Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+].COC1C2OC3C=CC=CC=3C=2C=CC=1[N+]([O-])=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: O=[N+]([O-])O
Agent: COc1c([N+](=O)[O-])ccc2c1oc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c2c1oc1ccccc12
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 4-methoxy-dibenzofuran (3.15 g; 15.89 mmol) in glacial acetic acid (50 mL), fuming nitric acid (2.6 mL; 63.50 mmol) was added dropwise. The reaction was kept at 20° C. during the addition and stirred for 3 h. Upon completion, the reaction mixture was poured carefully onto iced water; pH was adjusted to 7 by addition of 1 M sodium hydroxide, and the product was extracted in DCM. The organic layer was dried on magnesium sulfate, filtered and then concentrated. The residue was purified by flash chromatography using ethyl acetate/EP (1:19) as eluant. The first compound to come off the column was the 4-methoxy-3-nitro-dibenzofuran (270 mg, 1.11 mmol, 7%) then the title compound (1.85 g, 7.62 mmol, 48%) was obtained as a cream solid: Rf=0.13 (EtOAc-EP 1:19); mp: 155-156° C.; λmax (EtOH)/nm 239; IR (cm−1) 3092, 2917, 2851, 2042, 1876, 1630, 1568, 1506, 1438, 1396, 1342, 1297, 1274, 1239, 1205, 1159, 1129, 1091, 1002, 938, 888, 831, 812, 738, 676; 1H NMR, (300 MHz, CDCl3) δ 4.06 (3H, s, OCH3), 6.92 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.36 (2H, m), 8.17 (1H, d, J=8 Hz), 8.63 (1H, d, J=8 Hz); 13C NMR, (75 MHz, CDCl3) δ 56.81 (OCH3), 107.53, 111.81, 120.50 (Cq), 121.14 (Cq), 122.27, 123.71, 126.32, 129.55, 136.29 (Cq), 145.20 (Cq), 150.53 (Cq), 157.02 (Cq); MS (EI) m/z 243.1 M+; HRMS calcd for C13H9NO4 [M+H]+ 243.0526, found 243.0528.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[N:13]3[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)(=O)C>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[N:13]2[N:12]=[C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[C:20]3[C:15]([C:14]2=[N:21][N:22]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: Cc1ccccc1-c1nnc2c3ccccc3c(Nc3cccc([N+](=O)[O-])c3)nn12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1nnc2c3ccccc3c(Nc3cccc(N)c3)nn12
Temperature: 90 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a suspension of (3-nitro-phenyl)-(3-o-tolyl-[1,2,4]triazolo[3,4-a]-phthalazin-6-yl)-amine (compound B10) (263 mg, 0.66 mmol) in a 2:1 mixture of glacial acetic acid and 37% hydrochloric acid (18 ml) is added tin chloride dihydrate (450 mg, 1.99 mmol). The mixture is stirred at 90° C. for 2 days. Upon cooling, the precipitate is filtered and the filtrate concentrated. Purification of residue by column chromatography (CH2Cl2/MeOH, 95:5) gives 205 mg of an off-white solid which is triturated with a 1:1 mixture of isopropanol and petroleum ether to yield 77 mg of the title compound as off-white needles.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][NH:27][CH:28]([CH3:29])[C:8]2=3)=[CH:4][CH:3]=1.Cl.C1(C2C=CC=CC=2)C=CC(CN2C(=O)C(C(NCC(OC(C)(C)C)=O)=O)=C(O)C3CNCC2=3)=CC=1.[S:68]1[CH:72]=[C:71]([C:73](Cl)=[O:74])[N:70]=[CH:69]1.CCN(CC)CC>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][N:27]([C:73]([C:71]4[N:70]=[CH:69][S:68][CH:72]=4)=[O:74])[CH:28]([CH3:29])[C:8]2=3)=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1cscn1
Reactant: CC1NCc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(Cc3ccc(Br)cc3)c21
Agent: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(-c4ccccc4)cc3)c1=O)CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1c2c(c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2Cc2ccc(Br)cc2)CN1C(=O)c1cscn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To tert-butyl N-{[1-(4-bromobenzyl)-4-hydroxy-7-methyl-2-oxo-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (1.344 g, 2.73 mmol, prepared in similar fashion to Intermediate 6 utilizing the appropriate starting materials) was added the product of Step A (0.403 g, 2.73 mmol) and NEt3 (0.38 mL, 2.73 mL). The reaction stirred at rt for about 17 h and was then diluted with EtOAc and washed with aq Na2CO3 (2 M) and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-65% EtOAc/hexane to afford the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][CH3:28])[C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (500 mg, 1.49 mmol) in DMF (5 mL) was added NaH (60% suspension in mineral oil, 120 mg, 1.64 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added ethyl bromide (0.12 mL, 1.64 mmol) and the reaction mixture was stirred for 4 h. The reaction mixture was diluted with ice-cooled water and the solution was extracted with EtOAc, the EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient, EtOAc in hexanes) to give (300 mg, 55%) of the titled compound. 1H NMR (400 MHz, CDCl3): δ 7.36-7.30 (m, 5H), 5.18-5.12 (m, 2H), 4.18-4.13 (m, 2H), 3.68-3.62 (m, 1H), 3.22-3.17 (m, 2H), 3.01-2.85 (m, 1H), 2.68-2.59 (m, 1H), 1.89-1.81 (m, 1H), 1.78-1.73 (m, 2H), 1.55 (s, 9H), 1.54-1.48 (m, 1H), 1.08 (t, J=6.4 Hz, 3H). ES-MS: m/z [M+1]=363.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:45]=[CH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(N(CC)CC)C>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[CH:45]=[CH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: C=Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCC1(CCO)OCCc2c1[nH]c1c(C=Cc3ccccc3)cc(C(C)C)cc21
Temperature: 90 °C

