Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)=[CH:23][C:22]=1[F:30])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cn1nc(Br)c2cnc(N)nc21
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccc(OCc3ccccc3)c(F)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.33 g, 1.46 mmol) and 4-benzyloxy-3-fluoro phenylboronic acid (0.43 g, 1.75 mmol) are suspended in 1,4-dioxane (5 ml) in a microwave vial flushed with argon. A solution of Cs2CO3 (1.43 g, 4.38 mmol) in water (1.5 ml) is added followed by Pd(PPh3)4 (0.085 g, 0.073 mmol) and the reaction mixture is heated using microwave radiation at 150° C. for 0.5 hours. After cooling to room temperature the reaction mixture is diluted with EtOAc (100 ml) and washed with saturated NaHCO3. The organic portion is dried over MgSO4, filtered, concentrated in vacuo and the resulting crude solid is triturated with EtOAc (˜20 ml) to afford the title compound as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOCCc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a yellow solid; MS: 642 (M+H)+.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)O.C(C(C(C([O-])=O)O)O)([O-])=[O:27].[Na+].[K+]>C1(C)C=CC=CC=1>[C:19]1([C@@H:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][OH:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC1CCCCO1)c1ccccc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC[C@H](OC1CCCCO1)c1ccccc1
Reaction time: 1 h

