Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[O:21][CH3:22])[C:3]=1[C:23](=[O:25])[NH2:24].[Br-].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH2:30][Zn+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH2:30][C:29]2[C:28]([Cl:27])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])[N:5]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[O:21][CH3:22])[C:3]=1[C:23](=[O:25])[NH2:24]
Reactant: COC(=O)c1ccc(Nc2nc(SC)nc(N)c2C(N)=O)c(OC)c1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(N)c2C(N)=O)c(OC)c1
Temperature: 100 °C

Procedure:
A suspension of the product of Example 10B (1.1 g, 3.0 mmol), IM (2,6-dichlorobenzyl)zinc(II) bromide in tetrahydrofuran (30 mL, 30 mmol) and tetrakis(triphenylphosphine) palladium(0) (347 mg, 0.3 mmol) in tetrahydrofuran (50 mL) was heated in a sealed tube at 100° C. under nitrogen for 16 hours. The cooled mixture was washed with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 3/1 petroleum ether/ethyl acetate to give the title compound. MS: 476 (M+H+).
Reaction SMILES: BrCC1C(Cl)=C(Cl)C=C2C=1N=C(OC)C(OC)=N2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].Cl[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CC(C)([O-])C.[K+].Cl>O1CCCC1>[N+:28]([C:21]1[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[C:23]([Cl:27])[C:22]=1[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1c(Cl)c(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: -40 °C
Yield: 58.6 %

Procedure:
Preparation 1: 5-Bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (a) A solution of 2,4,5-trichloronitrobenzene (103 g, 0.46 mol) and t-butyl chloroacetate (79 mL, 0.55 mol) in dry tetrahydrofuran (400 mL) was added dropwise over 30 minutes to a solution of potassium t-butoxide (128 g, 1.14 mol) in dry tetrahydrofuran (800 mL) with stirring, under nitrogen keeping the temperature at -40° C. After the addition was complete, the resulting dark blue solution was stirred for a further 30 minutes. The mixture was poured into 0.5M hydrochloric acid (2 L) and the product was extracted into ethyl acetate (2.5 L and 1 L). The combined organic solutions were dried (MgSO4) and evaporated onto silica gel (70-200μ, 200 g). The silica gel was applied to the top of a silica gel chromatography column (800 g), and the product was eluted using a hexane/ethyl acetate gradient. Product-containing fractions were combined and evaporated to give a yellow solid, which was triturated with hexane to give t-butyl (2-nitro-3,5,6-trichlorophenyl)acetate (91.8 g, 59%) as a white solid. Found C, 42.32; H, 3.50; N, 4.03. C12H12Cl3 NO4 requires C, 42.32; H, 3.55, N, 4.11%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cc4[nH]cc(CCC(=O)O)c4cc3F)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of ethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D156) (120 mg) in isopropanol (25 mL) and water (5 mL) was added 0.5 mL of 20% aqueous NaOH solution. The reaction mixture was stirred at 20° C. overnight. Afterwards, the mixture was adjusted to pH 3 by addion of 6 M HCl and evaporated. The residue was treated with 6 mL DMF and filtered. The filtrate was purified by MDAP to give the designed product 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E109) (45 mg). δH (DMSO-d6, 400 MHz): 1.30 (6H, d), 2.59 (2H, t), 2.88 (2H, t), 4.82 (1H, m), 7.37 (1H, s), 7.38 (1H, d), 7.48 (1H, d), 8.04 (1H, dd), 8.06 (1H, d), 8.12 (1H, d), 11.20 (1H, s); δF (DMSO-d6, 376 MHz): −121.5; MS (ES): C22H19ClFN3O4 requires 443.1; found 444.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+:16]>C(Cl)(Cl)Cl>[CH:3]1[C:4]2[N:16]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:16]5[C:13]6[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=6[C:5]6[C:4]5=[CH:3][CH:2]=[CH:7][CH:6]=6)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reaction time: 0.25 h

