Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:12]([CH3:22])[C:13](=[O:21])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18].[Br:23]N1C(=O)CCC1=O>>[Br:23][C:14]1[C:13](=[O:21])[N:12]([CH3:22])[C:11]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(SC)cc1F
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate was added N-bromosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:26])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([CH3:16])[CH2:14][CH3:15])[S:9][CH:10]=1)C.[OH-].[Na+]>CO.O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:13]([CH3:16])([CH2:14][CH3:15])[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[N:7]=1)=[O:26]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(C)(CC)Oc2ccc(F)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(Oc1ccc(F)cc1F)C(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.202 g, 0.51 mmol) in MeOH (3 ml) and water (1.5 ml). NaOH (0.041 g, 1.1 mmol) was added and stirred at room temperature for 16 hrs. The organic solvent was evaporated and residue was diluted with water (2 ml) and acidified (pH˜2) with 5% HCl. The aqueous layer was extracted with ethyl acetate (2×10 ml) and organic layer was washed with saturated brine (10 ml). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain crude product which was solidified by triturating with hexane to afford {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid (0.158 g, 84%). 1H NMR (400 MHz, CDCl3): δ1.03 (t, J=7.6 Hz, 3H), 1.44 (s, 3H), 1.86-1.9 (m, 1H), 2.05-2.09 (m, 1H), 3.78 (s, 2H), 6.78 (s, 1H), 6.80-6.84 (m, 1H), 6.88-6.93 (m, 1H), 7.0-7.06 (m, 1H), 10.6 (s, 1H), MS (EI) m/z: 371.00 (M+1) and mp: 148-149° C.
Reaction SMILES: I.[CH3:2][N:3]1[C:7]([NH:8][C:9](=N)SC)=[CH:6][C:5]([CH3:13])=[N:4]1.[CH3:14][NH:15][CH2:16][CH2:17][NH2:18]>C(Cl)Cl>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]=[C:9]1[NH:8][C:7]1[N:3]([CH3:2])[N:4]=[C:5]([CH3:13])[CH:6]=1
Reactant: CSC(=N)Nc1cc(C)nn1C
Reactant: CNCCN
Agent: I
Solvent: ClCCl
Product: Cc1cc(NC2=NCCN2C)n(C)n1

Procedure:
N(1,3-Dimethyl-5-pyrazolyl)-5-methyl isothiourea hydroiodide (Example XXV) (20.0 g) and 11.5 g. -N-methyl ethylenediamine were heated to 120° for 30 minutes and to 160° for 1 hour. After cooling, methylene chloride was added and the solid which formed was filtered and discarded. The methylene chloride solution was shaken with 15% KOH solution, dried over potassium carbonate, concentrated and the residue crystallized from acetonitrile to get 10.16 g. product, mp. 128°-130°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]#[C:15][Si](C)(C)C.[C:20]([O:24][C:25](=[O:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1Br)([CH3:23])([CH3:22])[CH3:21].C(C1C=CC=C(S(CCC)(=O)=O)C=1)#C>>[C:20]([O:24][C:25](=[O:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:15]#[C:14][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:4]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Agent: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(F)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from tert-butyl(2-bromo-4-fluorophenoxy)acetate (Intermediate 119) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:53])[CH2:46][CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:53])[CH2:46][CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(CC1CCOCC1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 21.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16]Br>>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1ccc(F)c(CBr)c1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)ccc1F
Yield: 70 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (525 mg) was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 to give 1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one as a tan solid (70% yield). This amide was then reduced as in General Procedure 3 to give the title compound as a white solid (42% yield). M.p. 175° C., LCMS: m/z=388.10 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.26-3.30 (m, 2H), 3.36-3.42 (m, 2H), 4.44 (s, 2H), 6.63 (bs, 1H), 6.77 (s, 1H), 7.05-7.10 (m, 1H), 7.15-7.19 (m, 1H), 7.20-7.27 (m, 1H), 7.41 (s, 1H).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH:12]2N3[CH2:18][CH2:19][CH:14](C(=O)C3)[CH2:13]2)C[N+]([O-])=O)C=1.[CH2:21](O)C>[Ni]>[CH3:21][CH2:18][CH2:19][CH2:14][CH2:13][CH2:12][CH2:7][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCO
Reactant: O=C1CN2CCC1CC2C(C[N+](=O)[O-])c1cccnc1
Agent: [Ni]
Product: CCCCCCCCCCC
Reaction time: 48 h
Yield: 67 %

