Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-hydroxy benzoic acid methyl ester (4.665 g, 25 mmol), benzyl bromide (5.13 g, 30 mmol) and potassium carbonate (6.91 g, 50 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. The reaction mixture was poured onto crushed ice (ca. 300 g) and the product was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and precipitated by addition of hexane. Yield: 6.47 g (94%) white powder. 1H-NMR (400 MHz, CDCl3) δ=3.90 (s, 3H, —OCH3), 5.23 (s, 2H, —CH2Ar), 6.99 (d, J=9.0 Hz, 1H), 7.31-7.48 (m, 5H), 7.89 (dd, J=9.0, 2.3 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ccncc2N)cc1

Procedure:
0.569 g of a suspension of crude [4-(3-nitro-pyridin-4-ylamino)-phenyl]acetic acid methyl ester and 0.140 g of Raney Ni in 15 ml of MeOH is stirred for 21 hours at rt under a hydrogen atmosphere. The mixture obtained is filtered through a pad of Celite and the filtrate obtained is concentrated. The concentration residue obtained is triturated in CH2Cl2. [4-(3-Amino-pyridin-4-ylamino)-phenyl]-acetic acid methyl ester is obtained in the form of a solid: ES-MS: 258.0 [M+H]+; single peak at tR=2.54 min (System 1).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:4][CH:5]3[NH:14][C:13](=[O:15])[NH:12][C:6]3=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.II.C(OCC)C.[ClH:23]>>[ClH:23].[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]3[NH:14][C:13](=[O:15])[NH:12][C:6]3=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc2c1CC1NC(=O)NC1=N2
Agent: Cl
Agent: II
Solvent: CCOCC
Product: Cc1cccc2nc3[nH]c(=O)[nH]c3cc12
Yield: 72 %

Procedure:
If desired, acid addition salts of the Formula I products can be prepared by acidifying the residual material in an appropriate solvent. For instance, treating 8-methyl-1,3,9,9a-tetrahydro-2H-imidazo[4,5-b]quinolin-2-one with iodine as above and dissolving the insoluble product in a 10% methanolic hydrogen chloride solution followed by addition of diethyl ether provided a 72% yield of 8-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one hydrochloride, m.p. 360°-363° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4ccc(F)cc4)ccc3C)csc12

Procedure:
3-[5-(4-Fluoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 23 supra) and 4-fluorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=O)[CH3:11]>>[CH3:10][CH:11]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1
Reactant: CC(=O)Cl
Reactant: NCCc1ccccc1
Product: CC1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and acetyl chloride, 1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 91%) The product was used in the subsequent step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10](=O)[CH3:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]([S@:17]([NH-:19])=[O:18])([CH3:16])[CH3:15].[BH4-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([CH:10]([NH:19][S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)c1ccc2ncsc2c1
Reactant: CC(C)(C)[S@]([NH-])=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1ccc2ncsc2c1
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
To a THF (6 ml) solution of 1-(1,3-benzothiazol-6-yl)ethanone (European Journal of Organic Chemistry (1998), (9), 2047-2050., 250 mg, 1.41 mmol) and (R)-(+)-2-methyl-2-propane sulfinylamide (188 mg, 1.55 mmol), titanium(IV) ethoxide (2 ml) was added and the mixture was stirred for 40 minutes at 85° C. under microwave condition. The mixture was then cooled to 0° C. and sodium borohydride (188 mg, 5.0 mmol) was added to the reaction mixture. After stirring for 2 hours at the temperature, the reaction was partitioned with water and EtOH followed by stirring for 1 hour at room temperature. Then, filtration, evaporation gave N-[1-(1,3-benzothiazol-6-yl)ethyl]-2-methylpropane-2-sulfinamide (MS (ESI) m/z 281 (M−H)−, 283 (M+H)+) which was then added hydrochloric acid-MeOH (2.0 M, 7.0 ml) and 1,4-dioxane (7.0 ml). The mixture was then stirred for 1.5 hours at room temperature and the same reaction procedure as Example 14 was performed to give the title compound. MS (ESI) m/z 180 (M−H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])=[N:38][CH:39]=1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1ccc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cn4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 460 mg, 1.22 mmol) was diluted with DCM (5 mL) followed by the addition of oxalyl chloride in DCM (2M) (671 μL, 1.34 mmol) and DMF (1 drop). 5-Bromopyridin-2-amine (634 mg, 3.66 mmol) and pyridine (966 mg, 12.2 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with 2N HCl, water, dried over MgSO4, filtered and concentrated. The material was purified on silica gel eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (450 mg, 0.846 mmol, 69.3% yield).
Reaction SMILES: Cl.Cl.[F:3][CH:4]([F:15])[C:5]([NH2:14])([CH2:10][CH2:11][CH2:12][NH2:13])[C:6](OC)=[O:7].C[O-].[Na+]>CO>[NH2:14][C:5]1([CH:4]([F:15])[F:3])[CH2:10][CH2:11][CH2:12][NH:13][C:6]1=[O:7]
Reactant: COC(=O)C(N)(CCCN)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1(C(F)F)CCCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (±)-methyl 2-difluoromethyl-2,5-diaminopentanoate dihydrochloride (2.7 g) in dry methanol (30 ml) is added under nitrogen 2 equivalents of sodium methylate in methanol (0.46 g of sodium in 20 ml of methanol). The reaction mixture is stirred for 3 hours at room temperature, then the solvent is evaporated under reduced pressure. The residue is extracted with ether to yield crude (±)-3-amino-3-difluoromethyl-2-piperidone which is purified either by crystallization from CHCl3 /pentane (m.p. 149° C.) or by distillation (b.p. 135° C./0.05 mm Hg).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12]CC)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([OH:12])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CC(=O)O)OCC