Procedure:
The reaction was conducted for 15 minutes in the same experimental procedures as in Example 16 except for using 4,4′-dibromobiphenyl (9.8 g, 31.6 mol, 1.0 equivalent) as an aryl halide. To the reaction mixture was added an aqueous solution of ammonium chloride, and the mixture was poured into chloroform (500 mL). The aqueous layer was separated off, and the organic layer was passed through a silica gel pad and concentrated to remove the excess chloroform under reduced pressure. To the thus-obtained suspension was added methanol (150 mL), and the crystal was collected from the suspension by suction filtration, washed with methanol and dried under reduced pressure to afford 14.9 g of CBP as a pale yellow powder.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[N:18][O:19][CH3:20].C(O)(=O)C(O)=O.Cl[C:28]1CC2N(C)C(CC2)[C:29]=1[CH:37]=O.Cl.CON>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[N:18][O:19][CH2:20][CH:37]1[CH2:29][CH2:28]1
Reactant: CON=CC1=C(Cl)CC2CCC1N2C
Reactant: CN1C2CCC1C(C=O)=C(Cl)C2
Agent: CON
Agent: Cl
Agent: O=C(O)C(=O)O
Product: CN1C2CCC1C(C=NOCC1CC1)=C(Cl)C2

Procedure:
3-Chloro-2-(methoxyiminomethyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate from 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate and methoxyamine hydrochloride, M.p. 180°-185° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>[I-].[K+].O>[F:27][CH2:26][CH2:25][O:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[OH:13]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(O)c(OCCF)c(O)c1
Reaction time: 18 h
Yield: 18.1 %

Procedure:
To a 100 mL round bottom flask was added methyl 3,4,5-trihydroxybenzoate (7.00 g, 88.0 mmol) followed by 25 mL of dimethyl sulfoxide. Potassium Carbonate (7.88 g, 57.0 mmol), potassium iodide (31.6 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (5.79 g, 45.6 mmol) were successively added followed by 25 mL more of dimethyl sulfoxide. The reaction mixture was stirred for 18 h after which it was diluted by adding water (100 mL). The mixture was poured into a separatory funnel and extracted with DCM (3×40 mL). The organic layer was then washed with water (4×120 mL) and brine, and dried over magnesium sulfate. The organic layer was then concentrated to obtain an oil. The crude oil was purified using silica gel flash chromatography (DCM/ether 39:1) to obtain 1.9 g (22%) of the title compound (Rf˜0.17 in 19:1 DCM/ether). 1H NMR (600 MHz, CDCl3): δ 7.25 (s, 2H), 5.96 (s, 2H), 4.7 (t of d, 2H, J=48, 1.2 Hz), 4.37 (t of d, 2H, J=24, 1.2 Hz), 3.87 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 166.8, 149, 136.8, 126.4, 109.8, 82.16 (d, J=334 Hz), 72.6 (d, J=37.5), 52.3. MS (ESI): 231.4 (M+H, 100); FIRMS: Calc'd for C10H11FO5 (M+H): 231.06633; Found: 231.0664.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH3:5][CH:6]([C@H:8]([CH2:24][C@H:25]([NH2:43])[C@@H:26]([OH:42])[CH2:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([C:39]([NH2:41])=[O:40])([CH3:38])[CH3:37])=[O:33])[CH:29]([CH3:31])[CH3:30])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=1)[CH3:7]>>[CH3:7][CH:6]([C@H:8]([CH2:24][C@H:25]([NH2:43])[C@@H:26]([OH:42])[CH2:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([C:39]([NH2:41])=[O:40])([CH3:37])[CH3:38])=[O:33])[CH:29]([CH3:30])[CH3:31])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=1)[CH3:5].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Product: O=[N+]([O-])[O-]
Temperature: 25 °C