Procedure:
6-(1-(3-Pyridinyl)-2-nitroethyl)-1-azabicyclo[2.2.2]octan-3-one (14.0 g, 0.046 mol) was dissolved in ethanol (200 mL), and then Raney nickel was added under nitrogen. The mixture was subjected to hydrogenolysis (40 psi H2) for 48 h and then filtered through Celite and concentrated by rotary evaporation to a crude brown residue. The residue was purified by column chromatography, using chloroform/methanol/ammonia (80:20:1, v/v) as eluent, to yield 3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane as a yellow oil (8.0 g, 67%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[CH:4]([OH:11])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:39][CH2:40][CH3:41])=[CH:36][CH:37]=3)[CH:32]=[CH:31][N:30]=2)[CH2:25][C@H:24]1[C:42](O)=[O:43])=[O:22])([CH3:19])([CH3:18])[CH3:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:39][CH2:40][CH3:41])=[CH:36][CH:37]=3)[CH:32]=[CH:31][N:30]=2)[CH2:25][C@H:24]1[C:42](=[O:43])[NH:2][C@H:3]([CH:4]([OH:11])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6])[CH2:12][CH:13]1[CH2:15][CH2:14]1)=[O:22])([CH3:18])([CH3:19])[CH3:17]
Reactant: N[C@@H](CC1CC1)C(O)C(=O)NC1CC1
Reactant: CCOc1ccc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)nccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(O[C@@H]3C[C@@H](C(=O)N[C@@H](CC4CC4)C(O)C(=O)NC4CC4)N(C(=O)OC(C)(C)C)C3)nccc2c1
Reaction time: 1 h

Procedure:
To (3S)-3-amino-N,4-dicyclopropyl-2-hydroxybutanamide HCl salt (66 mgs, 0.28 mmol) in dichloromethane/N,N-dimethylformamide (10:3, 13 mL) was added (2S,4R)-1-(tert-butoxycarbonyl)-4-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid (114 mgs, 0.28 mmol), O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (128 mg, 0.34 mmol) and diisopropylethylamine (0.15 mL, 0.84 mmol). After 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), sodium bicarbonate (1×), and brine (1×). The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give (2S,4R)-tert-butyl-2-((2S)-1-cyclopropyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamoyl)-4-(6-ethoxy-isoquinolin-1-yloxy)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:10]([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.75 h
Yield: 7.8 %

Procedure:
(1R*,5S*,6S*)-8-Benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 19b; 750 mg, 1.91 mmol) was dissolved in THF (5 ml) and methanol (25 ml) was added. The mixture was cooled to +5° C. and treated with sodium borohydride (184 mg, 4.8 mmol). The reaction mixture was stirred for 45 minutes, quenched with saturated aqueous NH4Cl (10 ml) and concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to give crude product as a 10:1 mixture of diastereoisomers. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the (1R*,2R*,5S*,6S*)-isomer (710 mg, 92%) and the (1R*,2S*,5S*,6S*)-isomer (59 mg, 8%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[C:21]2[C:16](=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]=O>CO>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[C:21]3[C:16](=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:26]([F:28])([F:29])[F:27])[CH:13]=2)[O:11][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: OC(CNCc1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Solvent: CO
Product: FC(F)(F)c1cc(C2CN(Cc3ccccc3)CO2)c2cccc(C(F)(F)F)c2n1
Yield: 28 %