Procedure:
Into toluene (15 ml) was added (R)-2-phenyl-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)mandelic acid methyl ester (7.0 g) obtained in 2) above, and thereto was dropwise added a 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (8.73 g) with ice cooling. The resulting mixture was stirred at the same temperature for 1 hour, the reaction mixture was added into a 30% aqueous (+)−potassium sodium tartrate solution (31.3 g), then stirred for 1 hour, and the organic layer was separated. The organic layer obtained was washed with water and further with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was distilled off to obtain a colorless oily compound mentioned above (6.10 g, 97.9%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH:10]=[CH:24]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of (S)-(−)-2-(tert-butoxycarbonylamino)-3-phenylpropanal (6.87 g, 27.56 mmol) and (carbethoxymethylene)triphenylphosphine (9.60 g, 27.56 mmol) in toluene (150 mL) was stirred and heated to 80° C. for 70 min. The product was isolated by flash column chromatography on silica gel using a gradient elution of 5-25% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.33-7.22 (m, 3H), 7.19-7.17 (m, 2H), 6.92 (dd, J=4.8, 15.6 Hz, 1H), 5.86 (dd, J=1.6, 15.6 Hz, 1H), 4.62 (br s, 1H), 4.52 (br s, 1H), 4.19 (q, J=7.2, 14.0 Hz, 2H), 2.95-2.90 (m, 2H), 1.40 (s, 9H), 1.30-1.25 (m, 3H); ES MS [M-100 (loss of BOC)+1]=220.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:32]2[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([CH3:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-methylbenzylamine (465.3 mg, 3.84 mmol, 0.489 mL) resulting in the formation of a bright yellow precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrystallisation of the cream/yellow residue from a minimum amount of boiling ethyl acetate and excess petrol yielded the title product as a fine pale yellow crystalline solid (1.090 g, 3.10 mmol, 81%). 1H NMR: (300 MHz, DMSO) δ ppm 2.21 (s, 3H, H12), 4.20 (d, 1H, J=15.62 Hz, H9), 4.40 (d, 1H, J=15.36 Hz, H9′), 6.95 (d, 2H J=7.97 Hz, H11, H13), 7.04 (d, 2H J=8.00 Hz, H10-H14) 7.27 (m, 5H, H1-H5), 7.55 (m, 2H, H6-H7) 7.74 (d, 1H, Hs). 13C NMR: (75 Hz, DMSO) δ 20.90 (CH3), 42.53 (N—CH2), 90.57 (O—C—N), 122.89, 123.15, 128.36, 128.38, 128.61, 129.66, 130.85, 132.91, 133.03, 135.37, 135.84, 139.51 (Ar), 167.10 (C═O). IR: 1398, 1468, 1660, 2921, 3138 cm−1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C[N:10](C)[CH:11]=[O:12]>>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([NH2:10])=[O:12]
Reactant: C1CCNCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: NC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
Meanwhile sodium hydride (150 mg of a 60% dispersion in mineral oil) is added to a solution of N-(3,5-dichloro-1-oxido-4-pyridinio)acetamide (663 mg) in dimethylformamide (20 mL) and the mixture stirred for 2 hours. The mixture is then added to the solution of the acid chloride and stirring continued for 3 hours. Piperidine (0.26 mL) is added and stirring continued for a further 4 hours. After concentrating in vacuo the residue is dissolved in dichloromethane, the mixture filtered, the filtrate treated with decolourizing charcoal and refiltered. Evaporation in vacuo gives a brown oil which is purified by reverse phase high pressure liquid chromatography (methanol/water 4:1 v/v) to give (±)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.2.6]hept-2-yloxy)pyridine-2-carboxamide (60 mg) as a solid, m.p. 235-6° C. [Elemental analysis: C, 54.16; H, 4.21; N, 10.58% calculated: C, 56.04; H, 4.06; N, 9.95%].
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9](O)[CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([C:19](=O)[CH3:20])[CH:18]=1.[OH-].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][N:6]=1)[N:1]=[C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[CH3:22])[CH:20]=[C:9]2[CH3:10]
Reactant: CC(=O)c1cc(F)ccc1C
Reactant: CC(O)c1cc(Cl)ncc1N
Agent: Cl[Ru]Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc(C)c2cc(Cl)ncc2n1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
A screw-top vial was charged with 1-(5-amino-2-chloropyridin-4-yl)ethanol (46.3 mg, 0.268 mmol), 5′-fluoro-2′-methylacetophenone (82.0 mg, 0.540 mmol), tris(triphenylphosphine)ruthenium(II) dichloride (13.0 mg, 0.013 mmol), potassium hydroxide (15 mg, 0.27 mmol), and 1,4-dioxane (1.5 mL, 19 mmol). The reaction vial was flushed with nitrogen gas, sealed with a teflon lined cap, and heated at 80° C. for 2 hours. The reaction mixture was then diluted in ethyl acetate, filtered through celite, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in heptane) to yield 27.9 mg (36%) of 6-chloro-2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridine. LCMS (ESI): M+H=287.2; 1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.41 (m, 2H), 7.26 (m, 1H), 2.75 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:20])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[C:66]([NH2:71])[CH:65]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:70][C:67]2[CH:68]=[CH:69][C:64]([F:63])=[CH:65][C:66]=2[NH2:71])=[O:31])=[O:20])=[CH:32][CH:33]=1
Reactant: O=C(O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(F)ccc1NC(=O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
8-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)octanoic acid (452 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (358 mg, 64% yield) as a brown solid. LC-MS (m/z) 561 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Nc1ccc2ccncc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2ccncc2c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-aminoisoquinoline (D96) (88 mg, 0.61 mmol) in DCM (4 ml) was added 4-biphenylcarboxylic acid (145 mg, 0.73 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and the reaction stirred at ambient temperature overnight. The reaction mixture was filtered to give the title compound as a white solid. The filtrate was diluted with DCM, washed with 2M sodium hydroxide solution, dried over MgSO4 and concentrated in vacuo to give further crude product which was purified by silica SPE chromatography. Elution with an EtOAc/60-80° C. petroleum ether gradient gave a further title compound which was combined with the sample obtained from the filtration. This was dissolved in ethanol and treated with ethereal HCl and the resultant precipitate was collected to give the HCl salt of the title compound as a white solid. 1H NMR (250 MHz, DMSO) δ (ppm): 9.80 (s, 1H), 9.09 (d, 1H), 8.58 (d, 1H), 8.40 (dd, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 8.16 (d, 2H), 7.90 (d, 2H), 7.79 (d, 2H), 7.54 (t, 2H), 7.45 (t, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO[C@@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)C(=O)O
Yield: 69.7 %

Procedure:
(S)-Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate (1.0 g, 1 eq, 2.4 mmol) obtained in example 49, was hydrolyzed using lithium hydroxide monohydrate (151 mg, 1.5 eq, 3.6 mmol) in methanol-THF-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes→methanol and chloroform to afford the title compound (650 mg, yield 70%) as viscous liquid.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14])C1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[OH:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 28 h
Yield: 74.7 %

Procedure:
A solution of methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (10.0 g, 22 mmol) in dichloromethane (150 mL) was treated with trichloride dimethyl sulphide complex (40 ml, 2M, 80 mmol). The reaction was stirred at ambient temperature for 28 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the layers separated. The aqueous layer was washed with dichloromethane, the organic layers combined, dried (MgSO4) and evaporated to give an off-white solid. This was subjected to chromatography to give methyl 2-[N-(2-hydroxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (6.0 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Product: CCC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 100 °C