Procedure:
An ethanolic solution of nitric acid (0.1 M solution, 6 ml, 0.6 mmol) was added to a stirred 0.1M ethanolic solution of aliskiren base (AKN) (6 ml, 0.6 mmol), and the solution was stirred for an hour at room temperature. Ethanol was evaporated under vacuum at 40° C. to dryness. The solid was suspended in 1 ml of isopropanol. After an hour the suspension became unstirrable and 1 ml of isopropanol was added. The suspension was stirred at room temperature overnight. The solid was filtered and dried at 40° C. under vacuum overnight. The wet and dry samples were analyzed by XRPD.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]#[N:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+]>C1COCC1.CO.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CC#N)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a solution of 1 g of tert-butyl[3-(cyanomethyl)phenoxy]acetate in 20 ml of THF and 10 ml of methanol was added dropwise a suspension of 1.31 g of cobalt chloride and 20 ml of water, and then 459 mg of sodium borohydride was portionwise added thereto at room temperature. After stirring at room temperature for 10 minutes, the insoluble material was separated by filtration over Celite, washed with methanol, and then concentrated. The obtained residue was extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol-saturated aqueous ammonia) to obtain 632 mg of tert-butyl[3-(2-aminoethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[OH:21])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanone (75 mg, 175 μmol) and NaBH4 (10 mg, 264 μmol) in THF (5 mL) and MeOH (1 mL) was stirred at RT. Water (5 mL) and 10% aq.Na2CO3 (5 mL) was added and stirred for 10 min. The mixture was extracted with EtOAc; the organic layers were washed with brine (20 mL), dried over Na2SO4, filtered off and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([CH2:10][C:11](Cl)=[O:12])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:11](=[O:12])[CH2:10][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NCCCO
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
3-Amino-1-propanol (6.0 mL, 0.078 mol) was dissolved in dichloromethane (68 mL) then cooled at 0° C. A solution of tert-butylacetyl chloride (2.7 mL, 0.020 mol) in dichloromethane (25 mL) was added dropwise over 10 min. The reaction mixture was stirred for 1 h then concentrated to dryness. The residue was dissolved in EtOAC (100 mL) and washed with brine (3×). The organic extract was dried over Na2SO4, filtered, and concentrated to dryness to give the title compound as a clear oil (3.1 g, 91% yield). 1H NMR (DMSO, 400 mHz) δ (ppm): 7.64 (bs, 1H), 4.36 (t, J=5.3 Hz, 1H), 3.38-3.33 (m, 2H), 3.02 (q, J=6.8 Hz, 2H), 1.88 (s, 2H), 1.52-1.45 (m, 2H), 0.90 (s, 9H).
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:18][C@@H:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[I-:33].[Cs+].II.N(OCCC(C)C)=O>C(COC)OC.[Cu](I)I>[I:33][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:18][C@@H:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: Cn1nc(C(=O)N[C@H](CN2CCOCC2)c2ccccc2)c2c1-c1nc(N)ncc1CC2
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: Cn1nc(C(=O)N[C@H](CN2CCOCC2)c2ccccc2)c2c1-c1nc(I)ncc1CC2
Yield: 39.3 %

Procedure:
To a well stirred and warm suspension of 8-amino-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (3 g, 6.92 mmol) in dimethoxyethane (240 mL), maintained in an inert atmosphere of argon, cesium iodide (2.16 g, 8.3 mmol), bisublimated iodine (870 mg, 3.46 mmol), copper iodide (460 mg, 2.42 mmol) and isopentyl nitrite (1.71 mL, 1.5 g, 12.46 mmol) were added, in sequence. The reaction mixture was stirred vigorously at 65-70° C. for 18 hours. After cooling in an ice-water bath, the solid was filtered off and the filtrate was diluted with dichloromethane (100 mL), washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine and dried over anhydrous Na2SO4. The crude was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95:59) and 1.48 g of the title compound was isolated (40% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:55][CH2:56][OH:57]>C(#N)C.O>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:43][CH2:44][N:45]([CH2:55][CH2:56][OH:57])[CH2:46][CH2:47]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCNCC2)cn3C(COC)COC)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(CCO)CC2)cn3C(COC)COC)cn1
Temperature: 55 °C
Yield: 33.9 %

Procedure:
1-{5-[1-(1,3-Dimethoxypropan-2-yl)-4-oxo-3-(piperazin-1-ylcarbonyl)-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea (Example 140, 180 mg, 0.267 mmol) was dissolved in acetonitrile (15 mL). Potassium carbonate (73.7 mg, 0.53 mmol) was added, followed by the addition of 2-bromoethanol (40 mg, 0.32 mmol) and the mixture was heated to 55° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated and dried to give the crude compound. The crude was dissolved in water (10 mL) and the pH was adjusted to 2. The aqueous solution was washed with ethyl acetate, then basified to pH˜8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 65 mg (34%) of 1-{5-[1-(1,3-dimethoxypropan-2-yl)-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-4-oxo-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea as an off-white solid.
Reaction SMILES: [Li+].[Br-].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([O:30]C)=[C:18]2[C:23](=[O:24])[N:22]3[C@@H:25]([CH3:28])[CH2:26][O:27][C@@H:21]3[CH2:20][N:19]2[CH:29]=1)=[O:14]>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([OH:30])=[C:18]2[C:23](=[O:24])[N:22]3[C@@H:25]([CH3:28])[CH2:26][O:27][C@@H:21]3[CH2:20][N:19]2[CH:29]=1)=[O:14]
Reactant: COc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Alternatively, the demethylation can be carried out with LiBr: (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (8.609 g) was dissolved in THF (90 mL) and LiBr (3.942 g) was added. The mixture was heated to reflux for 12 h and quenched with H2SO4 (0.5 M, 94.467 g). The resultant suspension was stirred at 20° C. for 2 h and filtered. The solid product was re-slurried in water-THF (50 mL-50 mL) at 20° C. for 2 h. The product was collected by filtration, rinsed with water-THF (1-1, 30 mL), and dried under vacuum to afford the product.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[O:12][C:13]2[C:18]([C:19](=[O:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:17]([CH3:28])[CH:16]=[CH:15][CH:14]=2)[CH3:10])C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:8][C@@H:9]([C:11]1[O:12][C:13]2[C:18]([C:19](=[O:27])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:17]([CH3:28])[CH:16]=[CH:15][CH:14]=2)[CH3:10]
Reactant: Cc1cccc2oc([C@@H](C)OCc3ccccc3)c(-c3ccccc3)c(=O)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc2oc([C@@H](C)O)c(-c3ccccc3)c(=O)c12
Yield: 31.2 %

