Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:4][C:3]1=[O:17].[C:18](=[S:21])([NH2:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:18]1[S:21][CH:2]2[CH2:6][N:5]([S:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH2:4][C:3]2([OH:17])[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)C(Br)C2)cc1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=NC2(O)CN(S(=O)(=O)c3ccc(C)cc3)CC2S1
Temperature: 50 °C

Procedure:
To 4-bromo-1-[(4-methylphenyl)sulfonyl]pyrrolidin-3-one (159 mg) (W.-J Kim, et al., Heterocycles, 1995, 41, 1389-1398) in 2 mL of N,N-dimethylformamide was added ethanethioamide (38 mg) and the reaction mixture heated to 50° C. for 2 h. The mixture was cooled to ambient temperature and diluted with a mixture of ethyl acetate/saturated aqueous sodium bicarbonate solution (1:1, 20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo The product was used without further purification. LC/MS 313.1 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@@H:33]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1.[CH3:60][C:61]([C:63]1[CH:64]=[CH:65][CH:66]=[C:67](O)[CH:68]=1)=[O:62]>C1COCC1>[C:61]([C:63]1[CH:68]=[C:67]([CH:66]=[CH:65][CH:64]=1)[O:32][C@H:33]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1)(=[O:62])[CH3:60]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the desired product (2.73 mg, 39.9%) as a thick oil: 1H NMR (CDCl3) δ 7.70-7.64 (m, 2H), 7.54 (m, 2H), 7.49-7.44 (m, 6H), 7.25 (m, 1H), 7.05 (d, 1H, J=8.3 Hz), 6.96 (apparent d, 1H, J=7.7 Hz), 5.34 (apparent dd, 1H, J=4.8, 8.2 Hz), 3.15 (m, 2H), 2.67 (m, 2H), 2.52 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 499.4 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reaction time: 24 h
Yield: 71.1 %

Procedure:
Combine 6-(4-carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 mL), and TFA (25 mL) at room temperature. Stir for 24 hours, followed by the addition of 1.0 M K2CO3 (aq), and extract the product out of the aqueous layer with several washings of ethyl acetate/THF. Concentrate the organic phase under reduced pressure and add to 2, 10 g SCX Columns pre-treated with 5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, elute with 1.0 N NH3-MeOH solution to afford 2.08 g, 7.7 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO-d6); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[Br:16][CH2:17][CH2:18]Br>CC#N>[Br:16][CH2:17][CH2:18][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCBr)cc1
Yield: 44.5 %

Procedure:
A mixture of 4-cyanophenol (35.7 g, 0.3 mol), K2CO3 (41.4 g, 0.3 mol) and 1,2-dibromoethane (561 g, 3.0 mol) in MeCN (450 mL) was stirred under reflux overnight. The mixture was filtered and evaporated to give 30.2 g (45%) of the sub-title compound, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.CCCCCC.[O:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=c1ccocc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(Br)c2)CCOCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred −78° C. solution of 1,3-dibromobenzene (19.71 g, 81.05 mmol) in THF (150 mL) is added 1.6 M butyl lithium in hexane (50.66 mL, 81.05 mmol) and the reaction is stirred 10 minutes. 4H-Pyran-4-one, tetrahydro- (5.41 g, 54.04 mmol) is added dropwise and the reaction is stirred at −78° C. for 2 h. The reaction is quenched by addition of saturated aqueous ammonium chloride (25 mL) and is then diluted with minimal water and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (11.18 g, 76%). GC-MS (m/e): (79Br/81Br) 256, 258 (M−1).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[C:23](=[O:28])[N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.74 Hz, 1H) 7.89 (d, J=1.87 Hz, 1H) 7.42 (dd, J=8.73, 2.18 Hz, 1H) 7.25-7.31 (m, 2H) 6.18 (t, J=6.86 Hz, 1H) 3.57-3.68 (m, 1H) 3.15-3.25 (m, 1H) 3.02-3.10 (m, 1H) 2.72-2.85 (m, 1H) 2.59-2.68 (m, 1H) 2.44-2.53 (m, 2H) 2.31-2.43 (m, 1H) 2.20 (s, 3H) 1.91-2.02 (m, 1H) 1.79-1.88 (m, 1H) 1.65-1.76 (m, 1H) 1.44-1.64 (m, 2H) 1.15 (s, 3H). MS: (M+H)+=380.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH:23]([CH3:25])[CH3:24])[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3]1
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
A mixture of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (4.18 g, 15.5 mmol), 60% sodium hydride in oil (0.68 g, 17 mmol), and DMF (25 mL) was stirred approximately one hour at 25° C.; then 2-iodopropane (2.7 g, 16 mmol) was added and stirring was continued for three days. The solvent was removed under reduced pressure, and the residue was stirred with water (80 mL) for a few minutes. The insoluble solid was collected and purified by chromatography, eluting with ethyl acetate/hexane (60:40). tert-Butyl 2,4-dioxo-3-(1-methylethyl)-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (0.66 g, 2.1 mmol), m.p. 206°-208° C. was obtained as fine needles.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CCCNC(=O)c1ccc(Cl)cc1O
Temperature: 50 °C
Yield: 97.2 %

