Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:18].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[OH:18][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:16])=[O:17]
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCO
Yield: 22360.1 %

Procedure:
15-pentadecanolactone (10 g, 42 mmols), potassium hydroxide (10 g, 0.18 mmols) and tetra-n-butylammonium bromide (1.34 g, 4.2 mmols) were dissolved in a mixed solvent of THF (100 ml) and water (30 ml), and heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure to evaporate THF, and the aqueous layer was made acidic (pH=1) and then extracted With ether, The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from acetone to obtain 10.4 g (yield: 97%) of 15-hydroxypentadecanoic acid as colorless needle-like crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>CCOCC>[OH:1][C:2]1([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: CCOC(=O)C1CC(O)(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a solution of ethyl 3-oxocyclobutanecarboxylate (3.0 g, 21.1 mmol) in anhydrous Et2O (60 mL), cooled to −80° C., was added dropwise a solution of (4-methoxyphenyl)magnesium bromide (50.6 mL, 25.3 mmol, 2M in THF). The reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and then extracted with EtOAc (3×30 mL) The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 279A as a colorless liquid (3 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.58 (s, 1H), 4.08 (d, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.76-2.67 (m, 1H), 2.60 (s, 2H), 2.47 (s, 2H), 1.22-1.16 (m, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=[CH:37][CH:36]=1.[CH3:51][C:52]1([CH3:59])[O:56][C@H:55]([CH2:57]O)[CH2:54][O:53]1>C1COCC1.CCOCC.CCCCCCC>[CH3:51][C:52]1([CH3:59])[O:56][C@H:55]([CH2:57][O:34][C:35]2[CH:50]=[CH:49][C:38]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[CH:37][CH:36]=2)[CH2:54][O:53]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC1(C)OC[C@@H](COc2ccc(C(=O)OCc3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
In a 250 mL round-bottomed flask was added triphenylphosphine (6.54 g, 24.92 mmol) in THF (79 ml) to give a colorless clear solution. The solution was cooled to 0° C. by ice-bath. After stirring for 15 min, diisopropyl azodicarboxylate (5.11 ml, 24.96 mmol) (orange liquid) was added dropwise over 5 min. The reaction mixture turned into off-white suspension in the process. The reaction mixture was stirred at 0° C. for 30 min. Then a colorless solution of benzyl 4-hydroxybenzoate (5.69 g, 24.92 mmol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (3.00 ml, 23.73 mmol) in THF (39.5 ml) was added to the mixture, keeping the temperature at or below 0° C. The solution turned clear light yellow. The solution was stirred for 2 hr at 0° C. then slowly warmed to ambient temperature and stirred over the weekend. The mixture was concentrated in vacuo to give crude yellow oil (˜27 g). The crude oil was dissolved in ether. Then heptane was added. The resultant precipitate was sonicated and filtered. The filtrate was concentrated and purified via Analogix system using RediSep RS 120 g column, with a gradient of 0-20% EtOAc/Heptane over 10 min at 50 mL/min then hold at 20% ethyl acetate for 20 min. Fractions containing product were combined and concentrated to afford (R)-benzyl 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as white solid (6.17 g, 23.73 mmol). LCMS (Table 1, Method c) Rt=2.89 min, m/z 343.20 (M+H)+
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19]O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19][F:37])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCO)ccc(C#N)c1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(2-hydroxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (30 mg, 0.066 mmol) in DCM (3 mL) at 0° C. was added DAST (0.008 mL, 0.066 mmol) and stirred for 1 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was used in the next step without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[OH-].[K+].O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(Br)ccc1-c1cn(C)c(=O)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Br)ccc1-c1cn(C)c(=O)c2[nH]ccc12
Yield: 73.2 %

Procedure:
The product from Example 241a (0.2 g, 0.410 mmol), potassium hydroxide (0.460 g, 8.21 mmol) and cetyltrimethylammonium bromide (7.48 mg, 0.021 mmol) were combined in dioxane (8 mL) and water (4 mL) and heated at 100° C. for 18 hours. The reaction mixture was partitioned between equal volumes of ethyl acetate and water and the pH was adjusted to pH 7 by careful addition of concentrated HCl. The organic layer was separated and washed three times with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by trituration in dichloromethane afforded the title compound (0.1 g, 73%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.97 (s, 1H) 7.05-7.42 (m, 5H) 5.87-6.09 (m, 1H) 3.75 (s, 3H) 3.54 (s, 3H). MS (ESI+) m/z 333/335 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:7]=1)=[O:18]
Reactant: Nc1ncccn1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Nc2ncccn2)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 12 %

