Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:22]([C:21]1[C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][C:18]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:19][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)cc1NCC1CCNCC1
Reaction time: 3 h

Procedure:
4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyridin-4-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (91 mg, 0.17 mmol) was dissolved in CH2Cl2 (2.5 mL). TFA (2.5 mL) was added and the reaction was stirred for 3 h. The volatiles were removed and the resultant residue was redissolved in EtOAc and poured into 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified by SiO2 chromatography (1:10:89, NH4OH:CH3OH:CH2Cl2) to afford 5-nitro-N4-piperidin-4-ylmethyl-N2-(2-trifluoromethoxy-benzyl)-pyridine-2,4-diamine as a yellow solid, m/z 426.4 (M+H)+ (28 mg, 39%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[N:9]=[C:8]2[C:15]1[N:16]=[C:17]2[C:23]([C:24]([OH:26])=O)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)(=[O:4])=[O:3].[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:28]([NH:31][C:24]([C:23]1[C:17]2=[N:16][C:15]([C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)[N:10]([CH3:14])[N:9]=3)=[CH:20][N:19]=[C:18]2[NH:21][CH:22]=1)=[O:26])([CH3:30])([CH3:29])[CH3:27]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(S(C)(=O)=O)ccc21
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(S(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.2 %

Procedure:
A mixture of 2-(5-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.20 mmol), 2-methylpropan-2-amine (15 mg, 0.20 mmol), HOBt (108 mg, 0.80 mmol), EDCI (153 mg, 0.80 mmol) and DIPEA (103 mg, 0.80 mmol) in DMF (6 mL) was stirred at room temperature for 15 hours, then water (30 mL) was added, product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure and residue purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% methanol/70% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 50% methanol/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give N-tert-butyl-2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (7 mg, 8.1%) as a white solid. LCMS: (M+H)+=427; 1H NMR (300 MHz, CD3OD): δ 9.08 (s, 1H), 8.99 (s, 1H), 8.33 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.90 (d, 1H, J=8.7 Hz), 4.28 (s, 3H), 3.17 (s, 3H), 1.57 (s, 9H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.[OH-].[Na+]>CCO.N1C=CC=CC=1>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: CC1C(=O)C2CCN1CC2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 96.4 %

Procedure:
The product from Step 158b (3.2 g, 23.0 mmol, 1 eq) and hydroxylamine hydrochloride (1.6 g, 23.0 mmol, 1 eq) are dissolved in 20 mL EtOH/pyridine (4:1) and stirred at room temperature. After 5 days, water and solid NaOH are added to adjust pH to pH 11. The mixture is extracted with several portions of CHCl3. The combined organic layers are dried over MgSO4, filtered and concentrated to give 3.42 g (96%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime as a 1:2.6 mixture of oxime isomers. Partial 1H NMR (CDCl3, 300 MHz) δ 1.53 ppm (d, 2-CH3, 0.8H), 1.38 (d, 2-CH3. 2.2H). MS (ESI) for C8H14N2O m/z 154.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20].[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[N:10]([CH3:23])[C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20]
Reactant: CI
Reactant: COc1cc(C)c2c(c1OC)CCC1C(=O)NC(=O)C21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c2c(c1OC)CCC1C(=O)N(C)C(=O)C21
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A solution of 3a,4,5,9b-tetrahydro-6,7-dimethoxy-9-methyl-1H-benz[e]isoindole-1,3-(2H)-dione (1.66 g, 6.1 mmole) and dry DMF (28 mL) was stirred under N2 at 0° as a suspension of NaH (60% in oil, washed with hexane, 0.25 g, 6.4 mmole) and DMF (2.8 mL) was added portionwise. The reaction mixture was stirred for 0.5 hour at 0°, and for 0.5 hour at room temperature, then was cooled again at 0° as methyliodide (9.41 mL, 6.6 mmole) was added dropwise. After one hour at 0° and 1.5 hours at room temperature, the reaction mixture was poured onto ice water. The solid was filtered, washed with water, dried (in vacuo) to yield 1.60 g yellow solid (91%), mp 167°-9° C.; M+ 289.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>ClCCl>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22](=[O:23])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reaction time: 3 h
Yield: 36 %

Procedure:
To a stirred mixture of 65 parts of 1,3-difluorobenzene, 130 parts of aluminium chloride and 195 parts of dichloromethane was added dropwise a solution of 95 parts of 1-acetyl-4-piperidine-carbonyl chloride in 65 parts of dichloromethane while cooling. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 parts (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (intermediate 1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(Cc1ccc(O)cc1-c1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (400 mg) in dimethoxyethane (4.00 mL) and water (1.20 mL) were added phenyl boronic acid (182 mg), sodium carbonate (396 mg), and 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (50.9 mg), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (5-hydroxybiphenyl-2-yl)acetate (344 mg).
Reaction SMILES: FC(F)(F)S([Cl:6])(=O)=O.[C:9]1([C:15](=[O:27])[CH2:16][C:17](=[O:26])[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:6][C:18]1[C:17](=[O:26])[CH:16]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:27][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Cl
Reaction time: 2 h

