Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39]O)[NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:38]=1
Reactant: NC(=NO)c1ccccc1F
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccccc4F)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 41.4 mg (0.269 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 72.8 mg (55% of theory).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][OH:24])[CH3:21].[I-].[K+]>O1CCCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:24][CH2:23][CH:22]([CH2:20][CH3:21])[CH2:25][CH2:26][CH2:27][CH3:28])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCCCC(CC)CO
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC(CC)COCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
) 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (1.0 g, 3.7 mmol) is partly solved in tetrahydrofurane (20 mL) at 70° C. 2-Ethyl-hexan-1-ol (9.6 g, 73 mmol), potassium tert.butylate (1.0 g, 7.3 mmol), and a catalytic amount of potassium iodide are added subsequently. The orange reaction mixture is stirred at 70° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. Excess alcohol is removed and recovered by distillation. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 1.2 g of 2-(2H-Benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol. b.) 2-(2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (0.5 g, 1.9 mmol) is suspended in 2-ethylhexan-1-ol (5.0 g, 38 mmol) at 60° C. 1.1 equivalent K2HPO4 is added and the mixture is stirred for 12 hours at 60° C. resulting in 63.3% of 2-(2H-Benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol (determined by means of HPLC analysis). c.) 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methylphenol (1.0 g, 3.7 mmol) is suspended in 2-ethylhexan-1-ol (4.0 g, 31 mmol) at 80° C. 1.1 equivalent of the respective base as given in table 1 is added and the mixture is stirred for 15 minutes at 80° C. The turnover and impurity profile is determined by means of HPLC analysis.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([CH:24]=O)[CH:22]=[CH:23][C:17]=4[N:16]4[CH:26]=[CH:27][CH:28]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2].C[CH2:34][N:35](CC)[CH2:36]C>CN(C=O)C>[CH3:34][N:35]([CH2:24][C:21]1[CH:22]=[CH:23][C:17]2[N:16]3[CH:26]=[CH:27][CH:28]=[C:15]3[C:12]3([CH2:13][CH2:14][N:9]([C:7]([C:6]4[CH:29]=[CH:30][C:3]([CH2:1][CH3:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:8])[CH2:10][CH2:11]3)[O:19][C:18]=2[CH:20]=1)[CH3:36]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C=O)ccc2-n2cccc23)cc1OC
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CN(C)C)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbaldehyde (88 mg, 0.20 mmol) N,N-dimethylamine hydrochloride (83 mg, 1.0 mmol), Et3N (140 μL, 1.0 mmol) and NaHB(OAc)3 (130 mg, 0.60 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O) to yield (7-((dimethylamino)methyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone. ESI-MS m/z calc. 459.6. found 460.5 (M+1)+; Retention time: 1.40 minutes (3 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1ccccc1F
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3F)[nH]c2c1
Yield: 15 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-fluorobenzoic acid, in a manner similar to that of Example 31b. Yield: 15%; Rf (7/3 toluene/ethyl acetate): 0.55; IR (KBr): 2996, 1625, 1520, 1479, 1340 cm−1; 1H-NMR (d6-DMSO) 8.5-8.0 (m, 3H); 7.2-7.9 (m, 4H).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[CH:28]1[CH2:33][C:32](=[O:34])[CH:31]=[CH:30][CH2:29]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[C@H:28]1[CH2:29][C@H:30]([CH3:2])[CH2:31][C:32](=[O:34])[CH2:33]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a 0° C. solution of dimethyl copper lithium (2.47 mmole) in ether (3 ml) and hexane (2 ml) was added dropwise a solution of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-cyclohexen-1-one (500 mg, 1.24 mmole) in ether (1.5 ml). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium chloride (300 ml). The quenched reaction was extracted with three 50 ml portions of ether, the combined ether extracts washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 475 mg (92%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](F)[C:6]=1[N:15]1[CH:19]=[N:18][C:17]([CH3:20])=[N:16]1>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:2][CH3:1])[C:6]=1[N:15]1[CH:19]=[N:18][C:17]([CH3:20])=[N:16]1
Reactant: C[O-]
Reactant: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(C)n1
Reaction time: 2 h
Yield: 82 %

Procedure:
Step S (1): A solution of sodium methanolate (0.5 M in methanol, 17.5 mL, 8.74 mmol) was added to a round bottom flask charged with a solution of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.1 g, 8.74 mmol, from preparation R, step R(1) in THF (25 mL). A slight pink color resulted. After 2 h, the reaction mixture was concentrated under reduced pressure. The white solid residue was triturated with ˜50 mL of 1 N HCl. The solid was collected by vacuum filtration and dried under high vacuum for several hours to afford 1-(2-fluoro-6-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.84 g, 7.15 mmol, 82% yield) as a white solid. LC-MS (M+H)+ 253.1.0. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.22 (s, 1 H), 7.80 (dd, J=9.0, 2.3 Hz, 1 H), 7.76 (t, J=2.0 Hz, 1 H), 3.99 (s, 3 H), 2.52 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:17])[O:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:14][CH2:15][O:16][C:11]([CH3:17])([CH3:10])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CNCCO1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CN(Cc2ccc(Br)cc2)CCO1
Temperature: 85 °C
Yield: 96.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.5 g, 6.0 mmol), 2,2-dimethylmorpholine (0.69 g, 6.0 mmol) and potassium carbonate (0.99 g, 7.2 mmol) in acetonitrile (60 mL) was heated at 85° C. for 20 h. The mixture was allowed to cool to ambient temperature and the solid was removed by filtration and the filtrate evaporated. The resultant residue was dissolved in DCM/methanol and loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions afforded the title compound (1.65 g, 97%) as an orange oil. 1H NMR (CDCl3, 300 MHz): 7.44 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.39 (s, 2H), 2.37 (t, J=4.6 Hz, 2H), 2.16 (s, 2H), 1.23 (s, 6H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=4[F:39])=[O:30])=[CH:24][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O>C1COCC1>[F:39][C:33]1[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:32]=1[NH:31][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:13]3[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=3)[CH:20]=2)=[CH:27][CH:26]=1)=[O:30]
