Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.[ClH:35]>CO.O.C(O)C>[ClH:35].[ClH:35].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidinyl]butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazine monohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at reflux for 3 hours. At the end of the reaction, methanol was removed to leave a crude solid. This was dissolved in water and acidified with HCl to pH 2. The insolubles were filtered. The aqueous solution was basified with 50% N;aOH, and then extracted with dichloromethane. The dichloromethane solution was washed with water and brine, and then dried over MgSO4. The solvent was removed to a colorless oil: 4.48 g. This oil was treated with 2.5 equivalents of HCl in ethanol. The solid was collected. Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 g of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride as white crystals, m.p.=234-237° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:12].ClC1C(C)=CC([N+]([O-])=O)=CC=1C.Cl[Sn]Cl.[OH-].[Na+]>CCO.Cl.O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:12])[NH2:9]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Cl
Agent: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture 2-chloro-1,3-dimethyl-4-nitro-benzene and chloro-1,3-dimethyl-5-nitro-benzene (12.8 g, 69 mmol) in EtOH (75 mL), conc. HCl (75 mL) was added. Than SnCl2 (51.0 g) was added in two portions. The mixture was stirred overnight at RT, then heated at 60° C. for 30 min, cooled to 0-5° C. (ice bath). Neutralized with NaOH (70 g) in H2O (500 ml). The product was extracted with Et2O (500 ml). Extract was dried over Na2SO4, evaporated. The residue was crystallized two times from hexane providing 3.66 g 3-chloro-2,4-dimethyl-phenylamine as white crystals. The filtrates were evaporated in vacuo and the residue was separated on SiO2 column (200 g), hexane-EtOAc (0 to 10% v/v). providing additionally 3.11 g of the product. Yield 6.77 g (43.5 mmol, 63%).
Reaction SMILES: O1C=CC([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=C1.BrC1C=C2C[C@]3(C4CCN(CC4)C3)OC2=NC=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Reactant: OB(O)c1cc2ccccc2o1
Agent: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: c1ccc2oc(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)cc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of (2′R)-5′-(furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in Preparation 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and benzofuran-2-boronic acid. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform and obtained as a pale solid; m/z 333 (100%, MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[N:3]=1.[ClH:21]>>[ClH:21].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(CCc2cccc(N)n2)cc1
Agent: Cl
Product: Nc1cccc(CCc2ccc(C(=O)O)cc2)n1
Temperature: 60 °C

Procedure:
A suspension of ester 8-5 (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60° C. After ~20 h, the reaction was concentrated to give acid 8-6 as a tan solid.
Reaction SMILES: [PH5].[C:2]([O:5][CH2:6][C@@H:7]1[O:11][C@H:10]([C:12]2[CH2:13][S:14][C@@H:15]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:16]3[C:17]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8]1)(=[O:4])[CH3:3].[N+](C1C=C(C=CC=1)CO)([O-])=O.C([O-])(=O)C.[Na+].C(OC[C@H]1O[C@@H](C2CS[C@@H]3[C@H](NC(=O)CC4C=CC=CC=4)C(=O)N3C=2C(OCC2C=CC(OC)=CC=2)=O)CC1)(=O)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[C:2]([O:5][CH2:6][CH:7]1[O:11][CH:10]([C:12]2[CH2:13][S:14][C@@H:15]3[C@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:30](=[O:42])[N:16]3[C:17]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8]1)(=[O:4])[CH3:3]
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CC[C@H](COC(C)=O)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: CC(=O)[O-]
Agent: COc1ccc(COC(=O)C2=C([C@H]3CC[C@@H](COC(C)=O)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=[N+]([O-])c1cccc(CO)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(C3CCC(COC(C)=O)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1

