Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1>>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[C:3]([CH3:18])=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Product: Cc1c(Cl)sc2ncnc(NC3CCN(Cc4cccc(F)c4)CC3)c12

Procedure:
The title compound was prepared (119 mg, 91%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 mmol) and 1-(bromomethyl)-3-fluorobenzene (70 mg, 0.37 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95 (m, 1H), 5.30 (d, 1H), 4.05 (m, 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50 (s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 390.91; Observed: 391.2 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[C:7]([Cl:11])[N:6]=[N:5][C:4]=1[Cl:12].[C:13](=[O:16])([O-])[O-].[Na+].[Na+].C[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.CCCCCCC>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:12][C:4]1[C:3]2[CH2:2][N:25]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:16][CH3:13])=[CH:21][CH:22]=3)[CH2:9][C:8]=2[C:7]([Cl:11])=[N:6][N:5]=1
Reactant: Clc1nnc(Cl)c(CBr)c1CBr
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(CN)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc(CN2Cc3c(Cl)nnc(Cl)c3C2)cc1
Temperature: 70 °C
Yield: 40.5 %

Procedure:
To a suspension of 4,5-bis(bromomethyl)-3,6-dichloropyridazine (800 mg, 2.39 mmol) in 40 mL anhydrous THF was added with sodium carbonate (507 mg, 4.78 mmol) and tetrabutylammonium iodide (88.3 mg, 0.24 mmol). The reaction mixture was added with 4-methylbenzylamine (0.31 mL, 2.39 mmol) in 20 mL THF dropwisely for 2 h. The reaction mixture was heated at 70° C. for 8 h and concentrated. The crude material was dissolved in DCM and washed with water and brine. The organic solution was dried over Na2SO4 and concentrated to afford a crude oil. The mixture was purified by flash chromatography on silica gel, eluting with 10-80% EtOAc:heptane to afford a off-white solid (300 mg, yield: 41%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:7]([Mg]Br)=C.[C:11]([O:19]CC)(=[O:18])[CH2:12][C:13](OCC)=O.[OH-].[K+]>C1COCC1.CCO>[CH3:4][CH:3]([CH3:5])[CH2:2]/[CH:1]=[CH:7]/[CH2:13][CH2:12][C:11]([OH:19])=[O:18]
Reactant: CC(C)CC=O
Reactant: C=C[Mg]Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C/C=C/CCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of isovaleraldehyde (8.61 g, 100 mmol, 1 equiv) in THF (30 mL) was added dropwise via addition funnel to a solution of vinylmagnesium bromide (100 mL of a 1.0 M solution in THF, 100 mmol, 1.0 equiv) in THF (150 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 30 minutes at 0° C., and then was partitioned between saturated NH4Cl (150 ML) and Et2O (2×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford a yellow oil. This material was combined (neat) with diethyl malonate (16.7 mL, 110 mmol, 1.1 equiv) and Ti(OEt)4 (2.10 mL, 10.0 mmol, 0.10 equiv), and the combination was heated to 160° C. for 1 hour (distilling out EtOH as it was formed). The reaction mixture was then maintained at 190° C. for 4 hours and then cooled to 60° C. EtOH (50 mL) and 6.0 M KOH (50 mL) were added sequentially, and the brown reaction mixture was refluxed for 4 hours. After cooling to 23° C., the reaction mixture was filtered through a medium frit, and the filtrate was partitioned between water (150 mL) and Et2O (2×150 mL). The aqueous layer was then acidified to pH=2 (as indicated by pH paper) with concentrated HCl and extracted with a 1:1 mixture of EtOAc and hexanes (2×150 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was distilled at reduced pressure to afford trans-7-methyl-oct-4-enoic acid (4.62 g, 30%) as a colorless liquid: bp: 115-120° C. (1 torr); 1H NMR (CDCl3) δ 0.86 (d, 6H, J=5.5), 1.51-1.65 (m, 1H), 1.87 (t, 2H, J=6.5), 2.22-2.38 (m, 2H), 2.40-2.45 (m, 2H), 5.34-5.52 (m, 2H); Anal. (C9H16O2) C, H.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:9][C@@H:8]1[C@H:10]([O:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:12]([CH3:13])[O:14][C@H:7]1[N:6]1[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]1=[O:16])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5'-deoxy-5-fluorouridine (24.6 g) in dry pyridine (150 ml) was added dropwise 24.5 ml of benzoyl chloride over 10 minutes at 0° C. and the mixture was stirred for 5 hours at room temperature. After removal of pyridine under reduced pressure the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate - n-hexane to give 38.9 g of 2',3'-di-O-benzoyl-5'-deoxy-5-fluorouridine, MS 455 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Oc1cccc(F)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenol to give [1-(3-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Fe+2:6].[N+:7]([O-])([O-])=O.[NH4+]>>[NH4+:7].[O-:4][S:1]([O-:5])(=[O:3])=[O:2].[O-:4][S:1]([O-:5])(=[O:3])=[O:2].[Fe+3:6]
Reactant: [Fe+2]
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: [Fe+3]

