Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20].C(O)C.S([O-])(O)(=O)=O.[K+]>O>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 72.5 °C
Reaction time: 0.75 h

Procedure:
2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699 kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at 25-35° C. in round bottom flask. Followed by addition of Potassium hydrogen sulphate (0.15 kg) into the reaction mass and heated the reaction mass at 70-75° C. for two hrs. Cooled the reaction mass at 25-30° C. and stirred for 45 minutes. Filtered off the solid and washed with ethanol. Obtained solid and water (1.0 lit) stirred at 25-30° C. for 15 minutes and then heated at 50-55° C. for 1 hr. The solid was filtered at 50-55° C. and washed with water. Charge this wet cake in DMF (5.0 lit) and stirred at 25-30° C. In this solution 30% H2O2 was added at 25-30° C. within 1 hr. Followed by addition of water at 25-30° C. and stirred for 30 minutes. Filtered off the solid and washed it with water. The obtained solid was added in pre heated water and stirred at 45-50° C. Gradually increased the temperature up to 65-75° C. & stir it for 60 min. cooled the reaction mass at 45-50° C. and stirred it for 40 minutes. The precipitated Deferasirox filtered off and washed with water. Dry the solid at 65-75° C. in vacuum tray drier.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(=O)(O)[O-].[Na+].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2.Cl>C(Cl)Cl>[CH3:16][N:17]([C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:9])[CH2:18][CH2:19][CH2:20][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)c1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was suspended in methylene chloride (12 ml) cooled to 5° C. and sodium bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred for 3 hours at 5° C. The sodium chloride was removed by filtration and the organic solution was extracted with aqueous sodium bicarbonate, dried over sodium sulfate, filtered through Celite™ and concentrated. Ethyl ether (5 ml) was added to the oily residue and white crystals formed. Yield 62% (0.58 g), m.p. 84°-86° C. The product has the formula: ##STR1616##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][S:9](=[S:12])([O-:11])=[O:10].[Na+].CN(C=O)C>O>[CH3:8][S:9](=[S:12])([O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10]
Reactant: CCCCCCBr
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOS(C)(=O)=S
Temperature: 60 °C
Yield: 165 %

Procedure:
The reaction mixture of 1-bromohexane (1.046 g, 0.00635 mol), sodium methanethiosulfonate (0.850 g, 0.00635 mol) and dry DMF (6 mL) was heated at 60° C. for 2 hr. At room temperature, water (15 mL) was added and the resulting mixture was extracted with ether (3×30 mL). The extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a colorless liquid (2.057 g, 82%). IR (CDCl3 cast): 3030 (w), 3010 (w), 2955 (st), 2930 (st), 2860 (st), 1460 (m), 1320 (st), 1133 (st), 955 (st), 747 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.33 (s, 3H, CH3SO2S), 3.18 (t, J=7.4 Hz, 2H, SCH2CH2), 1.77 (pseudo p, J=7.2 Hz, 2H, SCH2CH2), 1.50-1.20 (m, 6H, CH2CH2CH2CH3), 0.90 (m, 3H, CH2CH3); 13C NMR (50 MHz, CDCl3): δ 50.64, 36.50, 31.13, 29.46, 28.26, 22.44, 13.96.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 3 h

