Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].C1C2C(COC([NH:23][CH2:24][P:25]([OH:50])([O:27][CH:28]([C:31]3[CH:47]=[C:46]4[N:34]([CH2:35][C:36]5[C:37]4=[N:38][C:39]4[C:44]([CH:45]=5)=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33](=[O:48])[C:32]=3[CH3:49])[CH2:29][CH3:30])=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1>O>[NH2:23][CH2:24][P:25]([OH:50])([O:27][CH:28]([C:31]1[CH:47]=[C:46]2[N:34]([CH2:35][C:36]3[C:37]2=[N:38][C:39]2[C:44]([CH:45]=3)=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33](=[O:48])[C:32]=1[CH3:49])[CH2:29][CH3:30])=[O:26].[NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CCC(OP(=O)(O)CNC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O
Solvent: CCNCC
Product: CCC(OP(=O)(O)CN)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Et2NH (10 mL) and (±)-7-[1-[[[[[(9-fluorenylmethoxy)carbonyl]amino]methyl]hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (328 mg, 0.51 mmol) was stirred at room temperature in a capped vial for 3 h. The reaction mixture was stripped to dryness, and H2O was added. The this partial solution was extracted with EtOAc, filtered and lyophilized to give a viscous oil which was triturated with CH3CN to produce a golden solid. The solid was dissolved in H2O and lyophilized to give the title compound as a partial Et2NH salt. 1H NMR (CDCl3 /MeOH-d4) d 8.49 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.84 (m, 1H), 7.69 (overlapping s and m, 2H), 5.59 (dd, J=14.9, 6.5 Hz, 1H), 5.27 (s, 2H), 2.98 (q, J=7.2 Hz, ~1.1H), 2.85 (dd, J=12.7, 2.6 Hz, 2H), 2.31 (s, 3H), 2.02-1.83 (m, 2H), 1.31 (t, I=7.3 Hz, ~1.8H), 1.05 (t, J=7.4 Hz, 3H). Anal. Calcd for C20H22N3O4P.1/4 C4H11N.5 H2O: C, 49.68; H, 6.90; N, 8.97. Found: C, 50.08; H, 6.49; N, 8.46.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:35].C(O)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:35])(=[O:10])[CH3:9]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 18 °C
Reaction time: 0.5 h

Procedure:
1,2,3,4,6-Penta-O-acetyl-β-D-glucopyranose (100 g, 0.251 mol) is suspended in toluene (210 ml). Acetic anhydride (9.5 ml; 0.1 mol) is added followed by hydrobromic acid 30% in acetic acid (200 ml, 1 mol). The mixture is stirred at 18° C. for 30 min. A mixture of ice/water (300 ml) and brine (100 ml) is then added with stirring. The phases are separated and the aqueous phase is extracted with toluene (100 ml). The organic phases are combined and washed with aqueous sodium hydrogencarbonate (100 ml) and brine (100 ml). Drying and evaporation of the solvent under reduced pressure yields an oil which is crystallised by addition of methyl-t-butylether (150 ml) and methylcyclohexane (300 ml). The product is isolated by filtration, washed with methylcyclohexane and dried under vacuo at 45° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:17]1[C:12]2=[CH:13][C:14]([C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=2)=[C:15]2[CH:33]=[CH:32][CH:31]=[CH:30][C:16]2=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:50]1[C:62]2[NH:61][C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:17]1[C:12]2=[CH:13][C:14]([C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([N:61]3[C:62]4[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=4[C:55]4[C:60]3=[CH:59][CH:58]=[CH:57][CH:56]=4)=[CH:37][CH:36]=2)=[C:15]2[CH:33]=[CH:32][CH:31]=[CH:30][C:16]2=1)=[O:8])[CH3:2]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)CCC(=O)OCC)cc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)Cn1c2ccc(C(=O)CCC(=O)OCC)cc2c2cc(C(=O)c3ccc(-n4c5ccccc5c5ccccc54)cc3)c3ccccc3c21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To 4-(11-(2-ethylhexyl)-5-(4-fluoro-benzoyl)-11H-benzo[a]carbazol-8-yl]-4-oxo-butyric acid ethyl ester (1.01 g, 1.75 mmol) in dimethylsulfoxide (DMSO) (10 mL) are added K2CO3 (738 mg, 5.33 mmol) and carbazole (297 mg, 1.77 mmol). The reaction mixture is heated to 150° C. and stirred overnight. After cooling to room temperature, the reaction mixture is poured into water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain a brown resin (760 mg; 60%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.84 (t), 0.92 (t), 1.20-1.52 (m), 2.28-2.36 (m), 2.82 (t), 3.48 (t), 4.16 (q), 4.74-4.21 (m), 7.33 (t), 7.46 (t), 7.60 (d), 7.63 (d), 7.68 (t), 7.72 (t), 7.77 (d), 8.15 (t), 8.19 (d), 8.22 (d), 8.50 (s), 8.58 (d), 8.67 (d), 8.81 (s).