Procedure:
The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(debenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90° C. (oil bath) overnight. It is quenched with water and extracted with ethyl acetate. Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title-compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:10]=[C:4]2[CH:3]=1.ClC1C=CN=C(N)C=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:60]1[CH2:65][CH2:64][N:63]([C:66](=[O:69])[CH:67]=[CH2:68])[CH2:62][CH2:61]1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](/[CH:68]=[CH:67]/[C:66]([N:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[O:69])=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:10]=[C:4]2[CH:3]=1
Reactant: O=c1n(Cc2nc3cc(Cl)ccn3c2I)c2cnccc2n1C1CC1
Reactant: C=CC(=O)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Nc1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(Cl)ccn12)N1CCOCC1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 3-((7-chloro-3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 12-a (prepared following the 3-step synthesis used for 7-b, using 4-chloro-2-aminopyridine instead of 2-aminopyridine in step 1) and Et3N (2.218 mL, 8 eq) in DMF (30 mL) was degassed with nitrogen for fifteen minutes. Then palladium acetate (45 mg, 0.1 eq), triphenylphosphine (173 mg, 0.33 eq) and 1-morpholinoprop-2-en-1-one (2.516 mL, 10 eq) were added and stirring in a closed vessel was allowed at 80° C. during two hours. After cooling the mixture was quenched with ice water. After one hour stirring the precipitate was filtered off and dried in vacuo. The solid was purified over silica with dichloromethane/methanol-NH3 98/2 as eluent to provide the target compound P24 in 92% yield (884 mg). m/z=479 (M+H)+;
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH:30]1[CH2:32][CH2:31]1)([CH3:29])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH:30]1([C:20]([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:29])[CH2:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)CC(C)(N)C1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)(C)OC(=O)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and tert-butyl 3-amino-3-cyclopropyl-butanoate (example 229b) as starting materials and isolated (890 mg, 88%); MS (ESI, m/z): 443.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([OH:15])=O)[CH2:8][CH2:7][CH2:6]2.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)CCCC2C(=O)O
Product: COc1ccc2c(c1)CCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 30.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:33]OS([O-])=O.[K+]>CO.O>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:16])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:28][CH2:29][S:30](=[O:33])[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCSCC2)n(Cc2ccccc2)c1C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCS(=O)CC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (1-benzyl-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(thiomorpholino)methanone [for synthesis see SC-26] (131 mg, 0.28 mmol) in MeOH (4 mL) and H2O (1 mL) was added oxone (85 mg, 0.138 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with DCM (60 mL). The organic layer was washed with brine, dried (Na2SO4) and purified by flash column chromatography (silica, heptane/EtOAc, 1:1→0:1) to give SC-19 (48 mg, 35%) as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].P(=O)(O)(O)O.C(O[C:17](=[O:19])[CH3:18])(=O)C>>[CH2:1]([C:3]1[S:4][C:5]([C:17](=[O:19])[CH3:18])=[CH:6][CH:7]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccs1
Agent: O=P(O)(O)O
Product: CCc1ccc(C(C)=O)s1
Temperature: 80 °C
Yield: 76 %

Procedure:
In a 50 ml three-necked flask, 5 g (44.6 mmol, 1 eq) of 2-ethylthiophene are dissolved in 28 ml of acetic anhydride, 0.5 ml of ortho-phosphoric acid are added and the reaction mixture is then heated for 1 hour at 80° C. The acids are evaporated off under reduced pressure, and the oil obtained is then filtered over a silica patch (eluent: 20% ethyl acetate, 80% heptane) after evaporation of the solvents: 5.2 g of 1-(5-ethylthiophen-2-yl)ethanone are obtained in the form of a brown oil. Yield: 76%.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[CH3:23]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.82 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.43 g of sodium hydride (50% in oil), 100 ml of dimethylformamide and 0.7 ml of ethyl iodide were reacted as described in Example 9, giving 1.20 g of the desired product as tan crystals mp 122°-127° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[N+:10]([O-])=O)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:5]=1)[NH2:10]
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(Br)cc1N
Temperature: 70 °C
Yield: 17.1 %