Procedure:
To a solution of α-benzylaminomethyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (142 mg, 0.34 mmol) in MeOH (3 mL) was added formaldehyde (0.2 mL, 37% in water), the mixture was refluxed for 30 mins, cooled, concentrated in vacuo, and the residue was suspended in heptane and filtered to give the title compound (41 mg, 28%) as a white solid: mp 108.5-108.9° C.; IR νmax (Nujol)/cm−1 2924, 2854, 1602, 1586, 1458, 1378, 1306, 1271, 1184, 1153, 1139, 1127, 1105, 775 and 726; NMR δH (400 MHz, CDCl3) 2.85 (1H, dd, J 11.7, 7.0 Hz), 3.77 (1H, dd, J 11.7, 7.4 Hz), 3.85 (1H, d, J 13.1 Hz), 3.90 (1H, d, 13.1 Hz), 4.71 (1H, d, J 5.8 Hz), 4.74 (1H, d, J 5.8 Hz), 5.72 (1H, t, J 7.0 Hz), 7.21-7.43 (5H, m), 7.72 (1H, t, J 7.9 Hz), 8.17 (1H, d, J 7.5 Hz), 8.11 (1H, s) and 8.03 (1H, d, J 8.1 Hz).
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]\Br)[CH3:2].C([Li])(C)(C)C.Cl[Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(OCC)C.CCCCC>[CH2:1]([O:3]/[CH:4]=[CH:5]\[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCO/C=C\Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
(Ref. Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am. Chem. Soc. 1977, 99, 22, 7365-7367.) To a −78° C. solution of (Z)-2-ethoxy-1-bromoethene (5.0 mL, 46.8 mmol) in diethyl ether (160 mL) was added a 1.7 M solution of tert-butyl lithium in pentane (55 mL), dropwise over 20 min. This pale yellow solution was stirred at −78° C. for 40 min, and then chloro-tri-n-butylstannane (13.3 mL, 49.0 mmol) was added, dropwise over 7 minutes. The resulting reaction mixture was allowed to warm slowly. Once the cooling bath had reached −30° C., saturated aq. NaHCO3 (150 mL) was added, and the cooling bath was removed. This mixture was stirred for 15 minutes, and then the layers were separated. The aq. layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford (Z)-2-ethoxy-1-tri-n-butylstannanylethene.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][C@@H:10](O)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.O>[N:27]([C@H:10]1[CH2:11][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1C=C[C@H](c2ccccc2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 5 h

Procedure:
A solution of Example 48A (458 mg, 2.86 mmol) and toluene (4.6 mL) was cooled to <5° C. and diphenylphosphoryl azide (0.740 mL, 3.43 mmol) and DBU (0.603 mL, 4.00 mmol) were added. After 5 hours at room temperature, LCMS showed complete reaction. Water (20 mL) and toluene (50 mL) were added and organic layer was washed with water (20 mL), 2N HCl (20 mL), and brine (10 mL) sequentially. The organic layer was dried (Na2SO4), filtered, and concentrated, and crude title compound was used in the next step. MS (DCI) m/z 203 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:13][CH2:14][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:21]3)=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1CBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCc1ccccc1C2

Procedure:
A mixture of 6-bromo-indan-1-one (3.57 g, 17 mmol), 1-(2-bromo-ethyl)-2-bromomethyl-benzene (4.7 g, 17 mmol) in THF (50 mL) was added NaH (816 mg, 34 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6-bromo-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (1.8 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])[CH:7]=[CH:6][C:5]2=1.C[Si](C)(C)[O-].[K+].Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:5]2=1
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Temperature: 50 °C