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:23](#[N:25])[CH3:24]>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:11])[CH2:24][C:23]#[N:25])=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=O)CC#N)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of methyl p-anisate in acetonitrile was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 M in THF) was added dropwise over a minimum of 3 hr. The mixture was held at −10 to 0° C. until reaction completion. The reaction mixture was quenched with water and the pH adjusted to 3-4 with conc HCl. The mixture was stirred for 1 hr. The product was isolated by filtration, washed with water and dried in a vacuum oven. The yield was 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>O1CCOCC1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:27]=1[CH2:28][N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COc1ccc(CCNc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccccn2)cc1
Yield: 43.3 %

Procedure:
A solution of N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine (150 mg; 0.66 mmol) in 3 ml of dioxane, under nitrogen, was treated with K2CO3 (113 mg; 0.82 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (0.13 ml; 0.69 mmol) and heated in a pressure tube at 190–220C for 16 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated brine, dried over sodium sulfate and concentrated. Purification by radial chromatography on silica gel using an ethyl acetate-hexane gradient (5–50%) afforded N-[2,4-bis(trifluoromethyl)benzyl]-N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine (130 mg; 44% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[N:10]=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:12]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)=[N:13][C:14]=1S(C)(=O)=O.Cl>CCCCCC>[NH2:8][C:9]1[N:10]=[C:11]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:12]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)=[N:13][C:14]=1[O:7][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCO
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCOc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in 1,2-dimethyl-2-imidazolidinone (0.6 ml) was added to 1-butanol (0.0716 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and a precipitate was collected by filtration. The precipitate was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was suspended in hexane and collected by filtration to give 6-(5-amino-6-butoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (83 mg).
Reaction SMILES: C(O)(=O)C.CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:31]([C:29]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N:14]3[CH:7]=[CH:11][CH:10]=[CH:9]3)=[CH:39][CH:38]=2)[CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc(-n2cccc2)cc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.25 mL of acetic acid and 4.1 μL of 2,5-dimethoxytetrahydrofuran were added sequentially to 10 mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid at room temperature and stirred at 90° C. for 5 minutes. After the reaction mixture was cooled so room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified wish silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate] to obtain 3.8 mg of 4-phenoxy-2-(4-(1H-pyrrol-1-yl)benzamido)benzoic acid a brown solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2>C(#N)C.O>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]=[C:14]4[C@:15]3([CH3:21])[CH2:16][CH2:17][C@H:18]([OH:20])[CH2:19]4)[C@@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:11]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Solvent: CC#N
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
The protocol was performed as follows. (1) Prepared 0.5 mM compound in acetonitrile/water 35:65. For androst-5-ene-30,170-diol, prepared 0.145 mg/mL, or 29.0 μL of a 1 mg/mL stock plus 171 μL solvent. For the standard curve dilutions of the 0.5 mM stock was used to obtain final concentrations of androst-5-ene-3β,17β-diol at 10 μM, 5 μM and 1 μM. (2) Set up samples as follows. Each assay consisted of an androst-5-ene-3β,17β-diol control and 1-8 unknown compounds. Tubes for each compound was follows: 1-0′2-0′3-0′4-0′*5-0′*6-5 μM 7-1 μM 8-30′9-30′10-30′ where * designated denatured microsome negative control reaction tubes. For additional compounds numbering was started at 11, 21, 31, etc. (3) Added 315 μL PBS (pH 7.3-7.5) to each tube. Added 10 μL of the appropriate test article solution to each tube. (4) The internal standard/acetonitrile solution. (5) The NADPH regenerating system (NRS) was 125 μL per tube. To PBS added 1.7 mg/ml NADP, 7.8 mg/ml glucose-6-phosphate, 6 units/mL glucose-6-phosphate dehydrogenase. Fresh NRS for each experiment was kept on ice