Procedure:
Ethyl diethylphosphonoacetate (100 g, 446 mmol) was dissolved in ethanol (275 ml), and after adding dropwise a 2 mol/l aqueous sodium hydroxide solution (275 ml, 550 mmol) while stirring and cooling with ice, it was stirred at room temperature for 1 hour. The reaction solution was then concentrated under a reduced pressure, and the concentrate was made acidic by concentrated hydrochloric acid while cooling with ice. Extractions into ethyl acetate (200 ml×4), chloroform (100 ml×2) and 5% methanol/chloroform (250 ml×2) were then performed. The combined organic layers were then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. 89 g (quantitative) of the title compound was thereby obtained as a colorless, oily substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[F:28])=[CH:14][C:13]=1[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37]1[C:38]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:41]3[CH:40]=[N:39][C:38]([O:52][CH2:53][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)=[C:37]([O:36][CH2:34][CH3:35])[CH:42]=3)=[CH:23][C:22]=2[F:28])=[CH:14][C:13]=1[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A suspension of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide (800 mg, 1.520 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added to a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (586 mg, 1.520 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL). PdCl2(dppf) (111 mg, 0.152 mmol) and Cs2CO3 (990 mg, 3.04 mmol) were added and the mixture was at 110° C. for 30 min under microwave. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1, Rf=0.5) to yield a light yellow solid of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (230 mg, 0.326 mmol, 21.5% yield): 1H NMR (400 MHz, CD3OD) δ 7.95-7.94 (d, J=2.0 Hz, 1H), 7.90-7.89. (d, J=2.8 Hz, 1H), 7.45-7.38 (m, 6H), 7.37-7.25 (m, 6H), 6.92-6.90 (m, 2H), 5.36 (s, 2H), 4.61 (s, 2H), 4.25-4.24 (m, 2H), 4.23-4.11 (m, 2H), 3.85-3.83 (m, 2H), 3.79-3.77 (m, 2H), 1.45-1.41 (t, J=4.8 Hz, 3H); ES-LCMS m/z 705.1 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17]O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:21])=O>>[CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17][Cl:21])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc2c(C3CCCCC3)nccc12
Reactant: O=P(Cl)(Cl)Cl
Product: ClCc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-hydroxymethylisoquinoline and phosphorus oxychloride were reacted in the same way as in step (g) of Example 13 to afford 1-cyclohexyl-5-chloromethylisoquinoline having a melting point of 88.4° to 89.4° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[CH:38]=[CH:37][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]3[N:33]([CH3:34])[C:32](=[O:35])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[CH3:36])[N:25]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][N:11]=1>CN(C=O)C>[CH3:34][N:33]1[C:32](=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH3:36])[N:25]=[C:24]1[CH:23]=[CH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]2[CH:37]=[CH:38][C:10]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CCO
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(OCCN(C)C)nc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
To a solution of 2-dimethylaminoethanol (53 mg) in DMF (3 ml) was added 60% sodium hydride (29 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 2-[2-[4-(6-chloronicotinoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (208 mg) was added and the mixture was further stirred at room temperature for 2 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was washed serially with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to 10 ml. To this organic was added 1N-hydrochloric acid (2 ml) and the mixture was extracted with water. The aqueous layer was diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness to provide 169 mg of yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[CH3:8].O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(C)c(C)c2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-dimethylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly brown amorphous powder (yield 69%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:25]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])C1
Yield: 96 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 3-(N-Boc-amino)piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperidin-3-ylcarbamate (96%). LCMS (m/z): 390.1 (MH+); LC Rt=3.28 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(#N)C.ClCCl.O>[N:9]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cc1ccccc1OCCCBr)OCc1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1OCCCN1CCCC1)OCc1ccccc1
Temperature: 90 °C

