Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].Br[CH2:19][C:20]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](OC)=[O:23]>CN(C)C=O.C(#N)C>[O:23]=[C:22]1[C:21]2[C:20](=[C:29]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:27][CH:26]=2)[CH2:19][N:9]1[CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Temperature: 52.5 °C

Procedure:
Triethylamine (140.8 g, 2.29 mol) was added at 25-30° C. to a solution of 3-amino-piperidine-2,6-dione hydrochloride (100 g, 0.61 mol) in N,N-dimethylformamide (800 ml). A solution of methyl 2-bromomethyl-3-nitro-benzoate (186.0 g, 1.13 mol) in acetonitrile (200 ml) was then added under stirring and a nitrogen atmosphere and the reaction mixture was heated to 50-55° C. for 8-10 hours. After completion of the reaction approximately 60% solvent was removed by distillation at 50-60° C. under reduced pressure (100 mbar). Water (1000 ml) was added to the residual mixture at 50-55° C. and stirred for 1 hour at this temperature. The resultant solid product was cooled to 25-30° C. and filtered. The solid was washed with water (500 ml) at 50-55° C., cooled at ambient temperature and filtered again. Finally the solid was washed with methanol (500 ml) at 50-55° C., cooled at 25-30° C. and filtered. The filtered solid product was dried at 50-55° C. under low pressure (200 mmHg) for 4 hours to give 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a purple to ash coloured solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.C([O:22][C:23](=[O:32])[CH2:24][NH:25][CH2:26][C:27]([O:29]CC)=[O:28])C>>[C:23]([CH2:24][N:25]([CH2:26][C:27]([OH:29])=[O:28])[C:17]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:16])=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)=[O:19])([OH:32])=[O:22]
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N(CC(=O)O)CC(=O)O)c(O)c2c1

Procedure:
Prepared from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid and (ethoxycarbonylmethyl-amino)-acetic acid ethyl ester analogously to Example D-49 MS-(+)-ion: 397.0 amu.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:52])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:52])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC(C)(C)C)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a solution of tert-butyl 3-(4-{({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (1.67 g, 2.21 mmol) and mercaptoacetic acid (0.51 mL, 6.64 mmol) in N,N-dimethylformamide (17 mL) was added lithium hydroxide monohydrate (0.56 g, 13.3 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate. and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/1) to give the title compound (1.17 g, yield 93%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:66][CH2:67][CH2:68][CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:29])[S:26][C:19]=23)=[CH:30][CH:31]=1)=[O:11]
Reactant: CCOC(=O)CCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in 10 ml of anhydrous THF were added HATU (122 mg, 0.32 mmol) and N,N-diisopropylethylamine (104 mg, 0.81 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 99%.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 20%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=1.C(CC(=O)C(C)(C)C)(=O)C(C)(C)C.[Cl-].[NH4+]>[Cu](Cl)Cl.CN1CCCC1=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:35]4[CH:36]=[CH:37][C:38]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:39][CH:40]=4)=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: Oc1ccc(CC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(CC3CCN(c4ccc(OC5CCCCO5)cc4)CC3)cc2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 53.3 %