Procedure:
Trifluoromethane sulphonyl chloride (3.95 ml) was added over 10 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (8.1 g) and triethylamine (6.5 ml) in dichloromethane (100 ml) at 0° to 5° C. The solution was stirred for 2 hours at 0° to 5° C., then made acidic by passing in hydrogen chloride gas. The mixture was stirred for 3 hours at room temperature, washed with water and evaporated to a brown oil which crystallised from ethanol-water. The product was recrystallised from ethanol-water and from ethyl acetate-petroleum ether 60°-80° C. to give ethyl 3-chloro-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 121° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:25][CH2:24][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[C:22]([F:23])=[C:14]3[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:29][N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][C@@H:53]3[CH3:62])=[CH:48][N:47]=2)[C:31]1=[O:63].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:34]2[CH:33]=[C:32]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH2:57][CH2:56][N:55]([CH:58]5[CH2:59][O:60][CH2:61]5)[CH2:54][C@@H:53]4[CH3:62])=[CH:48][N:47]=3)[C:31](=[O:63])[N:30]([CH3:29])[CH:35]=2)=[CH:8][C:9]([F:27])=[CH:10][C:11]=1[N:12]1[CH2:25][CH2:24][N:15]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[C:22]([F:23])=[C:14]2[C:13]1=[O:26])(=[O:3])[CH3:2]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 25 °C
Yield: 37.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 119c (150 mg, 1.0 eq., 0.33 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 113f (160 mg, 1.0 eq., 0.33 mmol), K3PO4 (210 mg, 3.0 eq., 0.99 mmol), PdCl2(dppf) (27.0 mg, 0.10 eq., 0.033 mmol), THF (20 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 119d as a yellow solid (90 mg, 37%). MS: [M+H]+ 728.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:40])([CH3:39])[C:35](=O)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:62]=[N+:63]=[N-:64].C1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[N:62]([C@@H:35]1[C:34]([CH3:39])([CH3:40])[C@H:33]2[C@@:27]3([O:26][C:11]4[C:12]5[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:15](=[O:18])[C:16]=5[CH:17]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:10]=4[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32]2)[CH2:37][CH2:36]1)=[N+:63]=[N-:64]
Reactant: [N-]=[N+]=N
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N=[N+]=[N-])CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of Compound (38a) (Step-3 in Example 42) (690 mg, 1.20 mmol) in 35 ml of dry benzene were added dropwise 480 mg (1.83 mmol) of triphenylphosphine and 1.0 ml (1.88 mmol) of 1.9M hydrazoic acid/benzene solution at room temperature with stirring, followed by the addition of 290 μl (1.84 mmol) of diethyl azodicarboxylate and stirring at 80° C. for 20 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size C; toluene:ethyl acetate=9:1) to give 474 mg (66%) of Compound (44).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]([N:26]5[CH2:30][CH2:29][CH2:28][C@H:27]5[C:31](O)=[O:32])=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:36][NH:37][CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:36][N:37]([CH3:38])[C:31]([C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][NH:22][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:35]=[CH:34][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])=[O:32]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC[C@H]3C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]amide (23 mg) was prepared by following General Procedure F starting from (S)-1-(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylic acid (33 mg), dimethylamine (35 uL, 2 M in THF), HBTU (29 mg), and DIEA (17 uL). LC/MS: m/z 540.7.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[Si]([C:20]1[N:21]([S:30](=[O:35])(=[O:34])[N:31]([CH3:33])[CH3:32])[C:22]([CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:23][N:24]=1)(C(C)(C)C)(C)C.C(OCC)(=O)C.CO>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH3:32][N:31]([CH3:33])[S:30]([N:21]1[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[CH:23][N:24]=[CH:20]1)(=[O:34])=[O:35]
Reactant: CN(C)S(=O)(=O)n1c(CCCCCl)cnc1[Si](C)(C)C(C)(C)C
Reactant: CC(=O)c1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(OCCCCc2cncn2S(=O)(=O)N(C)C)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2.87 g of 3-ethanoylphenol (21 mmol) in anhydrous DMF (30 ml) is cooled to 5° C. (ice bath) under an argon atmosphere, and 0.37 g of sodium hydride (60% suspension in mineral oil; 9.25 mmol) are then added. The mixture is stirred at 5° C. for 10 minutes and then at 20° C. for 2 hours. 0.70 g of 2-(t-butyldimethylsilyl)-5-(4-chlorobutyl)-1-(dimethylsulphamoyl)imidazole (1.85 mmol) (synthesized as described by R. C. Vollinga, W. M. P. B. Menge and H. Timmerman, Rec., Trav., Chem. Pays-Bas, 1993, 112, 123-125) and 45 mg of tetrabutylammonium iodide are added and the mixture is heated at 80° C. under argon for 3 days, then cooled to 20° C. and diluted with diethyl ether until the solution becomes cloudy. The resulting solid is filtered off and the filtrate evaporated to dryness in vacuo, giving a dark orange oil. The latter is subjected to column chromatography (SiO2; using an ethyl acetate/methanol mixture in the ratio 9:1) to give 1-(N,N-dimethyl-sulphamoyl)-5-[4(3-ethanoylphenoxy)butyl]imidazole in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[N:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:53])C>CCCCCC>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:53])=[C:4]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C#N)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C=O)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a mixture of 6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile (1.70 g) and anhydrous toluene (80 mL) was dropwise added a solution (0.95 M, 9.5 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (30 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and, after stirring the mixture at room temperature for 30 min., insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.98 g, 58%) of 6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[C:26]2[CH2:33][CH2:32][CH2:31][C:27]=2[N:28]=[CH:29][N:30]=1.Cl.C[O-].[Na+].CO>C(O)C.C(Cl)(Cl)Cl>[N:28]1[C:27]2[CH2:31][CH2:32][CH2:33][C:26]=2[C:25]([NH:21][C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[CH:14]=[C:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:23][CH:22]=2)=[N:30][CH:29]=1
Reactant: Clc1ncnc2c1CCC2
Reactant: Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(C=C1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
To a mixed solvent of 40 ml of chloroform and 20 ml of ethanol were added 2.33 g of 4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and 1.63 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and further 6 ml of an ethanol solution of hydrochloric acid (containing 0.4 g of hydrochloric acid) was added to the mixture and the mixture was stirred at 50° to 60° C. for 3.5 hours under heating. Then, under ice cooling, a 28% sodium methylate-methanol solution was added to the mixture to make it alkaline, and then the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.3 g of the title compound as yellowish white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][N:10]([CH3:20])[C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[C:21]([C:24]1[CH:25]=[C:26]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[C:37](=[C:39](Br)[N:40]([CH3:42])[N:41]=3)[N:38]=2)[C:27]([O:30][CH2:31][CH3:32])=[N:28][CH:29]=1)(=[O:23])[CH3:22]>O1CCOCC1.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>[C:21]([C:24]1[CH:25]=[C:26]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[C:37](=[C:39]([C:14]4[CH:15]=[N:16][C:11]([N:10]([CH3:20])[CH3:9])=[CH:12][CH:13]=4)[N:40]([CH3:42])[N:41]=3)[N:38]=2)[C:27]([O:30][CH2:31][CH3:32])=[N:28][CH:29]=1)(=[O:23])[CH3:22]
Reactant: CCOc1ncc(C(C)=O)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ncc(C(C)=O)cc1-c1nc2c(-c3ccc(N(C)C)nc3)n(C)nc2c(=O)[nH]1
Reaction time: 0.08 h
Yield: 53.2 %

