Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=3[CH3:31])=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.O=C1CCC(=O)N1[O:43][C:44](=O)[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][NH:59][C:60](=[O:70])[CH2:61][CH2:62][N:63]1[C:67](=[O:68])[CH:66]=[CH:65][C:64]1=[O:69].CCN(C(C)C)C(C)C>>[O:69]=[C:64]1[CH:65]=[CH:66][C:67](=[O:68])[N:63]1[CH2:62][CH2:61][C:60]([NH:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][C:44]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=3[CH3:31])=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:43])=[O:70]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCN)CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(4-aminobutyl)cyclopentanecarbonyl]amino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid (300 mg, 0.62 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (318 mg, 0.62 mmol), and DIPEA (160 mg, 215 uL, 1.24 mmol), and after HPLC purification, resulted in a light yellow solid (274 mg, 50%). ES(+)-HRMS m/e calcd. for C44H62N6O13 (M+H)+ 883.4448, obsd. 883.4449.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([OH:4])[CH3:3].I[CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([C:11]([CH2:10][C:7]1[CH:6]=[C:5]([C:2]([CH3:1])([OH:4])[CH3:3])[O:9][N:8]=1)([C:12]#[N:13])[C:14]#[N:15])[CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCI
Reactant: CC(C)(O)c1cc(CC(C#N)C#N)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(C#N)Cc1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
0.41 g of {[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile and 0.63 g of 4-iodo-1-butene were dissolved in 6 ml of N,N-dimethylformamide, and 0.55 g of potassium carbonate was then added under ice-cooling. The mixture was stirred at room temperature overnight. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.43 g of (3-butenyl){[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile represented by the following formula:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][CH2:38][C:39]([N:41]([CH3:49])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1)=[O:40])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][CH2:38][C:39]([N:41]([C:42]1[CH:43]=[CH:44][C:45]([NH:48]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[CH3:49])=[O:40])[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CCC(=O)N(C)c1ccc(N)cc1)Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C35H34N4O4
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[S:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:1](=[S:2])[NH2:3])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Yield: 37.9 %

Procedure:
The title compound (1.5 g) was prepared from 3.01 g (16.91 mmol) of thiocarbonyldiimidazole and 3.0 g (16.12 mmol) of 1-tert-butoxycarbonyl-piperazine according to the method of Intermediate 53 followed by purification via trituration with diethyl ether: low resolution MS (ES) m/e 246 (MH+).
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N[C:13]1C=CC(S(O)(=O)=O)=C[CH:14]=1.CO>C(O)(C)C>[CH2:13]=[CH:14][C:6]1[CH:5]=[CH:4][C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CO
Product: C=Cc1ccc(S(=O)(=O)O)cc1
Yield: 73 %

Procedure:
Example 13 was repeated, but instead of aniline-2-sulphonic acid the same amount of aniline-4-sulphonic acid and instead of methanol the same volume of iso-propanol were used. 15.0 g (73%) of styrene-4-sulphonic acid, Na salt, were obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[C:23]1([P:29]([O:33]CC)[O:30][CH2:31][CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#N)C>CCOC(C)=O>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[CH:7][C:8]=1[P:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:33])[O:30][CH2:31][CH3:32]
Reactant: CCOP(OCC)c1ccccc1
Reactant: Cc1ccc(C)c([Si](C)(C)C)c1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOP(=O)(c1ccccc1)c1cc(C)ccc1C

