Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C1COCC1>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a suspension of 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide (75 mg, 0.13 mmol) in THF (4 mL) was added morpholine (100 mg, 1.1 mmol) and the reaction mixture was stirred 15 min. The solvent was removed in vacuo and the resulting solid was triturated in methanol/ether to give the desired product (55 mg, 75%) as a white solid. MS(ESI+) m/z 566 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1H-imidazole (9f) (20 mmol) in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonyl chloride (2.82 mL, 22 mmol) was added and the reaction mixture was stirred overnight. After dilution by 100 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 2:1) to give a pale solid. Yield: 54.9%. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.38 (t, J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H). MS (ESI): calculated for C15H11ClN2O2S, 318.0. Found 341.0 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClCCl.[BH4-].[Na+].[NH4+].[Cl-]>O.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(methylsulfonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde (154 mg, 256 μmol, Eq: 1.00) was combined with dichloromethane (24 ml) and 2 mL MeOH. Sodium borohydride (14.5 mg, 383 μmol, Eq: 1.5) was added and the reaction suspension was stirred at ambient temperature for 1 h. 1 mL of saturated NH4Cl was added; followed by 5 mL H2O. The mixture was stirred for 5 min. The reaction mixture was poured into 50 mL H2O and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 1% to 3% MeOH in DCM) to afford the desired product (90 mg) as a white powder. (M+H)+=605 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9 H) 3.10 (s, 3 H) 3.77 (s, 3 H) 4.51 (br. s., 2 H) 6.94 (d, J=8.59 Hz, 1 H) 7.48-7.65 (m, 3 H) 7.88 (d, J=2.53 Hz, 1 H) 8.00 (dd, J=8.59, 2.53 Hz, 1 H) 8.33-8.45 (m, 2 H) 8.71 (d, J=5.05 Hz, 1 H) 8.82 (d, J=2.53 Hz, 1 H) 8.92 (d, J=2.53 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8]C(O)=O)[N:5]=[C:4]([NH:12][CH2:13][CH3:14])[N:3]=1>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCNc1nc(O)cc(CC(=O)O)n1
Solvent: CCO
Product: CCNc1nc(C)cc(O)n1

Procedure:
4-Hydroxy-2-ethylaminopyrimidin-6-yl acetic acid was suspended in ethanol (50 ml) and the mixture refluxed for 16 hours. Evaporation of the ethanol under reduced pressure yielded chromatographically pure 4-hydroxy-2-ethylamino-6-methylpyrimidine, melting at 176° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+]>CO.CCOC(C)=O>[Cl:9][C:4]1[C:3]([CH2:2][C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: [C-]#N
Reactant: Clc1ncccc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1cccnc1Cl
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In a 250 mL round bottom flask was dissolved 3-(bromomethyl)-2-chloropyridine (7.2 g, 35 mmol) in MeOH (70 mL). To the solution was added sodium cyanide (3.4 g, 70 mmol), then attached a reflux condenser, stirred the mixture at 80° C., while monitoring the reaction by LCMS. After about 1.5 h, the reaction was cooled to RT, concentrated, diluted with EtOAc, upon which a white solid crashed out. The solids were filtered and rinsed with EtOAc. The organic filtrate was concentrated to yield a crude reddish brown solid. The solid was dissolved in EtOAc, and purified by silica gel chromatography eluting with 40-70% EtOAc/Hexanes. The product fractions were concentrated to yield 2-(2-chloropyridin-3-yl)acetonitrile as an off-white solid. MS m/z=153 [M+1]+. Calc'd for C7H5ClN2: 152.58.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[O:3]1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:13])([CH3:1])[O:3][C:4]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2cscn2)=CC1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2cscn2)=C(Br)C1=O
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (90 mg, 0.46 mmol) in CHCl3 (1.8 mL) was added NBS (0.12 g, 0.69 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water (5 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (40 mg, 71%) as an off white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[C:7]([OH:8])[C:6]2C3C(COCC4C([C:4]=1[C:5]=2[OH:25])=CC=CC=4)=CC=CC=3)=[CH2:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH:9]=1)[OH:8])[CH3:2]
Reactant: C=Cc1cc(O)c2c(O)c1-c1ccccc1COCc1ccccc1-2
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(O)cc(O)c1
Reaction time: 14 h
Yield: 109.1 %