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (800 mg, 1.39 mmol) in 10 ml of THF was added 2M HCl (1 ml, 1 mmol). The mixture was stirred at room temperature under nitrogen for 1.5 hours, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as off-white solid. Yield: 680 mg, 98%.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:28]1CCOCC1>O>[S:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]([CH:1]=[O:28])[N:10]=[C:11]2[CH:17]=[CH:16]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.3 g, 193 mmol) in 1,4-dioxane (1500 mL) and water (300 mL) was added NaIO4 (165 g, 770 mmol) followed by OSO4 (5.00 g, 19.7 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was concentrated under reduced pressure then was partitioned with 10% aqueous Na2S2O3 (1000 mL) and DCM (1000 mL). The organic layer was washed with water (2×500 mL) and the layers were filtered to remove undissolved precipitate and separated. The organic layer was dried over anhydrous Na2SO4, filtered through Celite®, and concentrated. The residue was purified by filtration through a pad of silica gel (1000 g) eluting with 0-5% EtOAc in DCM. The fractions were concentrated and the solid was triturated with heptane. The mixture was filtered and the filter cake was washed with heptane. This procedure was repeated for the collected undissolved precipitate. The collected solid was then dissolved in 2% EtOAc in DCM and passed through a pad of silica gel (100 g) eluting with 2% EtOAc in DCM. The filtrate was concentrated under reduced pressure. The two batches were combined to give 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (39.1 g, 67%) as an off-white solid: LC/MS (Table 2, Method a) Rt=2.17 min; MS m/z: 302 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:7][N:6]1[C:2]([NH:1][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=[N:5]1
Reactant: CCOC(=O)CC(=O)Nc1cnn(C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The crude residue containing ethyl 3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropanoate was dissolved in N,N-dimethylformamide (20 ml), and trityl chloride (5.52 g) and triethylamine (4.14 ml) were added with stirring. The mixture was stirred overnight and quenched with water (10 ml). The whole mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residual oil, which was chromatographed on silica gel eluting with dichloromethane-ethyl acetate (2:3) to give ethyl 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoate (1.23 g).
Reaction SMILES: [S:1]([C:5]1[O:16][C:8]2=[N:9][CH:10]=[C:11](C(O)=O)[CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(Cl)(Cl)Cl.[OH-].[Na+]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:1]([C:5]1[O:16][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2cc(C(=O)O)cnc2o1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: NS(=O)(=O)c1cc2cccnc2o1
Temperature: 225 °C
Yield: 42 %

Procedure:
A suspension of 2-sulfamoylfuro[2,3-b]pyridine-5-carboxylic acid (726 mg, 3.0 mmol) in quinoline (5 mL) containing copper dust (0.5 g) was heated under a nitrogen atmosphere at 225° C. for 3.5 hours. After cooling the reaction mixture to room temperature, chloroform and dilute sodium hydroxide solution were added. This biphasic mixture was filtered through a filter aid pad to remove black suspended material and then the basic aqueous layer was separated and acidified with conc. hydrochloric acid. The product was extracted into ethyl acetate which was dried over anhydrous sodium sulfate and filtered through a pad of charcoal. The residue obtained after removal of the solvent in vacuo was triturated with diethyl ether to give crude product (291 mg). This material was recrystallized from ethyl acetate to give pure product (250 mg, 42% yield), mp: 222°-223° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][C@@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: C[C@H](N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 38.2 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (110 mg, 0.34 mmol) and 3-(S)-amino-butyric acid HCl salt (475 mg, 3.4 mmol) (Oakwood Products) in 2-methoxyethanol (10 mL) was added NaOMe solid (330 mg, 6.12 mmol). The resultant mixture was refluxed for 7 h. Reaction mixture was concentrated and the residue was dissolved in water (100 mL). It was acidified by 1 N HCl to pH=3-4 and then extracted with EtOAc. Organic layer was washed with water, brine and dried over MgSO4. It was filtered and concentrated. The crude product was triturated with (1/1) EtOAc/hexanes. Solid was collected and dried in vacuo to provide the title compound 52 mg (0.13 mmol) in 39% yield. LC-MS ESI−: 390.02 (M−1)−.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[N+:28]([O-])=O)[CH:10]=1>CO.ClCCl.[Pd]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCOCC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(OC2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)isonicotinamide (400 mg, 0.76 mmol, 1.00 equiv, 95%) in methanol/dichloromethane (10/5 mL). The solution was treated with Pd/C (400 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 270 mg (68%) of product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Reactant: Cc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Yield: 60.3 %

Procedure:
8-Methoxy-2,4-dichloroquinazoline (3.7 g, 0.016 mol) was stirred in a mixture of water (85 ml), tetrahydrofuran (125 ml), o-toluidine (1.7 g, 0.016 mol) and sodium acetate (2.2 g, 0.027 mol) for a total of 4 days with heating to 50° for a total of 32 hours and the addition of a total of 20 ml 0.01 mol NaOH dropwise over this period maintaining the pH at 7. The reaction mixture was evaporated in vacuo and crystallised from ethanol/water to give 8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (2.89 g, 60%) m.p. 218°-220°.