Procedure:
3,6-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.077 mmol), Cesium Fluoride (64 mg, 0.421 mmol), Diethyl phenylphosphonite (60 mg, 0.306 mmol), Acetonitrile (1 ml): Reaction Time: 32 h; Rf: 0.4 (1:1 EtOAc:Pet Ether); Thick oil; 13.0 mg, 62%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.81-7.70 (m, 3H), 7.52-7.40 (m, 3H), 7.23 (d, J=7.8 Hz, 1H), 7.12-7.05 (m, 1H), 4.11 (apparent quint, J=7.0 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 138.6 (d, J=10.8 Hz), 135.0 (d, J=12.3 Hz), 133.9 (d, J=9.3 Hz), 132.5 (d, J=124.1 Hz), 128.4 (d, J=13.4 Hz), 131.7, 131.5 (d, J=7.7 Hz), 131.4, 131.3, 129.0 (d, J=133.3 Hz), 128.4 (d, J=13.1 Hz), 60.7 (d, J=5.4 Hz), 20.9, 20.7 (d, J=3.9 Hz), 16.4 (d, J=6.9 Hz); 31P NMR (162 MHz, CDCl3,) δ 32.2; HRMS-ESI (m/z) calcd (C16H19O2P+H)+: 275.1195. found: 275.1193.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])=[CH:38][CH:39]=2)=[N:6][C:7]=1[C:8]1[N:9]=[C:10]2[CH2:16][CH:15]=[C:14]([CH3:17])[CH:13]=[C:11]2[N:12]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=CCC2=NC(c3nc(-c4ccc(C(=O)N5CCCNCC5)cc4)cnc3N)=NC2=C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
tert-butyl 4-[4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoyl]-1,4-diazepane-1-carboxylate (117 mg, 0.2218 mmol) was dissolved in DCM (3 mL) and the mixture was cooled to 0° C. TFA (3 mL, 38.94 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. Solvents were evaporated and the residue was dissolved in a mixture of MeCN and water (5 mL/5 mL) and submitted to Genevac evaporation to yield the product (119 mg, 99% Yield).
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[OH:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])(=[O:30])=[O:29])[CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cc(O)c2ccccc2c1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc(O)c2ccccc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
At 0° C. to 1.0 g (6.24 mmol) of 1,3-naphthalenediol in tetrahydrofuran (20 mL) containing 1.5 mL of 2,6-lutidine was added 1.35 g (6.40 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was stirred to ambient temperature overnight, quenched with 3 N hydrochloric acid, extracted into methylene chloride, and dried (MgSO4). Purification by flash chromatography (2% ethyl acetate/methylene chloride) gave 277 mg (13% yield) of the title compound as a colorless solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.06 (d, 1 H, J=1.7 Hz), 7.78-7.95 (m, 4 H), 7.43-7.57 (m, 3 H), 7.11 (d, 1 H, J=2 Hz), and 6.63 (d, 1 H, J=2 Hz).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CS(=O)(=O)c1ccc(-c2ccc(F)c(F)c2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,4-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M−H], 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O.CN(C=O)C>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 53a from 4-amino-3-nitro-benzoic acid with thionyl chloride and DMF in dichloromethane at reflux.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:26]([OH:36])=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:24][C:25]1[C:26]([OH:36])=[C:27]([S:32]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:34])=[O:33])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 1-(4′-chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (70 mg, 0.22 mmol) in THF (4 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (61.8 mg, 0.24 mmol) and TEA (0.08 mL, 0.54 mmol). The resulting mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in MeOH and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the title compound (46 mg, 39%) as a glassy solid. 1H NMR (CD3OD) 7.59 (d, J=4.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.36-7.35 (m, 5H), 7.22 (t, J=8.0 Hz, 1H), 7.16-7.09 (m, 5H), 7.05-7.03 (t, J=8.0 Hz, 1H), 6.90-6.85 (m, 2H), 4.46 (s, 2H), 4.41 (s, 2H). MS (ESI): 550.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si](C(C)(C)C)(C)C)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:36][C:37]([F:60])([F:59])[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]([C:49]3[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=3)[S:47][CH:48]=2)=[CH:40][CH:39]=1>>[OH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]1[NH:8][C@@H:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([NH:1][S:55]([C:52]3[CH:53]=[CH:54][C:49]([C:46]4[S:47][CH:48]=[C:44]([C:41]5[CH:42]=[CH:43][C:38]([C:37]([F:60])([F:59])[F:36])=[CH:39][CH:40]=5)[N:45]=4)=[CH:50][CH:51]=3)(=[O:57])=[O:56])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Product: O=S(=O)(Nc1ccc(C[C@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1

Procedure:
The title compound was prepared from tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4b) and 4-{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}benzenesulfonyl chloride (i-6) according to the procedure of Example 212, step A. The crude product was purified by preparative TLC plate eluting with 40% ethyl acetate in hexane to afforded the product (8.1 mg, 81%). mlz (ES) 865 (MH)+, 765 (M-Boc)+.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C(O)CO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[Cl:10])[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nc1ccccc1Cl
Solvent: OCCO
Product: Nc1c(Cl)ncnc1Nc1ccccc1Cl
Temperature: 100 °C
Yield: 85 %

Procedure:
4,6-Dichloropyrimidin-5-amine (CAS no. 5413-85-4) (2 g, 12.20 mmol) and 2-chloroaniline (CAS no. 95-51-2) (1.556 g, 12.20 mmol) were dissolved in ethylene glycol (12 mL) and sealed into a microwave tube. The reaction was heated to 100° C. for 1 hour in the microwave reactor and cooled to room temperature. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×50 mL), the organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 60% EtOAc in isohexane to afford the product (2.65 g, 85%). 1H NMR (400 MHz, DMSO) 65.38 (s, 2H), 7.19-7.25 (m, 1H), 7.32-7.38 (m, 1H), 7.49-7.54 (m, 1H), 7.57-7.62 (m, 1H), 7.73 (s, 2H), 7.19-7.25 (s, 1H); m/z (ES+), (M+H)+=255.25; HPLC tR=1.82 min.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([Cl:17])=[O:14]
Reactant: Cc1cccc2c1C=C(C(=O)O)C2C
Reactant: O=S(Cl)Cl
Product: Cc1cccc2c1C=C(C(=O)Cl)C2C
Yield: 100 %