Procedure:
Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20ClN3O); MS (ESI): 282 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][C:30]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CC#N)nc2[nH]1
Yield: 52.1 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-5-(chloromethyl)-3H-imidazo[4,5-b]pyridine (0.11 g) and potassium cyanide (30 mg) in N,N-dimethylformamide (5 ml) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC, and saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture. The mixture was extracted with dichloromethane, and the extract was concentrated to give the title compound (56 mg, yield 52%) as colorless crystals. purity 90%. M+H: 399.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCN(C)C)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.33 ml; 2.41 mmol; 5 eq) and N,N-dimethyl-1,3-propanediamine (0.3 ml; 2.41 mmol; 5 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (200 mg; 86%).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[N:16]([O-])=[O:17].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([N:16]=[O:17])=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)CN(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(N=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15.5 g (80 mmol) of ethyl N-methyl-N-phenylglycinate in 80 g of ice and 40 mL of conc.HCl was stirred at 0-5° while a solution of 6 g (87 mmol) of NaNO2 in 40 mL of water was added dropwise over 30 min. After stirring at this temp. for 1 hr, a solution of 27 g (250 mmol) of Na2CO3 in 150 mL of water was added dropwise with cooling. The green solid was collected, washed with cold water, extracted into CH2Cl2, passed thorugh silica with CH2Cl2 to remove an impurity, and the product eluded with 10% ethyl acetate/CH2Cl2 to give 14.7 g (66 mmol, 83%) mp 55-56° after washing with 10% ethyl acetate/hexane. Anal. C11H14N2O3 (222): Calcd.: C,59.45; H,6,35; N,12.60. Found: C,59.46; H,6.14; N,12.49. MS(FD) m/z 222. 1H NMR(CDCl3)δ: 7.8,broad s,2H,ArH; 6.69,d,2H,ArH; 4.22,q,2H,CH2 --O; 4.20,s,2H,CH2 --N; 3.23,s,3H,CH3 --N; 1.27,t,3H,CH3 --C.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (78) as white solid (817 mg, 92%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)=[O:24]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=2)=[O:24])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCC(=O)Oc1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)N1C(=O)C(NCCC(=O)Oc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(trifluoromethoxy)phenyl β-alaninate in a similar manner as described for Example 164. Mass Spectrum: [M+H]+ 513.12, [M−H]− 511.16.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]6[C:35](=[O:36])[CH:34]=[CH:33][CH:32]=[N:31]6)[CH:27]=5)[N:22](C(OC(C)(C)C)=O)[N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]6[C:35](=[O:36])[CH:34]=[CH:33][CH:32]=[N:31]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3ncccc3=O)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5ncccc5=O)cc34)nn2)cc1)N1CCOCC1

Procedure:
A solution of tert-butyl 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxopyridazin-1(6H)-yl)methyl]-1H-indazole-1-carboxylate (202 mg; 0.32 mmol; 1.00 eq.) and HCl (6.00 mL of a 4 N solution in dioxane; 24 mmol; 76 eq.) in MeOH (4 mL) was stirred at RT for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a white solid. HPLC (Condition A): Rt 2.67 min (purity 98.1%). MS (ESI+): 483.3, MS (ESI−): 481.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN(c1ccc(Cl)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CCN(c1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of the (4-chloro-phenyl)-ethyl-piperidin-4-yl-amine (0.150 g, 0.63 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.108 g, 34%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57 (s, 6H), 2.67-2.80 (m, 4H), 2.00 (m, 2H), 2.34-2.41 (m, 2H), 2.43-2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.37-3.51 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21-7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 532 (M+1), retention time 2.47.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][NH:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:25]([N:23]1[CH2:24][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH2:22]1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(c2ccccc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (735 mg, 2.21 mmol) in methanol (10 mL) was added acetaldehyde (107 mg, 136 μL, 2.43 mmol), then sodium cyanoborohydride (195 mg, 1.5 mL, 3.10 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was extracted with DCM (2×25 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography using (0-75% EtOAc/DCM) as eluent to give tert-butyl 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540 mg, 68%) as a viscous yellow oil. ESI-MS m/z calc. 360.5. Found 361.7 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(O)(=O)C.[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(O)(=O)C>C([O-])(=O)C.[Na+].O>[P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[C:27]([CH2:36][CH:35]=[CH:34][NH2:37])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: O=c1ccn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]1
Reactant: C=CCN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC=CCc1cn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
100 mg (0.19 mmol)of 1,5-Anhydro-2-(uracil-1yl)-2,3-dideoxy-D-arabino-hexitol 6 triphosphate and 106 mg (0.33 mmol) mercury II acetate were dissolved in 5 ml 0.1 M sodium acetate buffer pH5 The mixture was stirred for 4 h at 50° C. after cooling to room temperature the mixture was diluted with 40 ml water. A freshly prepared allylamine acetate solution. (0.77 ml (13 mmol) were neutralized with 4M acetic acid) and 150 mg (1.5 mmol) dipotassium tetrachloropalladinate were added and the mixture was stirred for 24 h at room temperature. The reaction mixture was filtered through a 0.45 μm membrane filter and the filtrate was applied on a DEAE-Sephadex column and it was eluated with a gradient from 0.1-1 M Trieethylammoniumbicarbonate pH8 monitoring at 260 nm. The major UV peak was collected (Ninhydrine reaction positive) and further purified by reversed phase chromatography with a gradient from buffer 100% A: 0.1M triethylammonium acetate pH 8.0 to 100% buffer B: 0.1 M triethylammonium acetate/Acetonitril 1:1 monitoring at 260 nm on a RP 18 Hypersil column) The fractions containing the aminoallyl triphosphate were collected and evaporated under vacuum. The presence of the aminogroup was verified by ninhydrine reaction Excess triethylammonium-acetate was removed by several coevaporations with water. Yield 80 mg
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[F:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][N:23]([CH3:39])[C:24]2[N:29]=[C:28]([C:30]3[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=3)[CH:27]=[N:26][CH:25]=2)=[CH:20][CH:19]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:36]([C:32]2[S:31][C:30]([C:28]3[CH:27]=[N:26][CH:25]=[C:24]([N:23]([CH2:22][C:21]4[CH:40]=[CH:41][C:18]([F:17])=[CH:19][CH:20]=4)[CH3:39])[N:29]=3)=[N:34][C:33]=2[CH3:35])=[O:37])[CH:12]=1
Reactant: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCc1cccnc1
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Yield: 82 %

