Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:27][C@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[CH3:27][C@@H:28]1[NH:29][CH2:30][CH2:31][N:32]([C:2]2[N:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[C:21]([CH:23]6[CH2:26][O:25][CH2:24]6)[CH:22]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[CH:5]=[CH:4][CH:3]=2)[CH2:33]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(c2cccc(-n3ncc4cnc(-c5cncc(C6COC6)c5)cc43)n2)CCN1
Yield: 24 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and (S)-2-methylpiperazine, 113 was obtained as an off-white solid (26.3 mg, 24%). 1H NMR (400 MHz, DMSO) δ 9.39-9.28 (m, 1H), 9.20-9.11 (d, J=2.1 Hz, 1H), 9.11-9.02 (s, 1H), 8.72-8.61 (m, 2H), 8.60-8.53 (t, J=2.1 Hz, 1H), 7.84-7.67 (t, J=8.1 Hz, 1H), 7.32-7.18 (d, J=7.7 Hz, 1H), 6.87-6.76 (d, J=8.5 Hz, 1H), 5.08-4.98 (dd, J=8.2, 6.2 Hz, 2H), 4.76-4.68 (t, J=6.3 Hz, 2H), 4.48-4.35 (m, 1H), 4.28-4.13 (dd, J=20.9, 11.0 Hz, 2H), 3.06-2.88 (ddd, J=19.7, 14.7, 7.1 Hz, 2H), 2.87-2.73 (m, 2H), 2.60-2.53 (m, 1H), 2.39-2.31 (d, J=7.7 Hz, 1H), 1.09-0.99 (dd, J=14.9, 6.2 Hz, 3H); MS (ESI) m/z: 428.2 [M+H]+
Reaction SMILES: [Cl-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)C>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:6]2[CH:5]=[CH:4][N:3]([CH3:2])[CH2:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: C[n+]1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Product: CN1C=CC(C2CCN(C)CC2)=CC1

Procedure:
N,N'-dimethyltetrahydro-4,4'-bipyridyl (DMTB) was prepared from N-methylpyridinium chloride by electrolytic dimerization and obtained in the form of a diethyl ether solution thereof. The so obtained diethyl ether solution was vacuum-distilled to obtain pure DMTB. As the pure DMTB tends to decompose immediately upon contact with oxygen in air, it was carefully handled in a nitrogen atmosphere. A 500 ml three-necked flask was sufficiently washed and dried and then completely filled with nitrogen gas. Into this flask were charged 200 ml of degassed water and 40 millimoles of nitrobenzene. 8 millimoles of DMTB was added, while stirring by rotating a magnetic stirrer having a length of 4 cm at 500 r.p.m., to the mixture charged in the flask, and the reaction was allowed to proceed at room temperature and atmospheric pressure in an atmosphere of nitrogen gas. The measurement of change, with the lapse of time, of pH showed that the pH changed from 6.8 to 12.7 one hour after the initiation of the reaction and it changed no more thereafter.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([C:20]2[O:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[O:24][C:23]([NH:25][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:22][N:21]=2)[CH2:19][CH2:18]1
Reactant: Nc1nnc(C2CC2)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnc(C2CC2)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 159-160° C. and MS: m/e=320.3 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:8]([F:21])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:23].O>C(O)C>[Na+:23].[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)[F:21])=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of 2-[5-(4-chlorophenoxy)-1-fluoropentyl]-2-oxiranecarboxylic acid methyl ester (2.53 g, 8 mmol) of Example 2 in 25 ml of absolute ethanol is treated with a solution of 320 mg (8 mmol) of sodium hydroxide in 12 m l of water. The mixture is maintained with stirring at room temperature for 2 hours and then is rotoevaporated. The obtained solid is triturated three times with ethyl ether, the solvent is removed by rotoevaporation and the solid is dried at high vacuum over phosphorus pentoxide to give 2.25 g (86.6%) of the title compound: m.p. 159°-175° C.; IR (KBr) 1630, 1608, 1490 and 1242 cm-1 ; NMR (d6 -DMSO) δ 1.54 (2H, m), 1.73 (4H, m), 1.73 (4H, m), 2.65 (1H, m), 2.73 (1H, d, J=6 Hz), 3.98 (2H, t, J=6 Hz), 5.22 (1H, ddd, JHF =48, 10, 3 Hz), 7.00 (2H, d, J=9 Hz) and 7.36 (2H, d, J=9 Hz).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[CH:11]=1>CS(C)=O.C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[CH:11]=[C:12]([CH3:27])[N:13]=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:15]=1[CH3:16])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
