Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24]C=C)=[O:19])=[C:4]([F:27])[CH:3]=1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(NOCCO)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide (150 mg, 0.34 mmol) in methanol (4.5 mL) and dichloromethane (8.9 mL) was added 4M HCl in 1,4-dioxane (0.13 mL, 0.5 mmol, 1.5 eq.), and the reaction mixture was stirred at ambient temperature under N2 for 1 h. Solid sodium carbonate (50 mg) was added to the reaction mixture. The reaction mixture was absorbed onto silica and then subjected to flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane) to afford the title compound as a white solid. (112.1 mg, 79.5%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.85 (broad s, 1H), 10.32 (broad s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.64 (dd, J=10.4 Hz, 2.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.77 (t, J=8.8 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 3.89 (t, 4.8 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H); LCMS (method D1): RT=0.786 min, [M+H]+=410/412.
Reaction SMILES: C(C1OC1)Cl.C(C(CCCC)CO)C.Cl[CH2:16][CH:17]([OH:28])[CH2:18][O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:18]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]1[O:28][CH2:16]1
Reactant: CCCCC(CC)COCC(O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC(CC)CO
Solvent: C1CCOC1
Solvent: ClCC1CO1
Product: CCCCC(CC)COCC1CO1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a flame dried, 500 mL round bottomed flask equipped with an addition funnel charged with epichlorohydrin (15.62 g, 0.17 moles), is added 2-ethylhexanol (16.5 g, 0.127 moles) and stannic chloride (0.20 g, 0.001 moles). The reaction is kept under an argon atmosphere and warmed to 90° C. using an oil bath. Epichlorohydrin is dripped into the stirring solution over 60 minutes followed by stirring at 90° C. for 18 hours. The reaction is fitted with a vacuum distillation head and 1-chloro-3-(2-ethyl-hexyloxy)-propan-2-ol is distilled under 0.2 mm Hg. The 1-chloro-3-(2-ethyl-hexyloxy)-propan-2-ol (4.46 g, 0.020 moles) is dissolved in tetrahydrofuran (50 mL) and stirred at room temperature under an argon atmosphere. To the stirring solution is added potassium tert-butoxide (2.52 g, 0.022 moles) and the suspension is stirred at room temperature for 18 hours. The reaction is then evaporated to dryness, residue dissolved in hexanes and washed with water (100 mL). The hexanes phase is separated, dried with Na2SO4, filtered and evaporated to dryness to yield the crude 2-ethylhexyl glycidyl ether, which can be further purified by vacuum distillation.
Reaction SMILES: C1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.N[C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.NC1CC2C(C=1)=CC=CC=2>C(O)(=O)C>[CH2:28]1[C:29]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH:24]1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1=Cc2ccccc2C1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1Cc2ccccc2C1
Yield: 58 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (55.8 mg, 0.24 mmol), triethyl orthoformate (0.53 ml), 2-aminoindene (59.25 mg, 0.45 mmol), and acetic acid (0.06 ml) were used to give 48 mg (0.14 mmol, 58% yield) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO>[CH3:27][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:18]1[C:16]1[CH:17]=[C:12]([NH:11][CH2:10][C:6]2([C:4]([OH:5])=[O:3])[CH2:9][CH2:8][CH2:7]2)[CH:13]=[N:14][CH:15]=1
Reactant: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(-c2cncc(NCC3(C(=O)O)CCC3)c2)cc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester (0.107 g, 0.288 mmol) in THF (2 mL) and methanol (1 mL) is added aqueous lithium hydroxide (1M, 0.58 mL, 0.58 mmol) and the solution is stirred overnight. The product is isolated by RP HPLC on an Xbridge C18 eluting with an acetonitrile in 0.1% aqueous NH4OH gradient to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.86 (m, 1H), 1.87-1.97 (m, 3H), 2.26-2.35 (m, 2H), 3.33 (br. s., 1H), 3.39 (s, 2H), 3.75 (s, 3H), 6.60 (s, 1H), 7.05-7.09 (m, 1H), 7.15 (m, 1H), 7.17-7.21 (m, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H). MS (ESI) m/z 336 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:9]([C:8]1[CH:7]=[C:6]([CH:15]=[CH:14][CH:13]=1)[NH:5][C:3](=[O:4])[CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:22](=[O:23])[C:21]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:25][CH2:26]1)=[O:10]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: COC(=O)c1cccc(NC(=O)CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc(NC(=O)CN2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)c1

Procedure:
5 Grams of methyl m-(α-chloroacetylamino)benzoate, 7.56 g of N-(3,4-dimethoxybenzoyl)piperazine monohydrochloride, 7.76 g of triethylamine and 30 ml of acetonitrile were mixed together and reacted at 45° to 50° C. for 5 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were removed by filtration. The mother liquor was concentrated to dryness, and extracted by adding 1 N-sodium hydroxide aqueous solution and chloroform. The chloroform layer was washed with water, dried and removed by distillation. The oily substance obtained was purified by a silica gel column chromatography to obtain 10.08 g of m-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless oily substance.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[ClH:17].[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C([N:29]([CH2:32][CH3:33])CC)C>C(O)C>[ClH:1].[ClH:17].[NH2:8][C@H:11]1[CH2:15][CH2:33][C@H:32]([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([I:18])[CH:20]=3)[N:3]=2)[CH2:13][CH2:12]1
Reactant: NCc1cccc(I)c1
Reactant: CCN(CC)CC
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: Cl
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2nc(NCc3cccc(I)c3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
Dissolve 2,6-dichloro-9-cyclopentylpurine (620 mg, crude), 3-iodobenzylamine hydrochloride (810 mg, 3.00 mmol) and triethylamine (835 μL, 6.00 mmol) in dry ethanol (20 mL). Heat at reflux for 15 hours, cool, and filter the solid to give the title compound as a white solid (680 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38]F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH3:38])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 314 Yield=56%. 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.49-7.46 (m, 1H), 7.11-6.97 (m, 4H), 6.45 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.86 (d, J=11.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H), 2.96 (q, J1=7.2 Hz, J2=5.2 Hz, 2H), 2.64-2.51 (m, 4H), 1.13 (d, J=6.0 Hz, 6H), 0.88-0.81 (m, 3H). ESI− MS: m/z=523 [M+H+]
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[O:22]=[C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=2[S:24]1>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH:4]([OH:21])[CH2:3][CH2:2][NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:26]3[NH:27][C:23](=[O:22])[S:24][C:25]=3[CH:31]=2)=[O:33])[CH2:11][CH2:10]1
Reactant: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Product: O=C(NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2[nH]c(=O)sc2c1

Procedure:
Prepared as described in Example 1 from 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.152 g). Title compound obtained as a white solid (0.105 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Br:11])[CH2:5][NH:6][NH2:7].[C:12](=[O:15])([O-])[OH:13].[Na+].[O:17]1[CH2:22][CH2:21]OCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Br:11])[CH2:5][N:6]1[N:7]=[C:9]([CH2:8][C:12]([OH:13])=[O:15])[C:10]2[C:21](=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:17]
Reactant: NNCc1ccc(Br)c(Cl)c1
Reactant: C1COCCO1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
3-Chloro-4-bromobenzylhydrazine (2.5 g.) was added to a stirred mixture of 3-oxo-Δ1,α-phthalanacetic acid (also known as phthalideneacetic acid) (1.92 g.) and sodium hydrogen carbonate (2.0 g.) in dioxan (50 ml.) and water (25 ml.). The mixture was then heated under reflux for 3 hours, cooled to room temperature and poured into water (200 ml.). The aqueous solution was extracted with ether (3×100 ml.) and the aqueous phase was acidified with concentrated hydrochloric acid to pH 2. The solid which deposited was collected, washed well with water, dried in vacuo, and then recrystallised twice from a mixture of toluene isopropanol and petrol (60-80) (6:2:3 v/v/v) to give 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (0.23 g.), m.p. 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](N)=[N:6][C:7]=1[CH3:8].N([O-])=O.[Na+].[OH-].[Na+].[ClH:16]>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Cl:16])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Cc1nc(N)ccc1Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 5-bromo-6-methyl-pyridin-2-ylamine (2.0 g, 10.6 mmol) in concentrated HCl (10 mL) was added NaNO2 (1.1 g, 15.9 mmol) at room temperature. The reaction was stirred for 2 hours, then cooled to 0° C., made basic with NaOH and extracted with Et2O. The Et2O layer was dried (MgSO4) and concentrated in vacuo to give 55A (0.63 g, 28%). HPLC Rt=2.29 min.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C=O.[C:32]([O-])([O-])=[O:33].[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][OH:33])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1

Procedure:
Ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31 (1 mmol) and paraformaldehyde (5 mmol.) are dissolved in dry DMSO (0.2-0.5M) and heated at 70° C. in the presence of Na2CO3 (5 mmol.) for 2-6 h until greater than 50% conversion is achieved by LC/MS monitoring. The mixture is diluted with EtOAc and washed with water. After concentration, the residue is purified by silica gel chromatography to yield ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate 32. MS (m/z) (M+1)+: 432.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C(O)C.C[O-].[Na+].Br[CH2:18][C:19]([OH:21])=[O:20]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C(O)COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-trichlorophenol, 100.7 gm, was added to 250 ml of ethanol. 