Procedure:
The operation is carried out as in Stage 2 of Example 3 and 161 mg of the product obtained in Stage 1 above, 3 ml of butanol and 0,132 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 90 to 110° C. for approximately 5 hours, then left to return to ambient temperature. After leaving to crystallize, the reaction medium is diluted with 10 ml of isopropanol, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. After chromatography on silica eluting with methylene chloride/ethyl acetate in a proportion of 50/50, In this way 179 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [ClH:1].FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1[O:9][C:10]1[C:15]2=[C:16](C)[C:17](OCCN3CCOCC3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(N)=O>[Cl:1][C:16]1[CH:17]=[CH:18][N:14]2[C:15]=1[C:10](=[O:9])[NH:11][CH:12]=[N:13]2
Reactant: Cl
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Solvent: NC=O
Product: O=c1[nH]cnn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (10.0 g, 57.3 mmol, WO 03/099286: Compound A of Example 9) in formamide (40 mL) was heated at 170° C. for 1 h and then at 190° C. for 1 h. Upon cooling to room temperature, the mixture solidified. The product was purified by recrystallization from ethyl acetate to give the title compound (6.53 g, 67%) as a white solid. 1H NMR (CDCl3) δ 10.24 (br s, 1H), 7.48 (d, 1H, J=3.6 Hz), 7.29 (d, 1H, J=2.8 Hz), 6.47 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 170.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=O)C.C(OCC)(=O)C.O>C1COCC1>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The aldol product 34 (10 mmol) was dissolved in absolute THF (20 ml) under an argon atmosphere. BH3xTHF (40 ml, 1 M solution, 40 mmol) was then added to the mixture, and the mixture was stirred at room temperature for 14 hours. The course of the reaction was monitored of TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with 30 ml portions of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was filtered over silica gel with ethyl acetate. After removal of the solvent, the product was obtained in the form of a sufficiently pure oil and crystallized spontaneously.
Reaction SMILES: Br[C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.N1C=CC=N1.CC1(C)OB([C:29]2[CH:34]=[CH:33][N:32]=[C:31]3[NH:35][CH:36]=[CH:37][C:30]=23)OC1(C)C.C([O-])(O)=O.[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.CN(C=O)C>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]3[NH:35][CH:36]=[CH:37][C:30]=23)[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4]1
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Reactant: CCOC(=O)c1nn(C2CCCCO2)cc1Br
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: CN(C)C=O
Product: CCOC(=O)c1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12

Procedure:
Ethyl 4-bromo-1-(oxan-2-yl)-1H-pyrazole-3-carboxylate (as a mixture of regioisomers of the tetrahydropyran group at the nitrogen atoms of the pyrazole) (7.9 g, 26.23 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (6.4 g, 26.23 mmol), and Pd(PPh3)4 (1.8 g, 1.57 mmol) were taken up in a degassed DMF (100 mL) and NaHCO3 (saturated, 50 mL) under an atmosphere of nitrogen.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11]>C1COCC1>[Cl:7][C:8]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 85.7 %

Procedure:
A suspension of LiAlH4 (7.4 g, 0.195 mol) in THF (500 mL) was stirred at 0° C. A solution of methyl 2,3-dichlorobenzoate (49 g, 0.244 mol) in THF (50 mL) was added dropwise into the above mixture at 0-5° C. Then the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ethyl acetate (15 mL), water (7.5 mL), 15% NaOH (7.5 mL) and water (22.5 mL), filtered and the filtrate was concentrated. The resulting residue was dissolved with DCM (500 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (37 g, 88%), as a white solid; 1H NMR (300 MHz, CDCl3) δ ppm 4.81 (d, J=6.3 Hz, 2H), 7.24 (t, J=7.8 Hz, 1H), 7.42-7.45 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4].[Cl-].Cl[C:15]([O:17][CH3:18])=[O:16]>O>[C:15](=[O:16])([O:17][CH3:18])[O:7][C:6](=[O:8])[CH:5]([CH2:3][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)Cl
Reactant: CCCCC(CC)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)OC(=O)OC
Yield: 100.2 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 45 g of water, 0.075 mole of a 33 wt % aqueous NaOH solution, 0.075 mole of 2-ethylhexanoic acid, and 0.23 g of Arquad CB50 (i.e. cocobenzyldimethylammonium chloride, ex Akzo Nobel) at 5° C. 0.075 mole of methyl chloroformate was dosed in 5 min at 5° C. The mixture was post-reacted for 30 min at 5° C. and a pH of 8. Then, the water layer was separated, giving 15.2 g of 2-ethylhexanoyl methyl carbonate having a content of 99.5% (determined by NMR) in a yield of 99.6%.