To a solution of 3-pentanol (0.2 ml, 0.5205 mol) in DMSO (1 ml) was added 60% sodium hydride in oil (30 mg) in a portionwise. After stirring at room temperature for 5 min, a solution of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyridine (98 mg) in 0.5 ml of dry THF was added and the resulting mixture was heated at 130° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane to chloroform as eluent to give 7 mg of the title compound as white crystals, mp 72.5–74° C. 1H NMR (CDCl3) δ 6.84 (s, 2H), 6.26 (s, 1H), 4.16 (m, 1H), 2.27 (s, 3H), 2.17 (s, 6H), 2.04 (s, 6H), 1.69 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:28])[CH3:27])[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:27])[CH3:28])[N:8]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCBr
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc2cc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (3.15 g, 7.48 mmol) in N,N-dimethylformamide (15 mL) is added potassium carbonate (3.09 g, 22.36 mmol), followed by 1-bromo-3-methyl butane (1.79 mL, 14.94 mmol), and the reaction is allowed to stir at ambient temperature for 16 h. Another equivalent of 1-bromo-3-methyl butane (0.9 mL, 7.5 mmol) is added and the reaction is allowed to stir for 16 h at ambient temperature. The reaction is poured over water and extracted three times with dichloromethane. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography and eluted with a gradient of 2-7% (hexanes-ethyl acetate) to afford the title compound as a yellow oil (2.5 g, 68% yield), along with N-isoamyl-N-(6-(3-methylbutoxy)naphthalene-2-sulfonyl)-D-valine tert-butyl ester as a yellow oil (0.3 g, 7.7% yield). LCMS (m/z): (492.26; M+1).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([C:9](Cl)=[C:10]([CH3:13])[CH:11]=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])=[CH:15][CH:16]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CC(C=O)=C(Cl)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Yield: 88 %

Procedure:
4-tert-Butyl-β-chloro-α-methylcinnamaldehyde (71 g), 1.0 g of 5% Pd/C, 40 g of 30% sodium hydroxide solution, 40 g of water and 32 g of methanol were placed in a Parr apparatus and hydrogenated at 20-50 psi until the theoretical amount of hydrogen had been absorbed (about 31/2 hrs.). The solution was filtered and the aqueous phase extracted with 100 g of ethylene dichloride. The solution was distilled to yield 53.9 g (76%) of the desired product, bp 100° (1.0 mm).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[S:30](Cl)([CH3:33])(=[O:32])=[O:31].OS(O)(=O)=O>N1C=CC=CC=1.O>[OH:27][CH:17]1[CH:16]2[CH:15]([CH2:14][CH:13]([OH:28])[C:12]3([CH3:29])[CH:11]2[CH2:10][CH2:9][CH:8]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([O:25][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:22][CH2:21]2)[CH2:18]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OS(C)(=O)=O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g of cholic acid are dissolved in 500 ml of pyridine and 23.1 ml of mesyl chloride are added dropwise over a period of 30 minutes at 0° C. The mixture is stirred at RT for 3 hours, then poured into a solution of 400 ml of H2SO4 in 3 l of water at 0° C. and extracted 4 times using 750 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The residue is crystallized using diisopropyl ether and 117.1 g are obtained; m.p. 121° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+:21].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:15][C:14]1[N:21]=[CH:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1
Reactant: [NH4+]
Reactant: CC(=O)CN(C=O)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