until use. (6) Each reaction used 125 μL of NRS in each tube. (7) Removed liver microsome preparation from −80° C. freezer and thawed in a room temperature water bath. The microsomal preparation was at a concentration of 20 mg/ml. Each reaction used 0.25 mg/tube and was diluted to a concentration of 5 mg/ml in PBS (i.e. 4-fold dilution) and kept on ice. (8) For the zero-time and denatured microsome control tubes 500 μL acetonitrile at −20° C. was added. Zero time tubes were transferred to ice and denatured microsome controls were preincubated at 37° C. for 5 minutes. (9) Assay tubes containing the microsomal preparation was also preincubated for 5 min at 37° C. (10) For each incubation tube, the reaction was started by addition of 50 μL of the microsome preparation and vortexing to mix. (11) Each reaction was terminated by adding 500 μL acetonitrile at −20° C. and vortexing. (12) After the reaction was terminated, 100 μL from each reaction tube was transferred to a fresh tube and 200 μL of water and 1400 μL of methyl-t-butyl ether was added to each tube. The tubes were Vortexed and centrifuged at 13,000 rpm for 10 min on a microfuge. The tubes were then put on a dry ice-methanol bath until aqueous layer was frozen solid. (13) The methyl-t-butyl ether was transferred from each tube to a fresh tube and the solvent was evaporated ether under nitrogen and the precipitate was then resuspended in 10 μL acetonitrile/water 35:65 and analyzed by LCMS. Results are shown in the table below for the incubation times shown below.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>[Zn]>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
An 8 mL scintillation vial was charged with NiCl2.6H2O (87.8 mg, 0.369 mmol) and 2,2′-bipyridine (119.2 mg, 0.763 mmol). The vial was closed and purged with nitrogen for 10 min, after which the vial was charged with DMF (4.5 mL) and water (0.5 mL). The mixture was allowed to stir for 5 min until a clear, bright blue solution was present. To the vial was added zinc dust (1.657 g, 25.3 mmol), and the mixture was allowed to stir under nitrogen for 35 min until a very dark blue/black solution was present. Solid 3,4,5,6-tetrachloropicolinic acid (0.831 g, 3.2 mmol) was added through the top of the reactor. The reaction mixture was allowed to stir at 27° C. for 5.5 h. The crude reaction mixture was filtered through a medium frit filter, and the filter cake was washed with DMF (2×). The resulting filtrate was diluted with an equal volume of 10% HCl (aq) to yield a clear, light yellow solution which was allowed to stir overnight at ambient temperature. The white solid was collected by vacuum filtration and was dried in an inert heating oven (50° C.; 1 h) to give the title compound (0.60 g, 83.1%) that was 69% pure as analyzed by calibrated HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:29][CH2:28]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:2]2[CH:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[N:20]([CH:21]6[CH2:25][CH2:24][O:23][CH2:22]6)[N:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:29][CH2:28]1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncnn3C3CCOC3)nc1-2
Reactant: CN1CCC(C2CCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC(C2CCCN2c2ccc3c(c2)OCCn2cc(-c4ncnn4C4CCOC4)nc2-3)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 163.4 %

Procedure:
A mixture of 12-bromo-4-[1-(oxolan-3-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (40 mg, 0.010 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (3.0 mg, 0.020 mmol), Pd(PtBu3)2 (1.0 mg, 0.0010 mmol), NaOtBu (2.9 mg, 0.030 mmol) in toluene (2.0 ml) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. The solid was filtered off and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to afford 232 (8.0 mg, 16% yield). LCMS (ESI): RT=3.39 min, m/z: 490.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.31 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 6.60 (d, J=9 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 4.54-4.52 (m, 4H), 4.29 (q, J=16 Hz, 1H), 4.16 (q, J=23 Hz, 1H), 4.03-4.01 (m, 1H), 3.97-3.95 (m, 1H), 3.86 (s, 1H), 3.55-3.53 (m, 1H), 3.24 (d, J=8 Hz, 1H), 2.98 (t, J=21 Hz, 2H), 2.56-2.48 (m, 2H), 2.29 (d, J=12 Hz, 3H), 2.04-1.93 (m, 5H), 1.78 (s, 1H), 1.69 (d, J=11.5 Hz, 1H), 1.53-1.44 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:21]([CH2:22][N:23]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:24][CH3:25])=[CH:20][C:5]([C:6]([CH:8]([OH:19])[C@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10])=[O:7])=[CH:4][C:3]=1[Br:32].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49](O)=[O:50]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49]([CH:17]([OH:18])[C@H:15]([C@H:13]([C@@H:11]([C@@H:9]([CH:8]([C:6](=[O:7])[C:5]1[CH:20]=[C:21]([CH2:22][N:23]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:24][CH3:25])[C:2]([NH2:1])=[C:3]([Br:32])[CH:4]=1)[OH:19])[OH:10])[OH:12])[OH:14])[OH:16])=[O:50]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc(Br)c1N)C1CCCCC1
