Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)=[C:13]([O:18][CH3:19])[CH:12]=1
Reactant: Cn1ccnc1CCl
Reactant: COc1cc(Br)ccc1O
Agent: Cl
Product: COc1cc(Br)ccc1OCc1nccn1C

Procedure:
The title compound was prepared by substituting 2-chloromethyl-1-methyl-1H-imidazole hydrochloride and 4-bromo-2-methoxyphenol for Example 627A and Example 474, respectively, in Example 627B. MS (ESI) m/e 329 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 7.17 (d, J=1.2 Hz, 1H), 7.11-7.15 (m, 2H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 6.85 (d. J=1.0 Hz, 1H), 5.09 (s, 2H), 3.77 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](OB(O)O)=[C:4]([O:13][CH3:14])[CH:3]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Br[C:27]1[N:32]2[N:33]=[C:34]([CH2:39][CH3:40])[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=1>C(OCCOCC)C.O.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>[CH2:39]([C:34]1[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=[C:27]([C:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:13][CH3:14])[N:32]2[N:33]=1)[CH3:40]
Reactant: COc1cc(C)cc(C)c1OB(O)O
Reactant: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOCCOCC
Agent: [Ba+2]
Solvent: O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98.3 %

Procedure:
After adding 4,6-dimethyl-2-methoxyphenylboric acid (191 mg), barium hydroxide octahydrate (334 mg) and tetrakis(triphenylphosphine)palladium (0) complex (123 mg) to a solution of 7-bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (159 mg) in a mixture of ethyleneglycol diethyl ether (15 mL) and water (7.5 mL), the mixture was heated at 80° C. for 30 minutes. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (185 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:10][N:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(Cl)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
To a suspension of 0.2 g of LAH in 25 ml of dry THF at 0° C. under nitrogen was added a solution of 1.11 g (5.2 mmol) of ethyl 3-(2-chloropyridin-5-yl)-propionate in 5 ml of THF. The reaction mixture was kept at 3°-5° C. for 1 h and quenched with 0.2 ml of water, 0.2 ml of 10% NaOH, and 0.6 ml of water successively. The mixture was filtered through celite (washing with ether) and the filtrate was concentrated in vacuo to yield 0.87 a (theory) of 2chloro-5-(3-hydroxypropyl)-pyridine as a yellow viscous oil (crude).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:21][C:22]([O-])=[O:23].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:27]([O:26][C:20](=[O:25])[CH2:21][C:22]([NH:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
The compound (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.8 g, 6.6 mmol, see procedure 4a) was dissolved in 32 mL of 2:1 CH2Cl2/DMF. The resultant solution was charged sequentially with mono-benzyl malonate (1.28 g, 6.6 mmol), N,N-diisopropylethylamine (5.8 mL, 33 mmol) and HATU (3.0 g, 7.9 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester (2.3 g, 77% yield). A portion (860 mg) of this material was dissolved in 10 mL of THF. The resultant solution was charged with 30 mL of acetic acid, heated at 65° C. for 3 h, and concentrated in vacuo. The residue was purified by flash chromatography to provide (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (343 mg, 54% yield). MS found: (M+H)+=335.2. (29b) The compound (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (105 mg, 0.32 mmol) was dissolved in THF (3.6 mL). The resultant solution was charged sequentially with MeOH (1.2 mL) and aq. LiOH (15 mg LiOH in 1.2 mL water), stirred for 12 h at RT, and concentrated in vacuo (the water bath was left unheated) to provide the lithium salt of (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid. This material was incorporated into procedure 28b in the place of the lithium salt of (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid. The resultant product was carried through procedure 28c to provide the title compound as a white powder after reverse-phase HPLC purification and lyopholization. MS found: (M+H)+=477.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(F)(F)F)n2CCO3)C1=O
Yield: 48.3 %

Procedure:
10-bromo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 56 mg (48.3%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([CH2:24][S:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)([OH:23])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-:37].[K+].[K+].C(OCC)(=O)C>CO.O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([CH2:24][S:25]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=3)=[O:37])([OH:23])[CH2:21][CH2:22]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(SCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(S(=O)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium metaperiodate (235 mg) was added to a solution of the compound (411 mg) obtained in Example 42 in a mixture of methanol (10 mL) and water (2 mL) under cooling with ice-water, followed by stirring at room temperature for one hour. Another portion of sodium metaperiodate (64 mg) was added, followed by stirring at room temperature for two hours. The reaction mixture was mixed with 10% aqueous potassium carbonate solution (10 mL) and ethyl acetate (20 mL), was stirred, and insoluble matter was removed by filtration. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [Chromatorex NH™] (eluent; hexane:ethyl acetate=3:1 to ethyl acetate) to yield the titled compound (180 mg) as crystals.
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13].C(O[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOCC>[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([O:14][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reaction time: 24 h
Yield: 56.4 %

