Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:13]O>CC(O)=O>[Br:1][C:2]1[CH:7]=[N+:6]([O-:13])[C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Solvent: CC(=O)O
Product: CN(C)C(=O)c1ccc(Br)c[n+]1[O-]
Temperature: 78 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
To a solution of 5-bromo-N,N-dimethylpyridine-2-carboxamide (730 mg, 3.19 mmol) in 10 mL of HOAc was added 1 ml of 35% H2O2. After stirring the mixture at 78° C. for 14 hours, it was cooled and concentrated under reduced pressure. The residue was made alkaline with excess solid Na2CO3 and diluted with 25 mL of CHCl3 with stirring. The inorganic salts were filtered off, and the organic layer was dried over Na2SO4. The solvent was evaporated under reduced pressure to provided the product (750 mg, 98%), which was used without further purification. MS (ESI, pos): 247.00.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[C:12]1[CH:17]=[CH:16][NH:15][CH:14]=[CH:13]1)[C:5]2=O.O.[NH2:20][NH2:21]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:6][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:21][NH:20]1
Reactant: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Reactant: NN
Solvent: O
Product: O=c1[nH]nc(Cc2ccncc2)c2cc(Br)ccc12

Procedure:
Under exclusion of air, 4.75 g (15.7 mmol) 5-bromo-2-(1H-pyridin-4-ylidene)indan-1,3-dione and 14 ml hydrazine hydrate are heated for 4 h to 130° C. Cooling, filtering, and washing with ethanol yields title compound A in the mixture with a little 1-oxo-4-[(pyridin-4-yl)-methyl]-6-bromo-1,2-dihydrophthalazine (B). A: HPLC: tRet(Grad5-40)=11.5; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.34 (d, J=2, 1H), 8.07 (dd, J=8, 2, 1H), 7.85 (d, J=8, 1H), 7.30 (d, J=6, 2H), 4.33 (s, 2H); B: HPLC: tRet(Grad5-40)=11.3; 1H-NMR (DMSO-d6) 12.76 (HN), 8.46 (d, J=6, 2H), 8.16 (d, J=8, 1H), 8.14 (d, J=2, 1H), 8.00 (dd, J=8, 2, 1H), 7.3 (d, J=6, 2H), 4.35 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=O)[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([Cl:23])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(I)cc1
Product: CCCCc1nc(C)nc(Cl)c1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 485 mg (1.27 mmol) 6-butyl-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine-4(3H)-one in 7 mL POCl3 was refluxed for 60 minutes. After cooling to room temperature, excess POCl3 was stripped off in vacuo. The crude product was partitioned between CH2Cl2 and a mixture of brine and NaHCO3. The organic layer was removed and the aqueous layer was extracted three more times with CH2Cl2. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 380 mg of 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine, 75% yield.
Reaction SMILES: OS(O)(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reaction time: 24 h

Procedure:
A solution of H2SO4 (5 ml) in dioxane (80 ml) was added to 4-hydroxyphenylacetic acid (20 gm, 0.13 mol) in a pressure bottle. Isobutylene (250 ml) was added and the bottle was sealed and the mixture was stirred for 24 hr. The reaction mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed successively with saturated NaHCO3, H2O (twice) and brine before being dried over Na2SO4 and evaporated to dryness. Crystals formed after standing overnight and they were filtered, washed with cold hexane and dried to give 20.99 gm of the title compound. M.pt. 95°-96° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=1.[CH3:30][O:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[C:34]([O:41][CH3:42])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=[C:2]([C:37]2[C:32]([O:31][CH3:30])=[N:33][C:34]([O:41][CH3:42])=[CH:35][CH:36]=2)[CH:3]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
Reactant: COc1ccc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)nc2OC)cc(C(C)(C)C)c1OC
Yield: 79.2 %

Procedure:
step 1—A sealed tube containing 315 (117 mg, 0.243 mmol), 2,6-dimethoxy-pyridin-3-yl boronic acid (53 mg, 0.290 mmol, CASRN 221006-70-8), Pd(PPh3)4 (28 mg, 0.024 mmol), Na2CO3 (76 mg, 0.717 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave reactor at 115° C. for 30 minutes. The reaction mixture was concentrated, diluted with EtOAc, washed with brine and dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20% to 30% EtOAc) to afford 104 mg (79%) of N-(4-{(E)-2-[3-tert-butyl-5-(2,6-dimethoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-3-methoxymethyl-phenyl) methanesulfonamide (322) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)c3ncco3)cc2)cn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 496 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:14]2[CH2:13][CH2:12][N:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:16][CH2:15]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c(OC)c1