Product: CCN(Cc1cc(C(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)C(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 1-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyl]-D-mannitol and 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetic acid analogous to Example 4. Amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1>O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:20][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)nc1C(=O)NNC(=O)c1ccccc1
Solvent: O
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Temperature: 100 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Polyphosphonic acid (25 mL of 84% w/v, 256.1 mmol) was heated to 100° C. and treated with 3-amino-N′-benzoyl-6-bromo-pyrazine-2-carbohydrazide (6.82 g, 20.29 mmol) in portions. Analysis after 1 hour showed SM remaining therefore further polyphosphonic acid was added (25 mL of 84% w/v, 256.1 mmol). The reaction was heated for a total of 3 hours and then allowed to cool. Water was added and the mixture allowed to stir to obtain a precipitate which was filtered and dried under vacuum (5.02 g, 78% Yield). MS (ES+) 317.86
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[CH:12]=[CH:13]/[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15].B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[CH:12]=[CH:13]/[C:14]([C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)=[O:15]
Reactant: COc1ccc2[nH]cc(/C=C/C(=O)c3ccncc3)c2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(/C=C/c1c[nH]c2ccc(O)cc12)c1ccncc1
Yield: 60.4 %

Procedure:
To a dried two-neck 250 mL round bottom flask under argon at −40° C., compound 13 (352 mg, 0.99 mmol) was partially dissolved in CH2Cl2 (30 mL). BBr3 (10 mL, 1.0 M in CH2Cl2, 10 mmol) was added dropwise via an addition funnel under argon. After four hours the reaction was poured onto ice and treated with 5 N NaOH until pH 12. The aqueous solution was isolated and treated with 5 N HCl until pH 7, forming a brown precipitate which was extracted with ethyl acetate (3×40 mL). Extracts were combined, dried with Na2SO4, filtered, concentrated and dried under vacuum to yield 158 mg of an orange solid (61%). NMR: 1H NMR (600 MHz, d6-DMSO): δ 11.840 (s, 1H, N—H), 9.109 (s, 1H, O—H), 8.826-8.816 (dd, J1=4.5, J2=1.5, 2H, pyr-2,6H), 8.063-8.058 (d, J=3.0, 1H, indole-2H), 8.048-8.022 (d, J=15.6, 1H, C═CH), 7.902-7.892 (dd, J1=4.5, J2=1.5, 2H, pyr-3,5H), 7.349-7.346 (d, J=1.8, 1H, indole-4H), 7.307-7.293 (d, J=8.4, 1H, indole-H7), 6.762-6.744 (dd, J1=8.4, J2=2.4, 1H, indole-H6). 13C NMR (150 MHz, d6-DMSO): δ 188.2, 152.9, 150.6, 145.0, 141.4, 134.8, 131.7, 126.0, 121.3, 113.6, 113.1, 112.7, 112.3, 104.9. Melting Point: 262-268° C. TLC (in ethyl acetate:hexane 4:1) Rf=0.35. Elemental analysis calculated for C16H12N2O2.0.1H2O: C, 72.22; H, 4.62; N, 10.53. found: C, 72.21; H, 4.42; N, 10.26.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:4][CH:3]=1.C(=O)=O>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCCC[C@@H]1Oc1ccc(Br)nc1
Agent: O=C=O
Solvent: CO
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)nc1

Procedure:
Separation of the enantiomers comprising cis-N-{2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide (7.96 g, 21.1 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1×25 cm, 5 μm; Mobile phase: 70:30 carbon dioxide:methanol; Flow rate: 65 g/min. The first-eluting compound was enantiomer [N-{(1R,2S)-2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide] and the second-eluting peak provided desired product N-{(1S,2R)-2-[(6-bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 3.13 g, 8.30 mmol, 39%. The absolute stereochemistry of these enantiomers was assigned by analogy to Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[BrH:10]>>[BrH:10].[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:10])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(CO)ccn1
Agent: Br
Product: Nc1cc(CBr)ccn1
Temperature: 120 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
(2-Aminopyridin-4-yl)methanol (15 g, 12 mmol) was suspended in a 47% aqueous hydrobromic acid solution (120 mL, 72 mmol) at room temperature, and the mixture was stirred for 6 hours at outer temperature 120° C. The mixture was stirred for 15 hours at room temperature, then the precipitated solid was filtered off and washed with ethyl acetate. The solid was dried under reduced pressure to give 23 g of the title reference compound as a gray solid. (Yield 71%)