Procedure:
A mixture of 1.07 g (3.39 mmol) of 5-vinylresorcinol dibenzylether, as prepared in the preceding step, and 200 mg of 10% Pd/C in 20 mL of ethanol was hydrogenated at atmospheric pressure and ambient temperature for 14 h. The reaction mixture was filtered through diatomaceous earth (ethanol rinse) and concentrated to give 511 mg of the crude title compound which was used as is in the next reaction. 1H-NMR (300 MHz, CDCl3): δ 6 6.27 (dd, 1H, J=0.4, 2.2 Hz), 6.18 (t, 2H), 2.53 (q, 2H), 1.19 (t, 3H). Mass spectrum (MALDI-TOF; sinapinic acid matrix) calcd. for C8H10O2 :139.1 (M+H). Found: 139.5.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[C-:33].[H-].[Na+].C1COCC1>C1COCC1>[CH2:38]([O:37][C:35]([C:34]1[N:32]=[CH:33][N:6]2[C:7]=1[CH:8]([CH3:17])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]2=1)=[O:36])[CH3:39]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccn2)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccn1)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
The 7-bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 125 (3.3 g, 10 mmol) was suspended in dry THF (200 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.31 mL, 16 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 0.56 g, 14 mmol) was suspended in dry THF (150 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.31 mL, 12 mmol) was added to the NaH/THF suspension, the solution which resulted was allowed to stir for 3 h. After 3 h, the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:1, 2:1, 3:1). The ester 126 was a white solid (1.40 g, 33%). mp 193-195° C.; IR (KBr, cm−1) 2962, 1719, 1260, 1021; 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1H), 4.41 (m, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.29 (d, J=7.2, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>O1CCCC1>[CH3:1][N:2]([CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:3]
Reactant: CNC
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 610.1 %

Procedure:
To a stirred solution of dimethyl amine (2.0M solution in tetrahydrofuran) (0.31 mL, 0.028 mmol) in tetrahydrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4R,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) and stirred at room temperature overnight. The solvent is evaporated in vacuo and the crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.072 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (S, 3H), 2.21 (s, 6H), 3.56 (s, 2H), 4.56-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H), 5.26 (d, J=3.76 Hz, 1H), 6.64 (t, J=52.36 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.59 (d, J=8.08 Hz, 2H), 7.78 (d, J=8.12 Hz, 2H), 8.07-8.09 (m, 1H), 8.81 (s, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: [N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N+]1C=CN(C)C=1)CCC.C([N+]1C=CN(C)C=1)CCC.[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.[C:58](Cl)(=[O:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Ni+2]>[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:65]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Ni+2]
Agent: CCCC[n+]1ccn(C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=C(c1ccccc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Nickel(II) bis-triflimide (0.062 g, 0.1 mmol) was added to 1-butyl-3-methylimidazolium bis-trifluoromethanesulfonimide ([bmim] [NTf2]) (1.0 g) in a 25 cm3 round-bottomed flask equipped with a magnetic stirrer and reflux condenser, and the mixture stirred until the catalyst dissolved. Chlorobenzene (1.68 g, 15 mmol) and benzoyl chloride (1.41 g, 10 mmol) were added. The mixture was heated under reflux for 72 hours and was analysed by gas chromatographic analysis as in previous examples. The reaction was cooled to room temperature. Petroleum ether (15 cm3, bp=40-60° C.) was added and the catalyst and ionic liquid formed a separate phase from the petroleum ether layer. The solution of the product (in petroleum ether) was decanted and the flask (containing the ionic liquid and catalyst) washed three times with 15 cm3 of petroleum ether. Concentration of the organic extract, followed by Kugenrohr distillation at 1 mm Hg (bp=170-190° C.), gave chlorobenzophenone (1.65 g, 74%) GC analysis showed 78% yield after 72 hours, with a 70:8 4- to 2-isomer ratio. This is a remarkable result, as chlorobenzene is known to be classically unreactive in acylation reactions. It has not previously been possible to isolate significant quantities of the products of the acylation of chlorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([OH:8])[CH:7]=1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)cc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
5-Fluoro-3-(trifluoromethyl)phenol (1.27 g) was dissolved in acetic acid (3 ml) and water (1.5 ml), and nitric acid (3.0 ml) was added thereto. The reaction mixture was stirred at 50° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with an aqueous saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developing solution:ethyl acetate-hexane=1:3) to obtain the title compound as oil (0.33 g, 21%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([Br:21])=[CH:13][CH:12]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[Br:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Brc1ccc(-c2ccccc2)c2ccccc12
Temperature: 78 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
Under an argon gas atmosphere, 128.0 g (1.049 mol) of phenylboronic acid, 300.0 g (1.163 mol) of 1,4-dibromonaphthalene, 24.2 g (21.0 mmol) of tetrakis(triphenylphosphine) palladium(0), 4.3 L of dimethoxyethane and 1.60 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture was further added with toluene and water, and then aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by hexane, 122 g of 1-bromo-4-phenyl naphthalene was obtained with an yield of 41%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2C=O)[CH:4]=[CH:3][CH:2]=1.C(O[CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])C.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:21]([O:20][CH:16]([O:17][CH2:18][CH3:19])[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:22]
Reactant: O=Cc1cccc2cccnc12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(OCC)c1cccc2cccnc12
Yield: 84.6 %