Procedure:
Potassium carbonate (35 mg, 0.25 mmol), 6-(dimethylamino)pyridin-3-yl boronic acid dihydrochloride (42 mg, 0.25 mmol) and 5-(5-acetyl-2-ethoxy-3-pyridinyl)-3-bromo-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 58) (50 mg, 0.13 mmol) were suspended in dioxan/water (2 mL of a 4:1 mix) and the reaction mixture was immersed in a pre-heated oil bath (120° C.) for 5 min. The mixture was cooled and Pd(PPh3)4 (14 mg, 0.012 mmol) was added. The mixture was reheated to reflux for 2 h. More Pd(PPh3)4 (15 mg, 0.012 mmol) and 6-(dimethyl-amino)pyridin-3-yl boronic acid dihydrochloride (32 mg, 0.25 mmol) were added and reflux was continued for 14 h. The cooled reaction mixture was concentrated and the residue partitioned between dichloromethane and water and filtered through a plug of Celite®. The organic layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and evaporated. The yellow residual solid was purified by flash column chromatography (gradient elution from dichloromethane/0.2% ammonia to 99% dichloromethane/methanol/0.5% ammonia) to give 30 mg of the title compound. Further purification by trituration with ether and recrystallisation from isopropyl alcohol to give 18 mg of pure product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].N#N.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: Cl
Agent: N#N
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
To a stirred solution of (4-bromophenyl)[4-(methyloxy)phenyl]methanone (1) (27.0 g, 0.93 mol) in toluene (400 mL) was slowly added AlCl3 (32.0 g, 0.23 mol, 2.5 eq) via a powder addition funnel under a nitrogen atmosphere at RT. The stirred reaction mixture was heated at reflux for 5 h under a blanket of N2. The reaction mixture was allowed to cool to RT and then poured into 10% aqueous HCl (1 L). The reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (4×250 mL). The combined organic layer was washed with brine (2×100 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure to afford 25.75 g (100%) of compound 2 as a tan solid that was used in subsequent reactions without any further purification. 1H NMR (300 MHz, DMSO-d6): δ 6.89 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 10.48 (s, 1H).