Procedure:
A solution of the phosphorane from Example 31(g) (517mg) in dry toluene (100ml) was heated at reflux under dry argon for 8 hours and evaporated. the residue was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give two fractions. The less polar fraction contained 4-methoxybenzyl (6R,7R)-3-[(2S,5R)-5-acetoxymethyltetrahydrofuran-2-yl]-7-phenylacetamidoceph-3-em-4-carboxylate, a foam (105mg); vmax (CHCl3) 3410, 1784, 1726 and 1683cm-1 ; δH (CDCl3) 1.53-1.83 (3H, m), 2.09 (3H, s), 2.19-2.36 (1H, m), 3.30 and 3.55 (2H, ABq, J 18.9Hz), 3.60 and 3.69 (2H, ABq, J 16.2Hz), 3.81 (3H, s), 4.01-4.21 (3H, m), 4.90 (1H, d, J 4.8Hz), 4.96 (1H, dd, J 8.3, 6.7Hz), 5.12 and 5.17 (2H, AA'q, J 12.5Hz), 5.81 (1H, dd, J 9.2, 4.8Hz), 5.97 (1H, d, J 9.2Hz), 6.85-6.92 (2H, m), 7.25-7.41 (7H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MH+ (581), MNa+ (603)]. The more polar fraction contained 4-methoxybenzyl (6R,7R)-3-[(2R,5S)-5-acetoxymethyltetrahydrofuran-2-yl]-7-phenylacetamidoceph-3-em-4-carboxylate, a solid (191mg), m.p. 185-187° C. (needles ex ethyl acetate/hexane); vmax (CHCl3) 3407, 1785, 1731 and 1682cm-1 ; δH (CDCl3) 1.53-1.78 (2H, m), 1.90-2.05 (2H, m), 2.08 (3H, s), 3.35 and 3.57 (2H, ABq, J 18.0Hz), 3.61 and 3.69 (2H, ABq, J 16.2Hz), 3.80 (3H, s), 4.01-4.19 (3H, m), 4.91 (1H, d, J 4.8Hz), 5.12-5.27 (3H, m), 5.74 (1H, dd, J 4.8, 9.0Hz), 6.04 (1H, d, J 9.0Hz), 6.85-6.91 (2H, m), 7.25-7.41 (7H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MH+ (581), MNa+ (603)].
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A round bottom flask was charged with 4-bromobenzaldehyde (69.6 g, 376 mmol), 4-(trifluoromethyl)phenylboronic acid (75.0 g, 395 mmol) and 1-propanol (627 mL). The reaction mixture was stirred for 15 minutes at 70° C. until a clear solution was obtained. The resulting solution was treated with triphenylphosphine (888 mg, 3.38 mmol), palladium(II) acetate (256 mg, 1.13 mmol), 2M sodium carbonate (226 mL, 451 mmol) and water (138 mL). The reaction was heated at reflux for 1 hour, open to air. Water (900 mL) was then added and the reaction was cooled to 7° C. in an ice bath. The reaction was thoroughly stirred for 30 minutes until the title compound precipitated out. The mixture was then filtered and the solid washed with cold water (˜600 mL). The solid was then solubilized in diethylether (500 mL) and filtered through a pad of celite and silica, rinsing with diethylether (2×500 mL). Removal of the solvent under reduced pressure afforded 4′-(trifluoromethyl) biphenyl-4-carbaldehyde (90.0 g, 96%) as a pure white solid. 1H NMR (400 MHz, CDCl3, δ): 7.75 (s, 4 H) 7.76-7.79 (m, 2 H) 7.96-8.04 (m, 2 H) 10.10 (s, 1 H). MS (M+1): 250.3.
Reaction SMILES: [Na].F[C:3]1[CH:8]=[C:7]([C:9]2[C:10]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:11][C:12]([NH2:20])=[N:13][C:14]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][N:4]=1>C(O)CCC>[CH2:15]([O:16][C:3]1[CH:8]=[C:7]([C:9]2[C:10]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:11][C:12]([NH2:20])=[N:13][C:14]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][N:4]=1)[CH2:14][CH2:9][CH3:7]
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccn1
Yield: 108 %

Procedure:
In a reaction vessel, sodium (21 mg, 0.931 mmol) was dissolved in n-butanol (4 ml) and then 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0.310 mmol) was added thereto, followed by stirring under reflux for 5 hours under an atmosphere of nitrogen gas. The reaction was terminated by adding water thereto. Then, the reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting solid was suspended in ethanol, collected by filtration and washed with ethanol, to give the title compound (63 mg, 54%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C.O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:6]2[CH3:12])=[CH:24][CH:23]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
4-Methoxy-2-methyl-1H-indole (805 mg, 5 mmol) was added to a mixture of 200 mg (5 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 10 mL of DMF and after stirring for 0.5 hours, 0.6 mL (5 mmol) of 4-fluorobenzyl chloride was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.1 g (84% yield) of 1-[(4-fluorophenyl)methyl]-4-methoxy-2-methyl-1H-indole, melting at 104-108° C.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 664 mg (1.62 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (enantiomer 1, Example 51A) in 28 ml of dry acetonitrile is mixed with 1743 mg (8.07 mmol) of 1,4-dibromobutane and 446 mg (3.23 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 790 mg (1.44 mmol, 89% of theory) of a colourless oil are isolated.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([CH3:12])[N:5]=[C:4]([SH:13])[N:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[CH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([SH:13])=[N:5][C:6]=1[CH3:12]
Reactant: Cc1nc(S)nc(O)c1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)nc(S)nc1O
Yield: 79 %

Procedure:
A solution of (4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl)-acetic acid (190 g, 0.95 mol) and concentrated sulfuric acid (50 ml) in methanol (1.51) is refluxed for 18 hours. The suspension is cooled and filtered to give methyl(4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl)-acetate (160 g, 79%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[C:14]([C:9]1[CH:8]=[C:7]([CH3:6])[C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:11]([CH3:13])[CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
85 ml Chlorosulphonic acid (1.3 mole) was added to a mixture of 81 g (0.5 mole) 3,5 -dimethyl-tert.-butylbenzene at 0± 2° C. The reaction mixture was stirred at 0° C. for 1.5 hours, poured on ice and the layers were separated. The organic layer was washed with water, sodium bicarbonate, and water and was then dried with sodium sulphate. The solvent was removed in vacuum giving pale-yellow crystals of the title compound, m.p. 65° C.
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CC(C)=[O:17]>O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([OH:17])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC(C)=O
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1O