Procedure:
Prepared analogously to Example 2 b from 1-(2,4-dimethoxy-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:28]1[C:29]([Cl:33])=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1ncc(Cl)c(Nc2ccccc2Cl)n1
Temperature: 100 °C
Yield: 83.6 %

Procedure:
Into a round bottom flask was added o-chloroaniline (6.46 mL, 39.2 mmol) and N-methylpyrrolidinone (37.8 mL, 392 mmol). N,N-Diisopropylethylamine (8.19 mL, 47.0 mmol) was added followed by 2,4,5-trichloro-pyrimidine (5.39 mL, 47.0 mmol) and the mixture was heated at 100° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in DCM (150 mL) and washed with water (150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-12% EtOAc/hex as the eluting solvent to obtain (2-chloro-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine as a yellow solid (9.0 g, 84%). LCMS (m/e) 274 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.54 (d, 1H, J=8.3 Hz), 8.28 (s, 1H), 8.00 (bs, 1H), 7.47 (d, 1H, J=8.0 Hz), 7.44-7.37 (m, 1H), 7.17-7.11 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[S:8][CH:7]=[N:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2scnc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2scnc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 5-(6-methylbenzothiazol-5-yl)-2-pyridylamine (55) (24 mg, 0.1 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (25 μl, 0.2 mmol) followed by addition of DIEA (105 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 1 h and then at 50° C. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methylbenzothiazol-5-yl)(2-pyridyl)]carboxamide (56) (29.6 mg, yield: 77.6%, purity>95%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:17]1[C:8](=[O:9])[C:3]2=[C:2]([CH3:1])[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]1=[O:7])[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C(=O)N(CC(C)C)C2=O
Temperature: 140 °C
Reaction time: 16 h

Procedure:
N-Isobutyl-3-methylphthalimide is prepared as described in Example 2, starting with 5.0 g of 3-methylphthalic anhydride, 3.0 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 50 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 2.5 hours and then stirred at a temperature in the region of 20° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase is separated out after settling has taken place, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 6.0 g of N-isobutyl-3-methylphthalimide are thus obtained in the form of a caramel-colored oil, Rf=0.76 (thin layer chromatography on silica gel, eluent: dichloromethane).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]([CH2:42][CH3:43])[N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:42]([N:35]1[C:36]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)[C:33]([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)=[N:34]1)[CH3:43]
Reactant: CCOC(=O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Reactant: CCn1nc(Br)c2ncccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cn1c(Oc2ccc(-c3nn(CC)c4cccnc34)cc2)nc2ccccc21
Yield: 18.6 %