Procedure:
4-({1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenyl]piperidin-4-yl}methyl)phenol (1.10 g, 3.0 mmol), cesium carbonate (0.977 g, 3.0 mmol), N-methylpyrrolidinone (5 ml), 1-bromo-4-(trifluoromethoxy)benzene (0.723 g, 2.99 mmol) and dipivaloylmethane (0.3 g, 1.5 mmol) were mixed, and the atmosphere was replaced with nitrogen. Copper chloride (0.030 g, 0.3 mmol) was added thereto and stirred at 120° C. for 24 hours. An ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to afford the title compound as a colorless powder (0.84 g, 53%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][C:32](=O)[CH3:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH:32]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH3:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC(C)=O)ccc1C#N
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 434.4 [M+1]+. (0.19 μM)
Reaction SMILES: [ClH:1].[NH:2]([CH:4]1[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]1)N.C(O)C.[OH-].[Na+].Cl>[Ni].C(O)CCC.O>[ClH:1].[NH2:2][CH:4]1[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]1
Reactant: CC1CC(NN)CCO1
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCCCO
Product: CC1CC(N)CCO1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a flask having an inner volume of 500 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 65.3 g (392 mmol) of 4-hydrazino-2-methyltetrahydropyran hydrochloride with a purity of 100% and synthesized in the same manner as in the above-mentioned (1), 18.0 g of developed Raney nickel, 120 ml of ethanol, 120 ml of water and 40 ml (320 mmol) of 8 mol/l aqueous sodium hydroxide solution, and the mixture was reacted at 75° C. for 24 hours under hydrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Then, 200 ml of n-butyl alcohol and 50 ml (600 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, the resulting mixture was concentrated under reduced pressure to obtain 38.2 g (Isolation yield: 63%) of 4-amino-2-methyltetrahydropyran hydrochloride with a purity of 98% (areal percentage by gas chromatography) as white powder.
Reaction SMILES: Cl.[NH2:2][C@:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:4]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]#[CH:67]>C(#N)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[NH2:2][C@:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([C:67]#[C:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][O:60][CH3:59])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Reactant: C#CCCCCCOC
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: CC#N
Solvent: N#Cc1ccccc1
Product: COCCCCCC#Cc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 97.4 %

Procedure:
To a 50 mL round bottomed flask equipped with a reflux condenser was charged successively (1R,3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate hydrochloride salt (0.500 g, 1.494 mmol), trans-bis(benzonitrile)dichloropalladium(II) (0.029 g, 0.075 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.107 g, 0.224 mmol), and cesium carbonate (1.947 g, 5.98 mmol). The flask was evacuated and back-filled with nitrogen for three cycles. Then 7-methoxyhept-1-yne (1.16 g, 9.19 mmol) as a solution in acetonitrile (7.0 ml) was added via syringe. The reaction mixture was heated to about 90° C. After about 4 hours the reaction mixture was cooled to ambient temperature and partitioned into water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with saturated sodium bicarbonate solution (50 mL), brine (50 mL), then dried (MgSO4) and concentrated to yield 1.98 g of crude yellow oil. The crude material was purified via Analogix flash chromatography system using RediSep RS 12 g column, with a gradient of 0-5% methanol in ethyl acetate over 25 min. at 15 mL/min. Fractions containing product were combined and concentrated to yield 0.5 g of greenish yellow oil of (1R,3S)-methyl 1-amino-3-(4-(7-methoxyhept-1-ynyl)phenyl)cyclopentanecarboxylate which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][C@@H:16]([CH3:18])[NH:15][CH2:14][C@H:13]2[CH3:19])=[N:4][N:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C@H:13]([CH3:19])[CH2:14][N:15]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[C@H:16]([CH3:18])[CH2:17]2)=[N:4][N:3]=1
Reactant: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@H](C)CN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@H](C)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-chloro-4-((2R,5R)-2,5-dimethylpiperazin-1-yl)phthalazine (245 mg, 0.885 mmol) was dissolved in DMF (3.5 mL) and N,N-diisopropylethylamine (0.70 mL). Benzoyl chloride (0.118 mL, 1.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white foam. MS (M+H)+=381.8
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:20][CH:19]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Reactant: Cc1ccc(Br)nc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: Cc1ccc(Nc2ccc(Oc3ncccc3C3CCOCC3)cc2)nc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.167 g, 0.619 mmol), 2-bromo-5-methylpyridine (0.0888 g, 0.516 mmol), BrettPHOS precatalyst (8.26 mg, 10.32 μmol), and sodium tert-butoxide (0.124 g, 1.291 mmol). The flask was placed under vacuum then flushed with argon. Dioxane (1.7 mL) was added and the reaction was heated to 90° C. to stir overnight. After cooling to room temperature, the reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 5-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 362.1 (M+1). IC50 (uM) 0.002387.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 5-nitroindazole (20.0 g, 123 mmol) in methylene chloride (400 ml) were added 3,4-dihydro-2H-pyran (16.8 ml, 184 mmol) and p-toluenesulfonic acid (4.22 g, 24.5 mmol) at room temperature, and stirred for 2 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (26.6 g, 88%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([O:11][C:1](=[O:5])[C:2]([Cl:4])=[O:3])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (232 μL, 2.8 mmol) and t-butyl alcohol (228 μL) were combined in ether (6.7 mL) under nitrogen at 0° C. The resulting mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under vacuum to form chloro-oxo-acetic acid t-butyl ester, which was then dissolved in DCM (10 mL) and combined with (2S,4S)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-pentanoic acid ethyl ester (HCl salt; 667 mg, 1.8 mmol), which had been dissolved in DCM with Et3N (2.6 mL) at 0° C. The resulting mixture was stirred for 5 minutes at room temperature. The crude product was concentrated, dissolved in DCM and purified by flash chromatography (20-80% EtOAc/hexanes). The solvent was removed and the residue was dissolved in DCM (5 mL) and TFA (1 mL), and stirred for 1 hour. The product was dried under vacuum and purified by preparative HPLC to yield the title compound (135 mg, purity 95%). MS m/z [M+H]+ calc'd for C22H25NO6, 400.17. found 400.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=C(C)C=1>[C:24]1([N:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1cccc(C)c1
Product: O=[N+]([O-])c1ccccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 47.8 %