Procedure:
To a solution of 2-ethyl-5-bromo nitrobenzene (9.71 g, 230 mmol) in ethanol (125 ml) is added tin(II) chloride dihydrate (35.72 g, 225.71 mmol), followed by heating at 70° C. for 2 hours. After cooling to room temperature the solution is poured into crushed ice (1 litre) then diluted with ethyl acetate (200 ml). Solid sodium carbonate is cautiously added until pH 7 is achieved, at which stage the viscous mixture is filtered through diatomaceous earth (further washing with ethyl acetate/aqueous sodium carbonate) and the phases separated. After additional extraction of the aqueous phase, all organic phases are combined, dried over anhydrous magnesium sulfate then concentrated in vacuo. The crude oil is purified by flash column chromatography on silica gel (hexane/ethyl acetate 8:2 ratio) to afford 5-bromo-2-ethylaniline (7.89 g) as a brown oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[O:34][CH2:33][CH2:32][CH2:31]4)[CH:20]=2)[O:7][CH:6]1OC(=O)C)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[BrH:47]>C(O)(=O)C.ClCCl>[C:12]([O:11][C@@H:10]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[O:34][CH2:33][CH2:32][CH2:31]4)[CH:20]=2)[O:7][CH:6]([Br:47])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:14])[CH3:13]
Reactant: Br
Reactant: CCc1ccc([C@@H]2OC(OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)CCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1ccc([C@@H]2OC(Br)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step-I: Acetic acid (3S,4R,5S,6S)-3,4,5-triacetoxy-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-tetrahydro-pyran-2-yl ester (300 mg) was taken in 33% HBr in acetic acid (1.2 ml) and stirred for 1 h at room temperature. To this was added dichloromethane (2 ml) and stirred for additional 30 min. This was diluted with dichloromethane (5 ml), poured into crushed ice and neutralized with sodium bicarbonate. Organic layer was separated, extracted with DCM (8 ml×2), combined organic layers were washed with water (10 ml×2), brine (10 ml), dried over sodium sulfate, concentrated to give 250 mg of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-tetrahydro-pyran-3-yl ester.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:33])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:32])[CH:12]=1.CO>C1COCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:33])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:32])[CH:12]=1
Reactant: CCOC(=O)CCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCC(=O)O
Reaction time: 4 h

Procedure:
Lithium hydroxide (0.5 mL, IM, 0.5 mmol) was added to a solution of ethyl 4-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)butanoate (12 mg, 0.026 mmol, Example 36), MeOH (0.5 mL), and THF (1.5 mL). The mixture was stirred 4 h, quenched with 1N HCl (20 mL), and extracted with EtOAc (30 mL×2). The organic extract was dried, filtered, and concentrated to give 4-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)butanoic acid: 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.00 (t, 2H), 3.91 (s, 3H), 2.46 (t, 2H), 1.88 (m, 2H); MS (ESI): 438.9.
Reaction SMILES: C([CH:3]([C:14]([NH2:16])=[O:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])C.[CH2:17](N)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=O.Cl>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14](=[O:15])[CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCC(C(N)=O)C(=O)NCc1ccccc1
Reactant: CCCCCCCCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)CC(=O)NCc1ccccc1
Yield: 0.1 %

Procedure:
A solution of 1.1 g (5.0 mol) of ethyl N-benzylmalonamide in 30 mL of toluene was heated to reflux under nitrogen and 1.29 g (10.0 mol) of n-octylamine was added. The reaction was heated to reflux for 5 h and 5 mL of N,N-dimethylformamide was added. This mixture was kept at reflux for 12 h and poured into 5% aqueous hydrochloric acid. the organic layer was washed with saturated aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Filtration and removal of solvents afforded a crude solid which was recrystallized from 50% ethyl acetate/hexane to give 0.8 g (53% yield) of N-n-octyl-N'-benzylmalonamide.
Reaction SMILES: [CH3:1][N:2]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:6][N:7]2COCC[Si](C)(C)C.C1(N)C=CC=C(N)C=1>C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([C:3]1[CH:4]=[C:8]2[C:9]([C:5]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:6][NH:7]2)=[CH:10][CH:11]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1cccc2c1c(C=Cc1ccccc1)nn2COCC[Si](C)(C)C
Agent: Nc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
Methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl)-1H-indazol-yl}-amine was converted to N-methyl-N{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine as described in Example 11, step (iv). Rf sm 0.55, Rf p 0.31 (ethyl acetate:hexane 3:7); FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, 1H, J=8.8 Hz) 7.58 (d, 2H, J=7.21 Hz), 7.26-7.50 (m, 5H), 7.12 (t, 1H, J=7.93 Hz), 7.01 (d, 1H, J=1.73 Hz), 6.95 (dd, 1H, J=1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, J=8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, J=8.13 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5, 77.8, 66.6, 41.0, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 471, Found 471.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Yield: 68.5 %

Procedure:
A solution of ethyl 6-chloro-7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.350 g, 1.12 mmol), glycine tert-butyl ester hydrochloride (0.244 g, 1.45 mmol), and Hunig's base (0.390 mL, 2.24 mmol) in 1,4-dioxane (15 mL) was heated at 120° C. for 2 hours in a sealed vessel. The solution was diluted with water (50 mL), extracted with EtOAc (2×50 mL), washed with water (50 mL), and then washed with brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-75% DCM in hexane) to give the title compound (0.305 g). MS m/e=396.5 (M−H)−.