Procedure:
1,4-Dimethyl-indene-2-carboxylic acid is converted to its acid chloride by treatment with thionyl chloride. Yield 100%.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)=[C:3]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]#[N:13])[C:6]=1[Br:14])(=[O:3])[CH3:2].Cl[CH2:16][C:17](=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:17]([C:18]1[O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:1]([CH3:2])=[O:3])=[C:6]([Br:14])[C:7]=2[C:12]=1[NH2:13])(=[O:19])[CH3:16]
Reactant: CC(=O)CCl
Reactant: CC(=O)Oc1ccc(O)c(C#N)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2oc(C(C)=O)c(N)c2c1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a mixture of 12D (7 g, 0.027 mol) and 1-chloro-propan-2-one (3 mL) in DMF (30 mL) was added K2CO3 (4.1 g, 0.029 mol). The reaction mixture was stirred at 90° C. for 1 hour. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and added dropwise to ice-water. The precipitated solids were collected by filtration to give a crude product 12E (6.8 g, 79.6% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:28]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CNc1cccc(OC2CCN(C)CC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(N(C)C(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 55 °C

Procedure:
Dissolve the above amine product in THF (6 mL), add triethylamine (219 mg, 0.29 mL, 2.08 mmol) and 2,4,6-trifluorobenzoyl chloride (303 mg, 1.56 mmol) sequentially, heat at 55° C. overnight. Quench with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 204 mg (43% two-step yield) of the title compound as a colorless oil: mass spectrum (ion spray): m/z=380.1 (M+1); 1H NMR (CDCl3, ppm): 7.47 (t, 1H), 6.53 (m, 4H), 4.74 (m, 1H), 3.48 (s, 3H), 2.71 (m, 2H), 2.32 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H). Mono-hydrochloride salt: Anal. calc for C19H20F3N3O2.HCl.0.5H2O: C, 53.72; H, 5.22; N, 9.89. Found: C, 53.84; H, 5.04; N, 9.73.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.29 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.62 g) and acetic acid chlorodifluoromethyl ester (0.31 mL) was stirred at 70° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume) gave title compound, 0.18 g.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].O=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
To a 0° C. mixture of KOtBu (5.90 g, 52.6 mmol) in 95 mL ether was added methyltriphenylphosphonium bromide (18.8 g, 52.6 mmol). The reaction mixture was warmed to ambient temperature and stirred 1.5 hours. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (4.50 g, 26.3 mmol) in 10 mL ether was added. The reaction mixture was heated to reflux for 2 hours, then cooled to ambient temperature. Solids were removed by vacuum filtration through compressed Celite and rinsed with ether, and the filtrate was concentrated. The resulting residue was suspended in 1:1 hexanes:ethyl acetate, and the solids were removed by vacuum filtration through GF/F paper and rinsed with 1:1 hexanes:ethyl acetate. The filtrate was concentrated, and the resulting oil was purified on silica gel (5-20% ethyl acetate in hexanes gradient) to give the desired product (3.50 g, 78.7% yield) as a clear colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-:25])=[O:24])[C:17]=1Cl)(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:29]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N+:23]([O-:25])=[O:24])[C:17]=1[OH:29])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 58.1 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[3-(tert-butoxycarbonylamino)propyl]-2,6-dichloro-3-nitrobenzenesulfonamide (450 mg, 1.05 mmol), 60% NaH (168 mg, 4.2 mmol) and water (21 μL, 1.15 mmol) were reacted to form the desired product (250 mg, 58%). EI-MS (m/z) 408.1, 410.1 (M-H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:35][CH:36](Br)[CH3:37].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1
Reactant: CC(Br)Br
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCCBr)ccc12

Procedure:
This compound (57) was prepared from 3′,4′-dibenzyloxy-7-hydroxy-flavone, 23 (2.3 g, 5.1 mmol), dibromo ethane (1.7 mL, 20.4 mmol) and potassium carbonate (3.5 g, 25.5 mmol) in dry dimethyl formamide (90 mL) using the identical procedure as described for 56. Yield 2.1 g (74%); mp 167-168° C.; MS (FAB) 557/559 (M++1); IR (KBr) 1626; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.8 Hz, 1H), 7.50-7.32 (m, 12H), 7.01 (d, J=9.1 Hz, 1H), 6.92 (dd, J=8.9 Hz, 2.2 Hz, 1H), 6.91 (s, 1H), 6.60 (s, 1H), 5.24 (s, 4H), 4.39 (t, J=6.2 Hz, 2H), 3.69 (t, J=6.3 Hz, 2H).