Procedure:
The method of claim 27 wherein the solution of iron sulfate is contacted with aqueous ammonium nitrate at a temperature of about 90° C. to about 150° C. to form a solution of ammonium jarosite and/or ferric ammonium sulfate.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863 mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at 120° C. for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (933 mg) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reactant: C[C@H]1NCCNC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3R)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C[I:19].[C:20](OCC)(=O)C>CO>[I-:19].[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:20])[CH3:3]
Reactant: CN(C)CCCCCCCCc1ccccc1
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CO
Product: C[N+](C)(C)CCCCCCCCc1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a solution of 193 mg of N,N-dimethyl-8-phenyloctylamine in 1.5 ml of absolute methanol, were added dropwise 258 μl of methyl iodide, and the mixture was stirred at a room temperature for 6.5 hours. After adding 3 ml of ethyl acetate, the mixture was stirred with ice-cooling for 30 minutes. Resulting crystal was filtered, washed with ethyl acetate, and dried under a reduced pressure to obtain 238 mg of the title compound as a colorless crystal.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][C:19]([CH3:26])=[CH:20][C:21]=2[O:23][CH2:24][CH3:25])[O:16][CH2:15]1>>[CH2:24]([O:23][C:21]1[CH:20]=[C:19]([CH3:26])[N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12)[CH3:25]
Reactant: CCOc1cc(C)nc2c1C(=NOC)CO2
Agent: NC1COc2nnccc21
Product: CCOc1cc(C)nc2c1C(N)CO2

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-ethoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: C1COCCN1
Reactant: Cc1ccc(OCCCBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of the 4-(3-bromo-propoxy)-1-methyl-2-nitro-benzene V-h (500 mg, 1.82 mmol) in dry dioxane (30 mL) was treated with K2CO3 (1.01 g, 7.28 mmol) and morpholine (319 μl, 3.65 mmol) and heated to 100° C. for 6 h. The cooled mixture was diluted with water and extracted with DCM. The combined organics were dried (MgSO4), filtered and evaporated before purification by column chromatography (SiO2; eluting with 2% EtOH in DCM) to afford the desired product as a yellow-orange oil V-i (356 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, 2.7 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 3.79-3.66 (m, 4H), 2.49 (dt, J=9.0, 5.1 Hz, 9H), 2.07-1.88 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][S:12](=[O:38])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCSCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc(N2CCS(=O)CC2)c1
Yield: 73.3 %