Procedure:
The product of Example 45 (2 g) was boiled under reflux in water (5 ml) and acetone (15 ml) for 31/2 hours. The product was then extracted into diethyl ether, the extracted solution then being washed twice with water, dried over sodium sulphate and run down under vacuum to give 1.7 g of crude product. Recrystallisation from toluene gave pure title product (1.3 g), mp 127°-129° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:14]1=[O:30])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:36][C:32]3[O:31][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)[C:14]1=[O:30])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccco1
Reactant: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC1CN(Cc2ccc(OCc3ccco3)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 318.5 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]formamide (0.1 g, 0.24 mmol) in tetrahydrofuran (3 mL) under argon was added furan-2-yl-methanol (0.041 mL, 0.048 mmol) and triphenylphosphine (0.07 g, 0.27 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.042 mL, 0.27 mmol) was added dropwise. The reaction mixture was warmed up to rt and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (3×10 mL). The combined extractions were dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-{4-butyl-1-[4-(furan-2-yl- methoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}formamide as a colorless oil (0.075 g, 63%). MS(ES) m/e 491 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[F:26].[C:27]([O-:30])(=[O:29])[CH3:28].[K+]>C(O)(=O)C.C(=O)([O-])O.[Na+]>[C:27]([O:30][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[F:26])(=[O:29])[CH3:28]
Reactant: Fc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Temperature: 25 °C

Procedure:
In a solution of crude 3-(4-bromomethyl-3-fluorophenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 30 ml of acetic acid, 1.50 g of potassium acetate was added, and stirred under reflux with heat for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and neutralized by pouring in 100 ml of saturated sodium hydrogen carbonate aqueous solution. The organic phase was collected, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.50 g of crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH:62][CH:63]5[CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67][CH2:68]5)=[O:26])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 8) (0.49 g, 1.2 mmol, 1 eq), TBTU (0.42 g, 1.3 mmol, 1.1 eq) and DIPEA (0.40 mL, 2.4 mmol, 2 eq) were stirred together in DCM (25 mL) for 30 min before addition of 4-amino-1-BOC-piperidine (0.29 g, 1.4 mmol, 1.2 eq). The RM was stirred at rt for 20 hours before diluting with DCM (30 mL) and washing sequentially with water (2×15 mL), 50% saturated aqueous sodium hydrogen carbonate (1×20 mL), saturated aqueous potassium carbonate (1×20 mL) and saturated brine (1×20 mL). Concentrated in vacuo to isolate 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-BOC-piperidin-4-yl)benzamide that was used without further purification (0.71 g). Rt=3.58 min (Analytical—1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([CH3:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]([CH3:16])[CH3:15]>C(O)C.[Pd]>[NH2:21][C:19]1[CH:20]=[C:2]([CH3:1])[C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[CH:14]([CH3:15])[CH3:16])=[C:17]([CH3:24])[CH:18]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Reaction time: 4 h
Yield: 31.5 %

Procedure:
25 mg of palladium/carbon (10%) are suspended in a solution of 175 mg (0.538 mmol) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indazole in 10 ml of ethanol. The mixture is shaken under a hydrogen atmosphere at 3 bar for 4 h, then filtered off through kieselguhr, the filtrate is concentrated in vacuo and the residue is purified on silica gel (cyclohexane/ethyl acetate 2:1). 50 mg (31%) of 5-(4-amino-2,6-dimethylphenoxy)-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:24][O:23][C:21](=[O:22])[C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 0.92 mmol) in dichloromethane (5.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organics were separated and dried over sodium sulfate and concentrated in vacuo. The product used without any further purification. ESI-MS m/z: 255 (M+1), UV retention time: 1.14 min.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1>C1(N)CCCCC1>[CH:14]1([NH:11][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: NC1CCCCC1
Product: c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Yield: 67.4 %

Procedure:
0.300 g (0.90 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) is placed in 4 mL of cyclohexylamine, then reacted for 0.1 hours at 130° C. in the microwave. Then the reaction mixture is concentrated by evaporation, the residue is stirred with water and suction filtered. 0.120 g of product I (34%) is obtained as a powder. 1H NMR (400 MHz, DMSO): 7.22 (2H, t); 6.97 (2H, d); 6.79 (1H, t); 6.08 (1H, d); 3.93-3.81 (1H, m); 3.80-3.69 (4H, m); 3.22 (2H, t); 3.18-3.11 (4H, m); 2.98 (2H, t); 1.92-1.79 (2H, m); 1.79-1.66 (2H, m); 1.66-1.55 (1H, m); 1.37-1.21 (4H, m); 1.18-1.04 (1H, m).