Procedure:
To a microwave tube were added N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.120 g, 0.347 mmol), 2-aminopyrimidine (0.040 g, 0.42 mmol), Pd2(dba)3 (0.030 g, 0.035 mmol), XantPhos (0.040 g, 0.070 mmol), Cs2CO3 (0.23 g, 0.70 mmol) and dioxane (2 mL). The mixture was degassed with N2 for 5 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 50 min and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (15 mg, 12% yield). 1H NMR (500 MHz, MeOH-d4): δ 8.72 (s, 1H), 8.56 (d, J=4.5 Hz, 2H), 8.21 (d, J=5.5 Hz, 2H), 7.53-7.45 (m, 4H), 6.95 (t, J=5.0 Hz, 1H). LCMS (ESI) m/z: 360.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.CS([Cl:29])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[Cl:29][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cc2c(Cl)nc(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (200 mg, 0.6 mmol) and methanesulfonyl chloride (0.47 mL, 5.9 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and then saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to provide the title compound as an off-white solid (170 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.97 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.75 (dd, J=7.4, 2.0 Hz, 1H), 7.52 (m, 1H), 7.46-7.33 (m, 2H), 1.70-1.60 (m, 1H), 1.25-1.18 (m, 2H), 1.02-0.94 (m, 2H). LCMS (Method E): RT=5.562 min, M+H+=358.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:16])[NH:7][C:6]=2[CH:17]=1.O1CCOC[CH2:19]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([S:16][CH3:19])=[N:7][C:6]=2[CH:17]=1
Reactant: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Reactant: C1COCCO1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 1.1 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-thione in 15 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 1.3 g. of potassium hydroxide in 15 ml. of methanol and 1.1 g. of methyl sulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml., diluted with water and the precipitate is collected. Recrystallization from methanol-water gives deep yellow crystals, m.p. 156°-158°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[O:46]1[C:48]2([CH2:53][CH2:52][S:51][CH2:50][CH2:49]2)[CH2:47]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([O:37][CH2:47][C:48]5([OH:46])[CH2:53][CH2:52][S:51][CH2:50][CH2:49]5)=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: C1CC2(CCS1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCC5(O)CCSCC5)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.698 g, 1.1 mmol) in N,N-dimethylformamide (8 mL) were added 1-oxa-6-thiaspiro[2.5]octane (0.286 g, 2.20 mmol) and potassium carbonate (0.304 g, 2.20 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 16 hr. To the reaction mixture were added reagents (1-oxa-6-thiaspiro[2.5]octane and potassium carbonate) in the same amount as mentioned above. After stirring for 8 hr, reagents (1-oxa-6-thiaspiro[2.5]octane and potassium carbonate) in twice the above-mentioned amount were added and the mixture was stirred for 16 hr. After cooling the reaction mixture, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give ethyl 3-(2-fluoro-4-{(4-{4-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2,6-dimethylphenyl}-2,3-dihydro-1H-inden-1-yl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate as a yellow oil. To the obtained oil dissolved in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.459 g, 1.86 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was washed with saturated brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-90% ethyl acetate/hexane) to give the title compound (0.426 g, yield 72%, 2 steps) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([OH:10])=O)=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:40][C@@:41]1([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47])[CH2:45][CH2:44][O:43][CH2:42]1>C1COCC1.CN(C=O)C>[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:40][C@@:41]2([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47])[CH2:45][CH2:44][O:43][CH2:42]2)=[O:10])=[CH:3]1
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Reactant: O=C(O)c1cn[nH]c(=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cn[nH]c(=O)c2)CCOC1
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid (11.5 g), TBTU (25.3 g), triethylamine (20.9 mL) and 40 mL DMF in 200 mL THF was stirred for 30 minutes at ambient temperature. Then n-butyl (S)-3-amino-tetrahydrofuran-3-carboxylate (14.0 g) was added and the mixture was stirred further overnight. For working up the mixture was evaporated to dryness in vacuo and the residue was stirred with 200 mL of ethyl acetate. This solution was washed twice with 5% sodium hydrogen carbonate solution, then dried and evaporated down. The product was thus obtained in a yield of 90% of theory.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:17][CH:14]([CH3:16])[CH3:15])=[S:13])[CH3:2]
Reactant: CC(C)N
Reactant: CCc1cccc(CC)c1N=C=S
Product: CCc1cccc(CC)c1NC(=S)NC(C)C

Procedure:
Reaction of 2,6-diethyl-phenyl isothiocyanate with isopropylamine in accordance with the process described above gives N-(2,6-diethyl-phenyl)-N'-isopropyl-thiourea of melting point: 108° to 110°.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(N(C)C)=O>[S:9]([C:6]1[CH:7]=[CH:8][C:3]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:4][CH:5]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: c1ccc(Sc2ccc(Sc3ccccc3)cc2)cc1
Temperature: 120 °C
Yield: 45 %

