bromo-2-(2,4-dichlorophenoxy)ethane (106 g, yield 62%). 1HNMR (CDCl3) δ 7.37 (d, 1H, J=2.4 Hz), 7.19 (dd, 1H, J1=8.8 J2=2.4 Hz), 6.88 (d, 1H, J=8.8 Hz), 4.31 (t, 3H, J=6.4 Hz), 3.65 (t, 3H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9]([O:12][Si](C)(C)C)=[CH:8][CH2:7]1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)([O-])O.[Na+].O>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]([F:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCC(=O)[C@@H](F)C1
Reaction time: 1.25 h
Yield: 37.5 %

Procedure:
Silyl enol ether (a) (3.5 g) in acetonitrile (40 mL) at 0° C. was treated portionwise with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), (Selectfluor™), (6.16 g). After 75 min, saturated sodium hydrogen carbonate (50 mL) and water (50 mL) were added and the mixture extracted with ethyl acetate. The organic soluble material was purified by careful chromatography on silica gel eluting with 5-60% diethyl ether in hexane to give an oil (1.02 g).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:26])[C:10](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3)nc2n(CCC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Yield: 84.2 %

Procedure:
Compound 1 obtained in Example 1 (2.00 g, 5.90 mmol) was dissolved in 65 ml of N,N-dimethylformamide. To the solution were added 2.04 g (14.8 mmol) of potassium carbonate and then 0.74 ml (11.8 mmol) of methyl iodide, and the mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble substances were removed by filtration, and 500 ml of water was added to the filtrate. The mixture was extracted three times with chloroform, and the combined organic layers were washed twice with water and twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20% ethyl acetate/hexane), followed by recrystallization from ethanol/water to give 1.75 g (yield: 84%) of Compound 2 as white needles.
Reaction SMILES: [C:1]([C@H:5]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([O:46]C)=[O:45])[O:36][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:48][CH2:49][CH2:50][C@H:9]2[O:8][C:7](=[O:51])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)C>C1COCC1.C(O)C.C(OCC)(=O)C.O>[C:1]([C@H:5]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([OH:46])=[O:45])[O:36][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:48][CH2:49][CH2:50][C@H:9]2[O:8][C:7](=[O:51])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN1CCCCC1)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[C@@H]1NC(=O)O[C@@H]2CCC[C@H]2CCCCCc2c(nc3ccccc3c2OCCCN2CCCCC2)O[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 2 (55.8 mg) in THF (0.8 mL) and ethanol (0.2 mL) was added 2M LiOH (0.4 mL). After 1 hour at room temperature, the reaction was done. The mixture was diluted with ethyl acetate and water. Then, acetic acid was added until pH=5. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered and concentrated. LRMS (ES−) m/z 691.3 (M−H)−.