A suspension of N-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (265 mg), ammonium acetate (919 mg) and acetic acid (0.3 ml) in xylene (5 ml) was refluxed for 2.5 hours and then evaporated under reduced pressure. To the residue were added ethyl acetate and an aqueous solution of sodium hydroxide (1N, 25 ml), and the mixture was stirred for 10 minutes. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give 4-methyl-1-(3-nitrophenyl)imidazole (203 mg, 83.9%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.[CH2:12]([O:19][C:20]([O:22]N1C(=O)CCC1=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C:20](=[O:22])[N:2]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH3:1])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC[C@H]1CC[C@H](CO)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g (13.35 mmol) trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) were dissolved in 20 ml methanol. 3.32 g (13.35 mmol) N-(benzyloxycarbonyloxy)-succinimide were added and the solution was stirred at room temperature for 2 hours, then for 1 hour at 50° C. Afterwards, the solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with water (2 times), then with brine and finally dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and diethyl ether as the eluent. 1.67 g (42.9%) trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid benzyl ester were obtained as colorless oil, M: 289 (M).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]=1>>[O:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:18]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: BrCc1coc2ccccc12
Product: O=C(O)c1cc2ccccc2n1Cc1coc2ccccc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-benzofuran (Lit. 19) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 290.2 ([M−H]−).
Reaction SMILES: C(OC(CCCCC(O[C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:34]=[CH:33][C:32](OC(CCCCC(OCC2C=CC=CC=2)=O)=O)=[CH:31][CH:30]=1)=O)=O)C1C=CC=CC=1.[H][H].C1COCC1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[O:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[CH:18]=[C:19]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: O=C(CCCCC(=O)Oc1ccc(-c2oc3ccccc3c(=O)c2OC(=O)CCCCC(=O)OCc2ccccc2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccccc2)oc2ccccc12
Yield: 130.9 %

Procedure:
A mixture of 3,4′-di-(benzyloxycarbonylbutylcarbonyloxy)flavone (435 mg, 0.629 mmol) and Pd(OH)2 (50 mg) in EtOAc (5 mL) was treated with hydrogen for 2 h resulting in a grey precipitate. THF was added to dissolve the precipitate and the mixture was filtered (Celite). The pad washed with THF, and the filtrate concentrated. The solid residue was recrystallised from THF/petrol to afford the bis(hemiadipate) as a colourless solid (183 mg, 50%); mp 133° C.; 1H NMR (500 MHz, d6-DMSO) δ 1.55-1.70 (m, 8H, CH2CH2), 2.24 (t, 2H, J=7.0 Hz, CH2CO), 2.27 (t, 2H, J=7.0 Hz, CH2CO), 2.63 (t, 2H, J=7.0 Hz, CH2CO), 2.64 (t, 2H, J=7.0 Hz, CH2CO), 7.37 app. d, 2H, J=9.0 Hz, H3′,5′), 7.55 (dd, 1H, J5,6=8.5, J6,7=7.5, Hz, H6), 7.80 (d, 1H, J7,8=8.5 Hz, H8), 7.88 (ddd, 1H, J6,7=7.5, J7,8=8.5, J5,7=1.5 Hz, H7), 7.96 (app. d, 2H, J=9.0 Hz, H2′,6′), 8.08 (dd, 1H, J5,6=8.5, J5,7=1.5 Hz, H5); 13C NMR (125 MHz, d6-DMS) δ 23.77, 23.82, 32.6, 33.2, 33.3; 44.3 (CH2), 118.7, 122.5, 122.6, 122.7, 125.1, 126.8, 129.7, 132.9, 134.8, 152.7, 154.9, 155.1 (Ar), 170.4, 171.1, 171.4, 174.3, 174.3 (5C, C═O); IR 3059, 2940, 2873, 1768, 1706, 1504, 759 cm−1; HRMS (ESI−) m/z 509.1441, C27H25O10 [M−H]− requires 509.1442.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a solution of 5-bromomethyl-2-nitrobenzoic acid methyl ester (3.00 g, 10.9 mmol) in CH2Cl2 (100 mL) was added triethylamine (3.30 g, 33.0 mmol) and 1-methylpiperazine (3.30 g, 33.0 mmol). The mixture was heated at 50° C. under nitrogen for 16 hours, then concentrated to give crude 5-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid methyl ester, which was purified by column chromatography (silica gel 230-400 mesh; 1-5% methanol in dichloromethane as eluent). Yield: 3.0 g (93%). It was further converted to its hydrochloride salt (3.7 g) by stirring in 1 M HCl in ether and was isolated by filtration.