Procedure:
A mixture of 19.6 parts of 86% potassium hydroxide, 33 parts of thiophenol and about 120 parts of dimethylacetamide was heated at a temperature of 120° C. with stirring to effect the removal of water. After about 6.5 parts of water was collected, there was added to the resulting mixture 26.3 parts of para-dibromobenzene and the mixture was heated to reflux. After 6 hours at reflux the reaction mixture was allowed to cool and 300 parts of water was added. There was obtained a tan colored solid which was filtered and washed with water several times. The product was then dried. There was obtained 34.7 parts of 1,4-dithiophenoxybenzene based on method of preparation.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)[C:6]=2[CH:24]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[C:2]([CH3:1])[C:3]([CH3:25])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c2cc1C
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 127 (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Br:1]Br.[CH:3]1([N:6]2[C:15]3[C:10](=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=4[F:26])[C:12]([F:17])=[CH:13][C:14]=3[F:16])[C:9](=[O:27])[CH:8]=[CH:7]2)[CH2:5][CH2:4]1>C(O)(=O)C>[Br:1][C:8]1[C:9](=[O:27])[C:10]2[C:15](=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])[N:6]([CH:3]2[CH2:5][CH2:4]2)[CH:7]=1
Reactant: BrBr
Reactant: O=c1ccn(C2CC2)c2c(F)cc(F)c(Nc3ccc(I)cc3F)c12
Solvent: CC(=O)O
Product: O=c1c(Br)cn(C2CC2)c2c(F)cc(F)c(Nc3ccc(I)cc3F)c12
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A solution of bromine (8.4 mg, 0.052 mmol) in acetic acid (0.1 mL) was slowly added to a stirred solution of example 2 (14.4 mg, 0.0316 mmol) in acetic acid (0.4 mL). The reaction mixture was stirred for 3 h. Purification by preparative HPLC mass triggered gave 3 mg (18%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.53 (d, 1H, J=1.2 Hz), 7.93 (t, 1H, J=10.4 Hz), 7.63 (d, 1H, J=10.4 Hz), 7.41 (d, 1H, J=8.8 Hz), 6.64-6.71 (m, 1H), 3.94-4.04 (m, 1H), 1.06-1.17 (m, 4H). MS (ES) [m+H] calc'd for C18H11BrF3IN2O, 535; found 535.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Oc2ccc3nc(N)cn3n2)c1
Yield: 36.8 %

Procedure:
A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (390 mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol) and N,N-dimethylformamide (3 mL) was stirred using a microwave synthesizer at 180° C. for 40 min. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→60/40). The objective fraction was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and precipitated from ethyl acetate to give the title compound (133 mg, yield 37%) as a purple solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[N+:9]([O-])([O-:11])=[O:10].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: Brc1cccc(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=[N+]([O-])c1ccc(Br)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
To an ice-cold solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in concentrated sulfuric acid (200 mL) was added ammonium nitrate (3.39 g, 42.4 mmol) portionwise. The reaction mixture was stirred at 0° C. for 15 min, then it was poured onto an ice-water mixture. The aqueous mixture was extracted with dichloromethane (2×). The combined organic layers were washed with water then a saturated aqueous solution of sodium bicarbonate (2×), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexane, filtered, and dried in vacuo to give 7.63 g of 2,4-dibromo-1-nitro-benzene as a yellow solid (64% yield): 1H NMR (CDCl3) δ 7.62 (dd, 1H), 7.78 (d, 1H), 7.95 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23](F)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].O1CCOCC1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ncccc2F)Cc2ccccc2C1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2ncccc2N2CCCCC2)Cc2ccccc2C1
Reaction time: 0.01 h
Yield: 85.3 %

Procedure:
A 10 mL microwave reaction vessel is charged with 2-[(3-fluoro-pyridine-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (359, 488 mg, 1.49 mmol), 1,4-dioxane (1.5 mL) and piperidine (1.51 mL, 15.23 mmol). A stirring bar is added. The reaction vial is crimped sealed. The reaction vial is placed in a Smith Microwave reaction apparatus. The temperature is set for 150° C. with a fixed hold time of 10 min. Pre-stir time is set for 20 sec. The reaction vial is removed from the apparatus. The stirring bar is extracted. The contents of the flask are transferred to a round bottom flask and the solvent removed under reduced pressure. Pumping to a constant weight gives 1.02 g of off white solid. This is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 65% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions of UV Active eluent are collected. Fractions 2-10 are combined and evaporated by pumping to constant weight to give white solid (0.5 g, 86%).