Procedure:
To a solution of 1-[2-(3-methoxy-5-thiomorpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (80 mg, 0.195 mmol) in methylene chloride (5 ml) and methanol (5 drops) was added m-CPBA (44 mg, 0.195 mmol). After 1 hour the crude material was loaded onto 2 preparative TLC plates, eluting with 10% methanol in methylene chloride. The product band was collected to afford 61 mg of 1-{2-[3-methoxy-5-(1-oxo-1lambda*4*-thiomorpholin-4-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a light yellow-brown solid. MP 259-260° C., M+H=427.
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C:15]1(CC(O)=O)CCCCC1.CC#N.O.CC#N>O>[C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:15]1)(=[O:3])[CH3:2]
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Solvent: O
Solvent: CC#N
Product: CC(=O)NC1(CC(=O)O)CCCCC1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (1-amino-cyclohexyl)-acetic acid. MS (LC-MS): [M+H]+=200.1. (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.81 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].[NH2:36][CH2:37][CH:38]([C:40]1[CH:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1cccc(O)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=543.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH:18]([CH:20]=[O:21])=O.[ClH:22]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]=[C:10]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:18][CH:20]([OH:21])[C:14](=[C:10]2[NH:11][CH2:12][CH2:13][N:9]2[CH2:8][C:5]2[CH:4]=[N:3][C:2]([Cl:22])=[CH:7][CH:6]=2)[N+:15]([O-:17])=[O:16])=[CH:6][CH:7]=1
Reactant: Cl
Reactant: O=CC=O
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Solvent: CC#N
Product: O=[N+]([O-])C(=CC(O)C(=C1NCCN1Cc1ccc(Cl)nc1)[N+](=O)[O-])C1=NCCN1Cc1ccc(Cl)nc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a 50 ml round bottom flask was added 1.27 g (0.005 mol) 2-chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine, 30 ml acetonitrile and 3 ml 30% oxaldehyde aqueous solution. After stirring for 0.5 hour, catalytic concentrated HCl was added. The reaction was then stirred and monitored by TLC until completion. The mixture was filtered afterwards to afford white powder, which was crystallized to give 1.05 g pure final product as white powder solid. Yield: about 76%.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:51][N:52]1[CH:56]=[C:55]([C:57](O)=[O:58])[N:54]=[CH:53]1>C(OCC)(=O)C.CN(C=O)C>[CH3:51][N:52]1[CH:56]=[C:55]([C:57]([NH:2][NH:1][C:3]2[N:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[C:6]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=2)=[N:8]3)=[O:58])[N:54]=[CH:53]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: Cn1cnc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)NNc2nccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc23)c1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (3.94 g, 8.18 mmol), EDC (1.34 g, 10.6 mmol), HOBt (1.44 g, 10.6 mmol), 1-methyl-1H-imidazole-4-carboxylic acid (1.34 g, 10.6 mmol), and DMF (40 mL). The reaction mixture was heated to 60° C. while stirring under an atmosphere of nitrogen in a hot oil bath. After 45 minutes the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl {1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) as red foam. MS (M+H)+: observed=590.3, calculated=590.69.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH:17]=O.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH2:17][CH2:16][N:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2ccn(CCNc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.10 g, 0.41 mmol) and 4-methoxyaniline (65 mg, 0.53 mmol) in methanol (2 mL) was stirred at rt for 30 mins. Then acetic acid (2.3 μL, 0.04 mmol) and sodium cyanoborohydride (64 mg, 1.0 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 70% EtOAc/hexanes) to afford methyl 2-{2-[(4-methoxyphenyl)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.12 g, 83%). LC-MS: (FA) ES+ 353.
Reaction SMILES: ClCS(O)(=O)=O.[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=3)=[N:15][CH:16]=2)[N:11]1[C:29]1[N:34]=[C:33]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[CH:32]=[CH:31][CH:30]=1)[CH:8]=[CH2:9].[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][NH:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:25][CH:26]=3)=[N:15][CH:16]=2)[N:11]1[C:29]1[N:34]=[C:33]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[CH:32]=[CH:31][CH:30]=1)[CH:8]=[CH2:9]
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(CO)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)CCl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCn1c(=O)c2cnc(Nc3ccc(CNC(C)(C)C)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloromethanesulfonic acid (37 μL) was added to a tetrahydrofuran solution (10 mL) of 6′-[2-allyl-6-{[4-(hydroxymethyl)phenyl]amino}-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one (110 mg) and triethylamine (164 μL), and stirred at room temperature for 1 hour, then tert-butylamine (500 μL) was added to the reaction liquid, and stirred for 6 hours. Chloroform and aqueous sodium hydrogencarbonate solution were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, filtered, the solvent was evaporated away, and the resulting crude product was purified through basic silica gel column chromatography (hexane-ethyl acetate/ethanol (19/1) mixture) to give the entitled compound as a white solid substance (9.2 mg).
Reaction SMILES: C(OC([NH:8][C:9](=[O:15])[C@H:10]([CH2:12][S:13][CH3:14])[NH2:11])=O)(C)(C)C.[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH3:14][S:13][CH2:12][C@@H:10]([C:9]([NH2:8])=[O:15])[NH2:11].[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1
Reactant: CSC[C@H](N)C(=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Product: CSC[C@H](N)C(N)=O
Yield: 83 %

Procedure:
After 1.83 g of the [(3,4-methylenedioxy)aniline]-N-t-butoxycarbonyl-S-methylcysteinamide obtained above in (A) were dissolved in 20 ml of ethyl acetate, hydrochloric acid gas was ebulated at room temperature under stirring until no fresh precipitate was formed. The colorless precipitate so obtained was collected by filtration and then dried, whereby 1.25 g of [(3,4-methylenedioxy)aniline]-S-methylcysteinamide hydrochloride were obtained (yield: 83%).