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c(OC)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 2,4-dimethoxyaniline gave N2-(2,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.35 (s, 1H), 8.14 (bd, 1H), 7.38 (d, 1H, J=9 Hz), 7.23 (s, 1H), 7.09 (d, 1H, J=8.7 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=2.4 Hz), 6.49 (dd, 1H, J=2.4 and 9 Hz), 4.22 (s, 4H), 3.77 (s, 6H); LCMS: ret. time: 20.93 min.; purity: 98%; MS (m/e): 399 (MH+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]([C:20]([OH:22])=O)[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)=[O:11])([CH3:8])[CH3:7]>>[C:6]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:20](=[O:22])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)([CH3:5])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.2 mmol) and Boc-L-3-(4-thiazolyl)alanine (1.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 1-16% ethanol In dichloromethane containing 0.5% ammonium hydroxide. Yield 124 mg, 41%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34](O)=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:71][CH2:72][C:73]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=1[C:75]([O:77][CH2:78][CH3:79])=[O:76]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:34]([NH:71][CH2:72][C:73]2[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=2[C:75]([O:77][CH2:78][CH3:79])=[O:76])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(Benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxylic acid (Example 1.2; 0.42 g; 0.85 mmol) was dissolved in dichloro methane (9 ml). DIPEA (0.58 ml; 3.42 mmol) and HBTU (0.39 g; 1.03 mmol) were added. The reaction mixture was stirred at room temperature during 5 min. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 0.24 g; 1.03 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 and washed with a saturated aqueous Na2CO3 solution (2×) and H2O. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromategraphy over silica gel (eluent: hexane/EtOAc 10:1 up to 1:1). The fractions were collected and the solvent evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc(C=O)o2)cc1
Reactant: CC(C)(C)NO
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)o2)cc1
Yield: 86.2 %

Procedure:
2-(4-Methoxyphenylthio)-5-furaldehyde (24.50 g) was mixed with N-tert-butylhydroxylamine (15.0 g, 168.16 mmol), molecular sieves (100 g) and silica gel (20 g) in CDCl3 (500 mL). The mixture was refluxed overnight under argon gas, and then filtered and concentrated on a rotary evaporator. The residue was recrystallized from hexanes (435 mL) to afford the title compound as yellowish crystals (27.52 g, yield 78.8%), m.p. 91.7° C. (Rf=0.15 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Oc2ccc3c(cnn3-c3ccccn3)c2)C(C)N)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3ccccn3)c2)C(C)NS(=O)(=O)C2CC2)cn1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-[6-methoxypyridin-3-yl]-1-[1-(pyridin-2-yl)indazol-5-yl]oxypropan-2-amine (50 mg, 130 μmol) in dichloromethane (5 mL) was added triethylamine (44 μl), followed by cyclopropane sulfonic acid chloride (28 mg, 200 μmol) and DMAP (1.6 mg, 13 μmol).The stirring was continued for 20 min at room temp The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 24 mg as a racemic mixture of two diastereomeres (37%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH2:25][O:21][C:20](=[O:22])[C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h and then cooled to 0° C. DBU (46.6 g, 0.03 mol) was then added and the reaction mixture was stirred for 2 h at 0° C. and quenched with HCl (1 N). The aqueous layer was basified with a NaHCO3 solution and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (600 mg, 15%) as a solid.