Procedure:
A mixed solution of 2.0 g of 2-(4-chlorophenyl)nitrobenzene, 1.7 g of diphenylamine, 0.99 g of t-butoxysodium, 0.19 g of (tris-t-butylphosphine)tetrafluoroborate, 0.43 g of bis(dibenzylideneacetone)palladium(0) and 30 ml of m-xylene was heated and stirred under a nitrogen gas stream at 140° C. for 5 hours. The solution was cooled to room temperature and filtered through Celite. The filtrate was evaporated, and then the concentrate was purified by silica gel column chromatography and vacuum-dried to obtain 1.5 g of 2-(4-diphenylaminophenyl)nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of o-chlorobenzoic acid (2.0 kg.) and chlorosulfonic acid (10.5 kg.) is heated at 90°-100° C. for 5 hours. The reaction mixture is cooled to 25° C. and then slowly poured into a 10 liter mixture of ice and water. The addition requires about 1 hour, and the temperature is maintained below 10° C. during this period by the addition of more ice. The final volume of slurry after the quench is about 40 liters. The solid material is collected and thoroughly washed on the funnel with fresh water. The crude wet cake is dissolved in 16 liters of diethyl ether. The ether layer is washed once with 2 liters of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The filtered ether solution is concentrated in vacuo with the continual addition of hexane. The resulting hexane slurry is concentrated to a final volume of approximately 8 liters and filtered. The crystalline cake is washed with hexane and dried in the atmosphere to give 2.5 kg. of product (76.8% of theory), m.p. 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:18][C:17]([O:16][CH3:15])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
To a solution of 3-chloroaniline and potassium carbonate (3 equiv.) in DMF is added methylbromoacetate (1.1 equiv.), and the reaction is stirred at 60° C. After complete reaction, the solution is poured into EtOAc and washed with water, sat. aq. NaHCO3 soln., and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography to provide the titled compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=S.[CH:25]1([C:28]([NH:30][NH2:31])=O)[CH2:27][CH2:26]1>O1CCCC1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:25]1([C:28]2[N:2]([CH3:1])[C:3]([C:5]3[CH:6]=[C:7]([CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:17]=3)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:31][N:30]=2)[CH2:27][CH2:26]1
Reactant: NNC(=O)C1CC1
Reactant: CNC(=S)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(-c3nnc(C4CC4)n3C)c2)nc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-[(methylamino)carbonothioyl]-5-(5-methylpyridin-2-yl)benzoate (0.56 g, 1.64 mmol) in tetrahydrofuran (15 mL) were added cyclopropanecarbohydrazide (0.49 g, 4.92 mmol) and mercury(II) acetate (1.05 g, 3.28 mmol). The reaction mixture was heated to 40° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound. MS 391.1 (M+1).