Procedure:
A 22L, five neck round bottom flask, was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Reagent acetone (13000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was pumped through a warm pressure filter dressed with Whatman #1 paper into a clean 22 L reactor. The clear yellow filtrate was heated to 50° C. while stirring. Sodium hydroxide solution (50% aqueous; 155 g, 1.94 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (60° C.) for 2.5 hours and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and dried in a vacuum oven at 50° C. for 24 hours to give 527.3 g of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate as an off-white solid. Using acetone in the final stage of the synthesis always resulted in the production of the anhydrous crystalline form. The yield was 97.2%.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: ClCc1ccccc1Cl
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2nc(CN3CCN(Cc4ccccc4Cl)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added o-chlorobenzyl chloride (0.015 mL; 0.12 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA). and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 17 mg of yellow colored 3-[4-(2-Chloro-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH3:21])[CH:17]=[CH:16][C:15]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>C(O)C.C(O)(C)C>[ClH:37].[F:34][CH:32]([F:33])[O:31][C:27]1[CH:26]=[C:25]([S:22]([N:20]([C:18]2[CH:17]=[CH:16][C:15]([O:35][CH3:36])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH3:21])(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.3 g (0.584 mmol) 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester from preparation example 2 were dissolved in 8 mL of ethanol and 0.8 mL of 5 N HCl in isopropanol were added. After stirring for 16 h at room temperature, the solvent was evaporated to yield 0.255 g of title compound.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[CH:33]([OH:35])[CH3:34].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33](=[O:35])[CH3:34]
Reactant: COCOc1cnccc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: COCOc1cnccc1C(C)=O
Reaction time: 24 h
Yield: 86.1 %

Procedure:
Dess-Martin periodinane (18 g, 43 mmol) was added to a stirring mixture of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol (4.6 g, 25 mmol), NaHCO3 (6.3 g, 75 mmol), and CHCl3 (75 mL) at RT. After 24 h, 1.0 M aqueous Na2S2O3 was added, the reaction mixture was stirred for 90 min, partitioned between ethyl acetate and 1.0 M aqueous Na2S2O3, the layers were separated, the organic layer was washed with 1.0 M aqueous Na2S2O3, water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (gradient elution; 2:1→1:1 hexane-ethyl acetate) to give 3.9 g (86%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanone as a clear yellow-orange oil.
Reaction SMILES: [C:1](Cl)(=O)C.[Cl:5][C:6]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1>CO>[Cl:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:1])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccnc1Cl

Procedure:
Acetyl chloride (0.651 mL, 9.16 mmol) was added to a suspension of (2-chloropyridin-3-yl)acetic acid (I117) (1.048 g, 6.108 mmol) in MeOH (30 mL). The mixture was heated at reflux for 20 hours. The volatiles were removed in vacuo and the residue partitioned between DCM (100 mL) and sat. NaHCO3 (100 mL). The layers were separated and the aqueous layer extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and the solvent removed under reduced pressure to yield an oil which was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I118) (0.863 g, 76%) as a pale yellow oil; 1H NMR (400 MHz, d6-DMSO) δ 8.34 (dd, J=4.8, 1.9 Hz, 1H), 7.88 (dd, J=7.5, 1.9 Hz, 1H), 7.43 (dd, J=7.5, 4.8 Hz, 1H), 3.86 (s, 2H), 3.65 (s, 3H). LCMS Method C: rt 5.04 min; m/z 186 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.O.[CH3:13][N:14]1CCCC1=O>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([C:13]#[N:14])=[CH:11][C:6]=2[N:7]=1
Reactant: CN1CCCC1=O
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1nc2cc(C#N)ccc2s1