Procedure:
2.06 g of potassium carbonate, 0.5 g of sodium iodide and 1.25 cm3 of pyrrolidine are added to a solution [lacuna] 5.3 g of benzyl [2-(3-bromopropoxy)phenyl)acetate in 100 cm3 of acetonitrile. The mixture is heated at 90° C. for 3 hours and then cooled to room temperature, 50 cm3 of water are added, and the mixture is then diluted with 50 cm3 of dichloromethane. The organic phase is separated off, washed with water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 5.3 g of benzyl {2-[3-(1-pyrrolidinyl)propoxy]phenyl}acetate are obtained in the form of an orange-coloured oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 200 parts of methanol, 1.2 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 5 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[F:34])#[N:24]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([F:34])=[C:25]([CH:30]=3)[C:23]#[N:24])[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(F)c(C#N)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and (4-cyano-3-fluorophenyl)boronic acid (from Aldrich). LCMS calculated for C23H20FN4O2(M+H)+: m/z=403.2. Found 403.2.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([O:21][CH3:22])[CH:20]=1)[NH:17][C:16](=[O:23])[C:15]12[O:27][CH2:26][CH2:25][O:24]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH3:1][C:2]1[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH3:22])[CH:20]=2)[NH:17][C:16](=[O:23])[C:15]23[O:24][CH2:25][CH2:26][O:27]2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: COc1cc(Br)cc2c1NC(=O)C21OCCO1
Reactant: Cc1noc(C)c1B(O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C21OCCO1
Temperature: 102 °C
Yield: 25.7 %

Procedure:
A mixture of 3,5-dimethylisoxazol-4-ylboronic acid (298 mg, 2.1 mmol), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (29 mg, 0.14 mmol), 5′-bromo-7′-methoxyspiro[[1,3]dioxolane-2,3′-indolin]-2′-one (210 mg, 0.7 mmol) and Na2CO3 (233 mg, 2.1 mmol) in dioxane (9 mL) and water (2 mL) was heated to 102° C. for 16 h. To the mixture was added EtOAc (50 mL), water (20 mL). The organic layer was separated and washed with water (20 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, using a mixture of 33% EtOAc in dichloromethane as the eluent, to give the desired product as a light brown solid (57 mg, crude, 26%). 1H NMR (400 MHz, DMSO-d6): δH 10.62 (s, 1H), 7.02-7.03 (m, 1H), 6.92-6.93 (m, 1H), 4.26-4.34 (m, 4H), 3.86 (s, 3H), 2.38 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M+1]+ 317.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:2].Br[C:17]1[CH:22]=[CH:21][N:20]=[N:19][CH:18]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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(O)C>[N:19]1[CH:18]=[CH:17][C:22]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=2)=[CH:21][N:20]=1
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 4-(2-ethoxy-2-oxoethyl)phenylboronic acid 37-2 (310 mg, 1.5 mmol), 4-bromopyridazine 37-1 (158 mg, 1 mmol), Pd(PPh3)4 (70 mg, 0.1 mmol), toluene (4 mL), ethanol (1 mL) and 2M Na2CO3 (1.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution and brine. The organic phase was dried over Na2SO4 and then concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 as pale yellow solid. MS m/z 243.1 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:15](=[O:20])N(OC)C)[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([CH:15]=[O:20])[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of [(S)-1-(Methoxy-methyl-carbamoyl)-2-methyl-propyl]-carbamic acid benzyl ester (8) (33 g, 112 mmol) in dry THF (300 mL) at −30 to −40° C. was added LiAlH4 (4.3 g, 113 mmol) portion wise over a period of 45 min. The reaction mixture was warmed to 0° C. and stirred at this temperature for 2 h. The reaction mixture was quenched with 1 M KHSO4 (330 mL) at 0° C. then 10% w/v Rochelle's salt (aq) (330 mL) was added and the mixture stirred for 20 minutes, then extracted with EtOAc (2×700 mL). The combined organic phases were washed with 10% w/v Rochelle's salt (aq) (330 mL) and brine (450 mL), dried over MgSO4, filtered and concentrated under vacuum to obtain the desired aldehyde as a clear oil (26.3 g) (AnalpH2_MeOH—4 min) Rt 2.59 min; m/z 236 (MH)+. (This was used without further purification in the next step.)