Procedure:
To (R)-2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one (0.850 g, 2.29 mmol) in dichloromethane (8.0 ml) at −78° C., boron tribromide (0.78 ml, 1M in dichloromethane, 4.58 mmol) was added slowly and maintained for 4 h. The reaction mass was quenched at −78° C. using 2N HCl (50 ml), extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was column chromatographed with ethyl acetate:petroleum ether to afford the title compound as pale-yellow liquid (0.200 g, 31%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.54 (t, J=8.0 Hz, 1H), 7.46-7.26 (m, 6H), 7.13 (d, J=7.4 Hz, 1H), 4.71 (q, J=6.6 Hz, 1H), 2.83 (s, 3H), 1.53 (d, J=6.6 Hz, 3H). Mass: 280.8 (M+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[C:6]([O:13][C:14](=[O:16])[CH3:15])=[C:5]([CH3:17])[C:4]=1[CH3:18].[H][H]>C(O)C.C(OCC)(=O)C.[Pt]=O>[C:14]([O:13][C:6]1[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]([NH:2][CH3:1])=[C:8]([NH2:9])[C:7]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 55.7 %

Procedure:
A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline [prepared as described in step (i) above] in a mixture of 20 ml ethanol and 20 ml of ethyl acetate was shaken at room temperature for 3.5 hours and then at 40° C. for 3 hours in an atmosphere of hydrogen and in the presence of 0.2 g of platinum oxide. At the end of this time, the reaction mixture was filtered to remove the platinum oxide and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.3 g of title compound, melting at 113-116° C.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:13][N:12]=2)=[CH:6][CH:5]=1.S(=O)(=O)(O)O.OO.O.[CH3:37][NH:38][CH:39]=[O:40]>>[CH3:37][NH:38][C:39]([C:25]1[CH:24]=[C:23]([CH2:22][O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=3)=[N:12][N:13]=2)[CH:28]=[CH:27][N:26]=1)=[O:40]
Reactant: CNC=O
Reactant: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CNC(=O)c1cc(COc2nnc(Nc3ccc(Cl)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Caution—this reaction is potentially explosive and latent violent exotherms have been noted, especially if the reaction is heated and unreacted hydrogen peroxide is present. The product of step 1 above (0.600 g, 1.65 mmol) was dissolved in 16.5 ml of N-methyl-formamide. The reaction was charged with concentrated sulfuric acid (0.264 ml, 4.96 mmol) followed by FeSO4-7H2O (0.115 g, 0.413 mmol). The solution was stirred at ambient temperature for 15 min then 30% wt. hydrogen peroxide/water (0.338 ml, 3.31 mmol) was added (exotherm noted). TLC analysis after 1 h indicates the reaction is 50% done. The reaction was again charged with concentrated sulfuric acid (0.264 ml, 4.96 mmol) followed by FeSO4-7H2O (0.115 g, 0.413 mmol). To the reaction is added 6 aliquots of 30% wt. hydrogen peroxide/water (each aliquot is 0.338 ml, 3.31 mmol) over 3 h. The opaque brown reaction was stirred for 24 h at 30 C. TLC analysis now indicates no starting material is present. The reaction was quenched with saturated potassium carbonate (100 ml) and the solids filtered off washing with water. The aqueous layer was extracted with diethyl ether (3×175 ml), and the combined organics dried (MgSO4) and concentrated to give an orange solid. The crude product was purified by silica gel chromatography (100% dichloromethane→10% acetone/dichloromethane) to give the clean desired compound as a tan solid (64 mg, 0.152 mmol; 9% yield). TLC (10% acetone/dichloromethane): Rf=0.38.