228.6 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 1 hour. Afterwards, 69.5 gm of bromoacetic acid was added and the system was then heated to reflux. After 18 hours, an additional equivalent of sodium methoxide in methanol (114.3 ml) was added as well as 34.7 gm of bromoacetic acid. The system was continued at reflux for 12 hours. The reaction was then stopped and the solvent removed by stripping. The resulting solid was washed with water and then with ether. Concentrated HCl was next added to the solid precipitate and the system was left standing for 12 hours. Afterwards, the product was filtered, washed with water and air dried. Toluene was then added to the product. The toluene was removed by stripping and any remaining water was azeotroped off with the toluene. 74.4 gm of 2,4,6-trichlorophenoxyacetic acid was recovered.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:30][CH:31]([CH3:33])[CH2:32][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:28])([F:29])[F:13])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: CC(C)C[Mg]Br
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
To a solution of methyl 6-formylnicotinate (0.200 g, 1.21 mmol) in tetrahydrofuran (8 mL) containing activated molecular sieves was added 4′-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol). The reaction was heated to 90° C. and stirred overnight. The reaction was concentrated to dryness and the residue was dissolved in tetrahydrofuran (8 mL). The solution was cooled to 0° C. Zinc chloride (3.52 mL, 1M in diethyl ether, 3.52 mmol) was added, followed by isobutylmagnesium bromide (1.47 mL, 2.0M in THF, 3.52 mmol). The reaction was stirred at 0° C. for 2 hours. The reaction was quenched with saturated ammonium chloride. The mixture was diluted with dichloromethane and water. The layers were separated and the aqueous was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (210 mg, 39%) as a yellow oil. 1H NMR (400 MHz, CD3OD, δ): 9.09 (s, 1H), 8.31 (d, 1H), 7.72-7.57 (m, 5H), 7.41 (d, 2H), 6.65 (d, 2H), 4.61-4.52 (m, 1H), 3.94 (s, 3H), 1.92-1.73 (m, 2H), 1.1.72-1.61 (m, 1H), 1.05 (d, 3H), 0.91 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@H:13]([OH:18])[C@@H:12]2[OH:19])=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1)[NH2:28]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Product: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R) 5-[2-chloro-6-(cyclopentylamino)purin-9-yl]-2-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) as prepared in Example 1A, was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed under reduced pressure and the residue triturated with ether and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:21]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28]
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), glutaric anhydride (0.042 g, 0.37 mmol) and toluene (10 ml) was heated under reflux until the starting materials were consumed (the reaction was followed by tic using a 3:1 mixture of ethyl acetate and ethanol as eluant), then it was allowed to cool to ambient temperature. The resulting solid was collected by filtration and recrystallised from ethanol to give 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]butyric acid (0.08 g) as a white solid, mpt. 190–194° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.5–1.65 (m, 2H) (—CH2CH2CH2—), 2.0–2.25 (m, 4H) (—CH2CH2CH2—) 4.1 (s, 2H) (ArCH2—), 6.8–7.0 (m, 2H) (2×ArH), 7.5–7.8 (m, 4H) (4×ArH), 8.05 (d, 1H) (ArH), 9.45 (s, 1H) (chain CONH), 12.85 (br s, 1H) (—CO2H), 12.4 (s, 1H) (ring CONH); m/z (M−H)+. 382, 100% purity.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu-]=O>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: c1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(ccc(-n3cccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.2 %

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone (0.300 g, 0.78 mmol), 1H-pyrazole (0.053 g, 0.78 mmol), copper (I) oxide (0.056 g, 0.39 mmol), cesium carbonate (0.508 g, 1.56 mmol) in N,N-dimethylformamide (5 mL) stirred for 18 h at 100° C. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:10, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1 (2H)-yl)methanone (0.050 g, 17%) as a yellow solid. MS (ESI, pos. ion) m/z 374 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.O.C(OCC)(=O)C>C1COCC1>[F:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([N:11]3[CH2:12][CH2:13][CH:8]([C:6]([O-:7])=[O:5])[CH2:9][CH2:10]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1.[Na+:2]
Reactant: CCOC(=O)C1CCN(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C([O-])C1CCN(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydroxide (1 M, 0.25 ml) is added to a solution of 1-[8-(3-fluoro-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid ethyl ester (96 mg, 0.25 mmol) in THF (1 ml). The solution is stirred at room temperature for 24 hours, then heated to 45° C. for 24 hours. Water and ethyl acetate are added and the aqueous phase separated and evaporated to give the title compound. MS: APCI 352.0 MH+.