Procedure:
28.0 g of 5-bromo-2-methylbenzothiazole was dissolved in 200 ml of N-methyl-2-pyrrolidone, the solution thus prepared was mixed with 13.8 g of cuprous cyanide and a catalytically effective amount of copper sulfate, and the mixture was stirred for 4 hours with heating at a temperature of 180° to 190° C. in a stream of nitrogen. The resulting reaction solution was poured into water, and insoluble materials thus formed were collected by filtration. The thus collected insoluble materials were mixed with a mixture consisting of 22 ml of methylenediamine and 50 ml of water, and the resulting mixture was stirred thoroughly. After extraction with benzene, the resulting organic layer was washed with water, and dried to distill of benzene. Thereafter, the residue thus formed was washed with ethanol to obtain 10.22 g of 2-methyl-5-benzothiazolecarbonitrile in the form of light brown crystals.
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.[Cl-].[NH4+]>C1COCC1.O.[Fe]>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=3)[O:6][CH2:5][CH2:4]1)[CH2:2][CH2:3]2
Reactant: O=[N+]([O-])c1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.5 %

Procedure:
2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-nitropyrimidine (Intermediate 222, 91 mg, 0.304 mmol) was dissolved in 9.0 mL of a 2/1 THF/water solution. Then iron (85 mg, 1.52 mmol) and ammonium chloride (81 mg, 1.52 mmol) were added and the reaction mixture was stirred at room temperature for 10 h. After dilution with AcOEt and filtration over a celite pad (washing with AcOEt), the organic phase was washed (two times) with an aqueous saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (52 mg).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[F:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[K+].[F:40][C:41]([F:45])([F:44])[CH:42]=[CH2:43]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:11][C:5]1[CH:6]=[C:7](/[CH:43]=[CH:42]/[C:41]([F:45])([F:44])[F:40])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C=CC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: O=C(O)c1ccc(/C=C/C(F)(F)F)cc1F
Temperature: 180 °C
Reaction time: 96 h

Procedure:
A mixture of methyl-2-fluoro-4-bromobenzoate (5.0 g, 0.021 mol), tri-o-tolylphosphine (1.31 g, 0.00429 mol), tetra-N-butylammonium bromide (2.08 g, 0.00644 mol), potassium acetate (4.2 g, 0.043 mol), 3,3,3-trifluoroprop-1-ene (20 g, 0.2 mol), palladium acetate (0.24 g, 0.0011 mol) was sealed in a Parr instrument and stirred at 180° C. for 96 h. After cooling, the reaction mixture was filtered through Celite® and the filtrate was partitioned bewteen EtOAc and 1 N aq. HCl. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed with hexane-EtOAc(5% AcOH) (0 to 60%) to give the product as a white solid. LC-MS: t=2.98 min, m/z=233.2 (M−1).
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.B(Br)(Br)Br.CO>ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:21]=3)[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Nc1nc2cccnc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 17 h
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.40 g, 0.96 mmol) in dichloromethane (25 mL) was cooled on an ice bath, and boron tribromide (2.4 mL of a 1 M solution in dichloromethane) was added. The reaction was stirred for 17 hours, and an analysis by HPLC indicated the presence of starting material. Additional boron tribromide (1 mL) was added after 17 hours and then again after 32 hours of reaction time. After 32 hours of reaction time, methanol was added, and the solvents were removed under reduced pressure. The residue was triturated with water, isolated by filtration, washed with diethyl ether, recrystallized from methanol, and dried under high vacuum at 100° C. to provide 0.14 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl)methanol as a white solid, mp 247.0-248.0° C.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][O:3]1>C(O)(=O)C>[CH3:15][C:13]1([CH3:16])[O:12][C@@H:10]2[C@@H:9]([C@@H:8]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:7]([C@H:5]([OH:6])[CH2:4][OH:3])[O:11]2)[O:14]1
Reactant: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Solvent: CC(=O)O
Product: CC1(C)O[C@H]2O[C@H]([C@H](O)CO)[C@H](OCc3ccccc3)[C@H]2O1

Procedure:
Partial hydrolysis of 30B (50 g) was achieved in 75% acetic acid in a period of 20 h. Concentration to a smaller volume and extraction with ethyl acetate yielded 30C, 40 g, (90%). Homogeneous by TLC.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:19]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with methyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.