Procedure:
To a solution of methyl 2-(6-Chloro-9H-carbazol-2-yl)-2-methyl-propionate in THF (1.5 mL) was added potassium trimethylsilanolate (189 mg, 2.5 eq) and the mixture heated to 50° C. for 3 hrs. The solution was diluted with EtOAc and acidified to ˜pH 3 with 2M HCl. The organic layer was separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and evaporated to dryness to afford the desired acid, 2-(6-chloro-9H-carbazol-2-yl)-2-methyl-propionic acid, as a colorless solid. 1H NMR (500 MHz, MeOD) δ 7.98 (1H, d, J=1.8 Hz), 7.96 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=1.5 Hz), 7.37 (1H, d, J=8.6 Hz), 7.29 (1H, dd, J=8.6, 2.1 Hz), 7.21 (1H, d, J=8.4, 1.7 Hz), 1.63 (6H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CS(C)=O.O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 90 °C
Yield: 79.9 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (3.18 g, 20 mmol) in DMSO (35 mL) were added K2CO3 (6.08 g, 44 mmol) and pyrazole (1.50 g, 22 mmol) with stirring. The reaction mixture was heated at 90° C. for 18 h, and cooled to rt. The mixture was diluted with water (50 mL) and filtered. The filtrate was extracted with DCM (50 mL×3), the combined organic phases were concentrated in vacuo. The crude product was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=1:1) to give the title compound as a yellow solid (3.31 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Cl[CH2:16][O:17][CH2:18][CH3:19].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]([O:11][CH2:16][O:17][CH2:18][CH3:19])([CH3:10])[CH3:9]
Reactant: CC(=O)c1ccc(C(C)(C)O)c(Br)c1
Reactant: CCOCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOC(C)(C)c1ccc(C(C)=O)cc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of 1-(3-bromo-4-(2-hydroxypropan-2-yl)phenyl)ethanone (0.9 g, 3.51 mmol), (chloro-methoxy)ethane (660 mg, 7.02 mmol) and DIPEA (2.5 mL, 14.04 mmol) in DCM (20 mL) was stirred at 40° C. overnight under argon. Water (50 mL) was added and the mixture was extracted with DCM (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (10:1) to give 1-(3-bromo-4-(2-(ethoxymeth-oxy)propan-2-yl)phenyl)ethanone (990 mg; yield 90%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[CH3:46][O:47][C:48](=[O:58])C1C(=CC=CC=1)C(O)=O>>[CH3:46][O:47][C:48](=[O:58])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:11]=2[N:12]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: COC(=O)c1ccccc1C(=O)O
Agent: Nc1cc(F)c(F)cc1N
Product: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2[nH]1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and phthalic acid monomethyl ester (CAS Reg. No. 4376-18-5). Off-white powder (12%). MS (Turbo Spray): m/z=289.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>CCCCC.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:29]#[N:30])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCC
Solvent: ClCCl
Product: N#CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
4-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.829 g of 4-fluorobenzoyl chloride (98%, Aldrich) (11.54 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.8 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution 0.29 mL of tin (IV) chloride (2.5 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from clear to dark yellow and within 4 min the color of the solution was dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 90 mL of ice-cold water, and finally extracted with two 90-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 90-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation. The dark brown residue which resulted was stirred with pentane. The pentane solution was decanted and the pentane removed by rotary evaporation to yield 0.911 g of 4-fluorobenzoyl cyanide as a yellow oil. The product was further purified by Kugelrohr vacuum distillation which afforded 0.666 g (39%) of 4-fluorobenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2220, 1685, 1600, 1505, 1410 cm-1.
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH:36]=[CH:35]1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:34](=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38]
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)C=CC(=O)O)C(=O)C=CC(=O)O
Yield: 79.5 %

Procedure:
A reactor was charged with 20 g (0.04 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane and 100 g of xylene, to which 10 g (0.1 mole) of maleic anhydride were then added with stirring to conduct a reaction at 50° C. for 6 hours. After xylene was distilled off under reduced pressure, 300 ml of water were added, and 10% sodium hydroxide was further added to keep the pH of the reaction mixture at 7. Thereafter, the reaction mixture was subjected to electrodialysis and lyophilized, thereby obtaining 22 g (isolation yield: 80%) of 6,10-dihydroxy-4,12-dioctyl-3,13-dioxo-8-sulfoethyl-4,8,12-triaza-1,14-pentadecadiene-1,15-dicarboxylic acid as white powder.