Procedure:
Part C. Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with 3-(aminomethyl)-pyridine to react with 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 82% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.55-8.60 (m, 2H), 8.48 (d, J=4.0 Hz, 1H), 8.06 (s, 1H), 7.65-7.70 (m, 1H), 7.21-7.28 (m, 3H), 6.95-7.02 (m, 2H), 6.25 (bs, 1H), 4.78 (s, 2H), 4.56 (d, J=4.0 Hz, 2H), 3.11 (s, 3H), 2.69 (s, 3H); MS (ES+) m/z 449.2 (M-1-1), Rt=1.33 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3].[CH2:12]([O:14][C:15](=O)[O:16]CC)[CH3:13].[H-].[Na+]>>[CH2:12]([O:14][C:15](=[O:16])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3])[CH3:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl

Procedure:
Synthesis of Intermediate 1a was done by standard procedure starting from 2,4-dichloroacetophenone, diethylcarbonate (25 eq) and NaH (2 eq) at 80° C. for 60 minutes.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)=O.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[CH3:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:3][OH:2])=[N:6]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: Cn1nc(CO)c2ccccc21
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a stirring solution of 440 mg (2.31 mmol) of 1-Methyl-1H-indazole-3-carboxylic acid methyl ester (Fludzinski, P. et. al. J. Med. Chem. 1987, 30, 1535) in 10 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 5.8 mL (5.8 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 3 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 340 mg of the title compound as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ7.80 (d, 1H), 7.42-7.12 (m, 3H), 5.02 (d, 2H), 4.00 (s, 3H), 2.27 (m, 1H); Rf =0.25 in hexane/EtOAc 1/1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>ClC1C=CC=CC=1Cl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=1[N:1]1[C:16]([CH3:18])=[CH:17][C:12]([OH:11])=[CH:13][C:14]1=[O:15]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1cc(CO)ccc1F
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1F
Reaction time: 0.17 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar, Dean-Stark trap and reflux condenser was charged with (3-amino-4-fluorophenyl)methanol (4.5 g, 31.9 mmol), 4-hydroxy-6-methyl-2-pyrone (4 g, 31.9 mmol) and o-dichlorobenzene (5 mL). The system was immersed in a 170 C oil bath for 10 minutes. The solvent was removed in vacuo and the residue was chromatographed on reverse phase (75:25 water:acetonitrile with 0.05% TFA). The product contained some starting materials after purification and was used without further purification (1.27 g, 15%). 1H NMR (400 MHz, dmso-d6) δ 7.39 (m, 1H), 7.20 (dd, J=2.2 and 7.6 Hz, 1H), 6.74 (dd, J=2.7 and 9.6 Hz, 1H), 5.93 (dd, J=1.2 and 2.2 Hz, 1H), 5.22 (dd, J=0.4 and 2.2 Hz, 1H), 2.12 (s, 3H) ppm. ES-HRMS m/z 250.0862 (M+H calcd for C13H13FNO3 requires 250.0874).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, 3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as an off-white powder, MS (ESI+): m/z=448.9 [M+H]+.