Procedure:
Perchloric acid (70% aqueous, 0.521 cm3, 6.05 mmol) was added dropwise to a stirred suspension of (S)-pyroglutamic acid 9 (1 g, 7.75 mmol) in tert-butyl acetate (12 cm3, 85.5 mmol). The mixture was stirred for 24 h then sodium carbonate (0.80 g, 7.60 mmol) was added cautiously, ether was added and the organic phase washed with saturated sodium hydrogen carbonate solution and brine. The aqueous phase was extracted with ethyl acetate, dried (MgSO4), filtered and the solvent removed to yield an oil to which was added carbon tetrachloride and the solvent evaporated in vacuo to remove traces of acetic acid to give ester 10 (0.81 g, 56%) as a white solid: δH (300 MHz; CDCl3; Me4Si) 1.48 [9H, s, C(CH3)], 2.33-2.45 (4H, m, 3-H2, 4-H2), 4.12-4.16 (1H, m, 5-H) and 6.16 (1H, br s, N—H); δC (75 MHz; CDCl3) 24.7 (CH2, 4-C), 27.8 [CH3, C(CH3)], 29.2 (CH2, 3-C), 55.9 (CH, 5-C), 82.3 [quat., C(CH3)], 170.9 (quat., 5-CO) and 177.7 (quat., 2-C).
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH2:10][NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:7][CH:6]=1.Cl>C(O)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][N:11]([C:12]([CH3:15])([CH3:16])[CH2:13][OH:14])[CH3:1])=[CH:17][CH:18]=1
Reactant: C=O
Reactant: COc1ccc(CCNC(C)(C)CO)cc1
Agent: Cl
Solvent: O=CO
Product: COc1ccc(CCN(C)C(C)(C)CO)cc1
Yield: 89.9 %

Procedure:
37% Aqueous formaldehyde solution (2.68 g) was added to a stirred solution of 2-(4-methoxyphenethylamino)-2-methylpropanol (3.35 g -- see Preparation 6) in formic acid (3.45 g) and the mixture was heated under reflux for 2.5 hours, acidified with 2M hydrochloric acid, washed with ether, basified with solid sodium hydroxide and extracted into ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was triturated with hexane to give the title compound as a colourless solid (3.20 g, 90%), m.p. 40°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O.O1CCCC1>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:21][CH:22]=1
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Yield: 65.4 %

Procedure:
A mixture of 37.8 g of 8-bromo-1-octanol, 30.77 g of 4-phenylphenol, 8.31 g of sodium hydroxide and 34 g of N-methyl-N,N-diocyl-1-octanaminium chloride in 100 ml of water and 175 ml of tetrahydrofuran was refluxed for 17 hours. The tetrahydrofuran was removed and the residue extracted with warm chloroform. The chloroform extract was washed with water, dried and the solvent removed. The residue was recrystallized from methanol, giving 35.26 g of the desired compound as a white solid, mp 101°-103° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7](/[CH:9]=[N:10]/[OH:11])=O)=[CH:3][CH:2]=1.O.[NH2:13][NH2:14]>CO>[N:13](=[C:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH:9]=[N:10][OH:11])[NH2:14]
Reactant: NN
Reactant: O=C(/C=N/O)c1ccccc1
Solvent: O
Solvent: CO
Product: NN=C(C=NO)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 2-isonitrosoacetophenone (50 g, 335 mmol) in methanol (500 ml) was treated with hydrazine monohydrate (19.5 ml, 402 mmol). The reaction mixture was stirred at room temperature for 20 h at which time the methanol was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 20% EtOAc in hexanes) to afford 37 g (227 mmol; 68%) of hydrazono-phenyl-acetaldehyde oxime as a white solid. δH (360 MHz; CDCl3) 7.22-7.42 (3H, m, aromatics), 7.42-7.60 (2H, m, aromatics), 7.99 (2H, br s, NH2), 8.26 (2H, br s, ArC(NNH2)CHNOH); m/z (ES+) 164 (M++H, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[O:17]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(Cl)nc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy[1,5]naphthyridine-3-carboxylate (Preparation 58, 694 mg), potassium carbonate (588 mg), and iodomethane (264 μL) in DMF (15 mL) is stirred at room temperature for 5 hours. The mixture is poured into water (50 mL), and the solution is extracted with CH2Cl2 (3×50 mL). The organic layers are dried (MgSO4) and concentrated. Trituration with ether (50 mL) affords 473 mg (65%) of the title compound as an off-white solid. Physical Characteristics. 1H NMR (DMSO-d6) δ 8.70, 8.31, 7.90, 4.24, 3.92, 1.29; HRMS (FAB) m/z 267.0535 (C12H11ClN2O3+H). Anal. Found: C, 54.14; H, 4.24; N, 10.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:33])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 62.8 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl alcohol (4.9 g, 24.4 mmol) in 150 mL of dichloromethane was added triphenylphosphine (4.2 g, 31.7 mmol). The reaction was cooled to 0° C. and N-chlorosuccinimide (8.3 g, 31.7 mmol) was added. The reaction was warmed to room temperature and then heated gently to 50° C. for 2 h. The reaction was poured into aqueous sodium carbonate solution and the aqueous layer was extracted with dichloromethane and then ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent to give 4-methoxy-3-nitrobenzyl chloride (3.09 g, 63%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=2.4 Hz, 1H), 7.73 (d, J=8.8, 2.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.78 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>CN(C)C(=O)C>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][C:33]7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:42][N:43](CCCl)[CH3:44]>>[CH3:42][N:43]([CH3:44])[CH2:33][CH2:32][O:31][C:27]1[C:26]([O:39][CH3:40])=[C:25]2[C:30]([C:21]([N:17]3[CH2:16][C:15]4[CH:41]=[C:11]([C:8]5[CH:9]=[CH:10][C:4]6[N:3]=[C:2]([CH3:1])[NH:6][C:5]=6[CH:7]=5)[CH:12]=[CH:13][C:14]=4[O:20][CH2:19][CH2:18]3)=[N:22][CH:23]=[N:24]2)=[CH:29][CH:28]=1
Reactant: CN(C)CCCl
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Product: COc1c(OCCN(C)C)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and 2-(N,N-dimethylamino)-1-chloroethane in step 2. 1H NMR (400 MHz, d6-DMSO): 8.57 (s, 1H), 7.93 (s, 1H), 7.82 (m, 3H), 7.59 (d, 1H), 7.51 (d, 1H), 7.01 (d, 1H), 7.01 (d, 1H), 5.38 (br s, 2H), 4.61 (m, 4H), 4.45 (br s, 2H), 3.95 (br s, 2H), 3.72 (t, 2H), 2.90 (s, 6H), 2.77 (s, 3H); MS (EI) for C30H32N6O3: 525 (MH+).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].CO.Cl>O.C(Cl)Cl>[N+:17]([C:5]1[CH:6]=[C:7]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=1[OH:1])([O-:19])=[O:18]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1O
Temperature: 110 °C
Yield: 25.1 %