Procedure:
A mixture of ethyl {2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (540 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (289 mg), Pd(PPh3)4 (44.3 mg), Na2CO3 (474 mg) in DME (10 mL) and water (2 ml) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (105 mg).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])[C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]1=[O:29])C.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:7](=[O:29])[CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:9]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]1=2
Reactant: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2C(CC(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC1C(=O)N(CC(=O)O)CC(c2ccccc2Br)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
185 mg of the compound from Example 14A (0.38 mol) are dissolved in 6 ml of THF/methanol (1:1) and 1 ml of 1 N sodium hydroxide solution is added. The reaction mixture is stirred at room temperature for 16 h. It is diluted with water and acidified with 2 N hydrochloric acid, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. 172 mg (99% of theory) of the title compound are obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9].[C:22](Cl)(=[O:24])[CH3:23].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
392 Gram of granular anhydrous aluminum chloride and 700 ml of nitrobenzene were introduced into 5 l three neck flask, and dissolved with stirring. A solution of 600 g of 4-n-pentylbiphenyl and 220 g of acetyl chloride dissolved in 500 ml of nitrobenzene (prepared in advance) was dropwise added to said three neck flask over 1 hour, followed by stirring for one hour, further stirring at 40°-45° C for 2 hours, cooling to room temperature, pouring cautiously into a mixed liquid of 250 ml of conc. hydrochloric acid and 1.25 l of water, distilling off nitrobenzene from nitrobenzene layer by distillation under a reduced pressure, separating the resulting solid by filtration, and recrystallizing it from ethanol, to give 597 g of 4'-n-pentyl-4-acetylbiphenyl (m.p. 81°-82°) (Yield 84%).
Reaction SMILES: C[O-].[Na+].C([O:8][C:9]([CH:11]1[C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=[CH:12]1)=O)CCC.C(OC(C1C2C=CC(Cl)=CC=2C(C2C=CC=CC=2)=NCC=1)=O)CCC.C(O)(=O)C.[CH:58]([NH2:60])=[NH:59]>C(O)C.O.CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[CH:11]3[C:9](=[O:8])[NH:60][CH:58]=[N:59][CH:12]3[CH2:13][N:14]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:21]=1
Reactant: CCCCOC(=O)C1C=CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: N=CN
Agent: CCCCOC(=O)C1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1NC=NC2CN=C(c3ccccc3)c3cc(Cl)ccc3C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dropwise 9.5 mL (41 mmol) of a 4.3M methanol solution of sodium methoxide was added to a solution of 8.0 g (22.6 mmol) of a mixture of 8-chloro-1-phenyl-5H-2-benzazepine-5-carboxylic acid butyl ester and 8-chloro-1-phenyl-3H-2-benzazepine-5-carboxylic acid butyl ester and 6.5 g (62.4 mmol) of formamidine acetate in 70 mL of ethanol. When the addition was complete stirring at room temperature was continued for 30 min. The reaction was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was crystallized from a mixture of ether and petroleum ether to give a yellow solid. Recrystallization from a mixture of ether and methylene chloride gave pale yellow prisms, mp 150°-155°.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH2:5][O:4]1.[H-].[Na+].[CH2:11]([O:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:8][CH:7]1[CH2:6][CH2:5][O:4][CH:3]1[O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1OCCC1O
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1OCCC1OCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-tetrahydro-furan-3-ol in DMF 200 mL was added sodium hydride in small portions with stirring at 0° C. for 2 hrs, then 2-Benzyloxy-ethanol was added from the dropping funnel over a period of 1 hour, the resulting mixture was stirred at 25° C. for 15 hrs, it was poured into 400 mL water, EtOAC(1 L) were added and separated. The organic layer was washed with sat. NaHCO3(500 mL), dried over Na2SO4, filtered and concentrated, The residue was purified by column chromatography (PE:EA=5:1) to yield 10 g of 3-(2-Benzyloxy-ethoxy)-2-methoxy-tetrahydro-furan (oil).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][N:22]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCNCC4)C3)cnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCN(C(=O)C(C)(C)C)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Cyclohexyl-1-ethyl-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (70 mg, 0.00016 mole) (example 22) was taken in dichloromethane (10 ml). Triethyl amine (0.07 ml, 0.00050 mole) and pivaloyl chloride (0.030 ml, 0.00025 mole) were added at 0° C. The reaction mixture was stirred at room temperature overnight. It was diluted with dichloromethane, washed with sodium bicarbonate solution, extracted with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by preparative thin layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1COCC1.C(Cl)Cl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 3-aminopyridine 244 (3.03 g, 32.23 mmol) in THF (70 mL) and DCM (135 mL) was added 4-nitrobenzene sulfonyl chloride 245 (1.5 g, 67.68 mmol), triethylamine (7.17 g, 70.9 mmol) and dimethylamino pyridine (catalytic amount). The reaction mixture was allowed to stir at room temperature for 1 h then concentrated. The residue was taken up in MeOH (200 mL) then solid sodium methoxide (20 g) was added and the reaction mixture was stirred at 50° C. for 3 h, carefully neutralized with 1N HCl until pH 7. The formed precipitate was collected by filtration to give the title compound 246 (7.67 g, 85% yield).
Reaction SMILES: Br[C:2]1C=C(C=CC=1)C(O)=O.C[Al](C)C.[CH3:15][C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)=[CH2:17]>CCCCCC>[C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)([CH3:2])([CH3:15])[CH3:17]
Reactant: C=C(C)c1cccc(Br)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A suspension of 4.02 g (20 mmol) of m-bromobenzoic acid (Compound 23) in 10 ml hexane was cooled in an ice-bath under nitrogen and then treated slowly with 40 ml of 2 M (80 mmol) trimethylaluminum in hexane. The hexane was removed by distillation under nitrogen and the apparatus modified for reflux. The reaction mixture was then heated in an oil bath at 140-150 degrees C. for 3 hours. The oil bath was then replaced by an ice-water bath and the reaction mixture was quenched by the slow dropwise addition of water. The mixture was acidified with dilute HCl and mixture heated at reflux until the aluminum salts were dissolved. The reaction mixture was allowed to cool and extracted with 3×8 ml ether. The ether extracts were combined, washed with dil. HCl, water and saturated NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled to give a mixture of the title compound and 3-(1-methyl-ethenyl) bromobenzene as a colorless oil. A small portion (200 mg) of this mixture was dissolved in 1 ml of methylene chloride and then treated with a solution of 200 mg of m-chloroperbenzoic acid in 4 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour and the methylene chloride removed invacuo. The residue was dissolved in hexane and filtered through a short silica column and the filtrate concentrated in-vacuo to give pure title compound as a colorless oil. PMR (CDCl3): & 1.30 (9H, s), 7.25 (1H, m), 7.41 (2H, m), 7.65 (H, t, J~2.1 Hz).