Procedure:
A mixture of 8-quinolinecarboxaldehyde (0.248 mol), triethoxymethane (0.4464 mol) and 4-methylbenzenesulfonic acid (4 g) in ethanol (250 ml) was stirred and refluxed for 1 hour, brought to room temperature, poured out into K2CO3 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The product was used without further purification, yielding 48.5 g (80%) of 8-(diethoxymethyl)-quinoline (interm. 29).
Reaction SMILES: CC(OC([NH:8][CH:9]1[C@@H:14]2[C@H:10]1[CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13]2)=O)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:8][CH:9]1[C@@H:14]2[C@H:10]1[CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13]2
Reactant: CC(C)(C)OC(=O)NC1[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl(1R,5S)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Bioorganic & Medicinal Chemistry Letters (2004), 14(11), 2773-2776, Compound 9; 6.74 g, 20.3 mmol) was stirred and dissolved in DCM (90 mL) at ambient temperature and TFA (10 ml) was added. The solution was stirred at room temperature for 2 hours. Sat. bicarbonate (100 ml) was added followed by potassium carbonate solid until neutral. The DCM layer was separated and washed once more with water. The DCM solution was dried (MgSO4), filtered and evaporated to a gum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=1)[OH:11]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 70 °C

Procedure:
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0° C. with stirring and then allowed to reflux at 70° C. for 40 h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NaHCO3 solution (2×1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:20]1[CH:21]=[CH:22][C:23]2N(O)N=[N:26][C:24]=2[CH:25]=1.NC1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:26][C:24]1[CH:25]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1

Procedure:
A solution of pyrrolidine-1,2(S)-dicarboxylic acid 1-t-butyl ester (50 g, 233 mmol), EDC (45 g, 233 mmol) and HOBT (12 g, 77.5 mmol) in 1500 ml of dichloromethane was cooled to 0° C. and aniline (21 ml, 233 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred over night, evaporated and partitioned between ethyl acetate and 1N-HCl. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and evaporated. The crude solid was crystallized from diethyl ether. Yield: 104 g (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C(N(CC)C(C)C)(C)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[O:39][CH3:38]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OC(=O)c2ccccc2OC)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-bromo-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (200 mg), N,N-diisopropylethylamine (390 μl) and 2-methoxy-benzoyl chloride (53 μl) in dichloromethane (4 ml) was stirred for 4 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(-c6ccc(Cl)cc6)n5)c4c3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cccc(-c5ccc(Cl)cc5)n4)c3c2)s1
Temperature: 120 °C
Yield: 44.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-(4-chlorophenyl)pyridin-2-yl)-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (174 mg, 0.332 mmol) in TFA (1.0 ml). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min, then solvent was removed. The residue was purified with RP-HPLC to give 5-(3-(6-(4-chlorophenyl)pyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (60.0 mg, 0.149 mmol, 44.7%) as an off-white solid. MS (ESI, pos. ion) m/z: 404 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.62 (1H, s), 8.90 (1H, s), 8.06-8.21 (3H, m), 7.70 (2H, d, J=4.1 Hz), 7.55-7.65 (2H, m), 7.50 (2H, d, J=8.4 Hz), 7.36 (1H, d, J=8.6 Hz), 7.16 (2H, s).