Procedure:
Sodium hydroxide (211 mg, 5.28 mmol) was added to a suspension of 1-chloro-2-nitro-4-[(trifluoromethyl)sulfonyl]benzene (297 mg, 1.03 mmol) in H2O (5 mL) at rt, followed by methanol (0.5 mL) to solubilise the starting material, and the reaction was heated at 110° C. for 1 h. The mixture was allowed to cool to rt, diluted with H2O (10 mL) and neutralised with 5 M HCl. DCM was added, the 2 layers were partitioned and the aqueous layer was extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give 2-nitro-4-[(trifluoromethyl)sulfonyl]phenol (D82, 70 mg, 25%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:11][C:12](=O)[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH:14]=O)C>CCO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12](=[O:11])[N:3]3[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]3=[N:1][CH:14]=2)=[CH:21][CH:20]=1
Reactant: Nc1ncccc1O
Reactant: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Solvent: CCO
Product: O=c1c(-c2ccc(Cl)cc2)cnc2c(O)cccn12

Procedure:
2-Amino-3-hydroxypyridine (5.51 g, 0.05 mol) and 2-(4-chlorophenyl)-3-oxo-propanoic acid ethyl ester (13.6 g, 0.06 mol) in EtOH (100 mL) were heated under reflux for 15 h and then allowed to cool. The precipitate was isolated via filtration to yield a 9:1 mixture of the enamine and the cyclized product (11.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]C(=O)C)=[CH:4][C:3]=1[N:12]([CH2:30][CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)CCC>>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:12]([CH2:30][CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:16]([F:29])[CH:15]=1
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC(C)=O)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1-c1nc2ccccc2s1
Yield: 5.9 %

Procedure:
Synthesized from acetic acid 4-bromo-3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}phenyl ester (50 mg) and 2-tributylstannylbenzothiazole (100 mg) according to an analogous synthetic method to Example 19, the title compound (3 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]([Cu])#[N:19].Cl>CN1C(=O)CCC1>[CH2:9]([O:8][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]([N+:15]([O-:17])=[O:16])=[C:2]([CH:7]=1)[C:18]#[N:19])[CH3:10]
Reactant: N#C[Cu]
Reactant: CCOc1cc(Br)c([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 91.2 %

Procedure:
A mixture of 1-bromo-5-ethoxy-2-nitro-4-trifluoromethyl-benzene from step 2 (61.81 g, 197 mmol) and CuCN (18.51 g, 207 mmol) in NMP (197 mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl, extracted with TBME, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. Silica gel column chromatography with heptane/EtOAc 4:1 gave the title compound as a yellow solid (46.73 g, 91%). MS (EI) 260.1 [M].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][OH:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:11][O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(=NO)c1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A stirred solution of 2-(4-fluorophenyl)-2-hydroxyiminoacetonitrile (42.8 g, 0.26 mole) in 200 ml of pyridine was cooled to 0° C., and p-toluenesulfonyl chloride (76.0 g, 0.39 mole) was added portionwise. Upon complete addition, the reaction mixture was stirred at 0°-5° C. for one hour and then stored in a refrigerator for 16 hours. The resultant slurry was poured into a mixture of ice and water and stirred for 30 minutes. The mixture was then filtered and the white filter cake dried under vacuum without heat to give 2-(4-fluorophenyl)-2-(4-methylphenylsulfonyloxy)iminoacetonitrile (77.3 g, mp 129°-140° C.).