Reaction SMILES: C(O)(=O)C.[C:5]([NH:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([N+:28]([O-])=O)=[C:13]([CH:27]=1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:7])[CH3:6]>[Fe].O>[C:5]([NH:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([NH2:28])=[C:13]([CH:27]=1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:7])[CH3:6]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Temperature: 80 °C
Yield: 72.8 %

Procedure:
Into a mixture of 40 ml of acetic acid and 40 ml of water was added 2.2 g of an iron powder, and the mixture was heated to 80° C. Into the mixture was added 3.0 g of methyl [2-(5-acetylamino-4-fluoro-2-nitrophenoxy)phenoxy]acetate, and the mixture was heated for 30 minutes under reflux. Thereafter, the mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain 2.01 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]1([C:24]2[CH:59]=[CH:58][C:27]([C:28]([O:30][C@@H:31]3[CH2:39][C@@H:34]4[O:35][C:36](=[O:38])[CH2:37][C@@H:33]4[C@H:32]3/[CH:40]=[CH:41]/[C@@H:42]([O:51]C3CCCCO3)[CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[OH:51][C@H:42]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)/[CH:41]=[CH:40]/[C@@H:32]1[C@@H:33]2[C@@H:34]([O:35][C:36](=[O:38])[CH2:37]2)[CH2:39][C@H:31]1[O:30][C:28](=[O:29])[C:27]1[CH:58]=[CH:59][C:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][CH:26]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
Pyridinium p-toluenesulfonate (20 mg) was added to a stirred solution of the compound [8a] (0.44 g), obtained in previous step, in methanol (20 mL) at room temperature. The mixture was stirred at 40-50° C. for 3-4 hours (TLC monitoring) and evaporated under reduced pressure. The residue was diluted with dichloromethane (30 mL). The solution was washed with saturated aqueous solution of sodium bicarbonate (10 mL) and brine(10 mL), dried over sodium sulfate, filtered and evaporated to give 0.35 g (93.4%) of oily residue. The residue was crystallized from a mixture of hexane and ether to give compound [6a] as white crystals with mp 81-83° C. and [α]D20 −124.5° (c 1, MeCN). 1H NMR (CDCl3) δ: 7.08-8.05 (m, 14H); 5.51-5.74 (m, 2H); 5.21-5.30 (m, 1H); 5.02-5.07 (m, 1H); 4.09-4.13 (m, 1H); 2.46-2.92 (m, 7H); 2.18-2.28 (m, 1H); 1.66-1.86 (m, 3H). 13C (CDCl3) δ: 31.6; 34.8; 37.6; 38.7; 42.7; 54.1; 71.6; 79.0; 83.1; 125.9; 127.1; 127.2; 128.2; 128.3; 128.8; 128.9; 130.1; 136.2; 139.9; 141.5; 146.1; 165.9; 176.2.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CC(C)([O-])C.[K+].Br[C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][C:43]=4[CH3:44])[C:35]([NH:37][CH:38]4[CH2:40][CH2:39]4)=[O:36])[CH:28]=3)[C:23]2=[O:45])=[CH:17][CH:16]=1>C1COCC1>[CH:38]1([NH:37][C:35](=[O:36])[C:34]2[CH:41]=[CH:42][C:43]([CH3:44])=[C:32]([C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:45])[N:22]([CH2:21][C:18]3[CH:19]=[N:20][C:15]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:16][CH:17]=3)[CH:31]=[CH:30]4)[CH:33]=2)[CH2:39][CH2:40]1
Reactant: CN(C)CCCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(Br)nc3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCN(C)C)nc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To solution of 3-(dimethylamino)propan-1-ol (0.03 mL) in THF (1 mL) was added potassium tert-butoxide (28 mg) and the reaction stirred at room temperature for 10 minutes. A solution of the product of step i) (100 mg) in THF (2 mL) was added, and the mixture heated at reflux for 100 hours.