Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][N:35]([CH3:41])[CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:40][C:37]([CH3:39])([CH3:38])[CH2:36][N:35]([CH3:41])[CH3:34])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CN(C)C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A mixture of 1 g of the compound obtained in EXAMPLE 13, 1 g of 2-dimethylamino -1,1- dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 10-12), 1 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 16 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of NaOH, extracted with a 6N solution of HCl, washed with AcOEt, the acidic aqueous phase is rendered alkaline by the addition of 2N NaOH, extracted with AcOEt and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.65 g of the expected product after crystallization from iso ether. M.p.=161° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].C(N(CC)CC)C.I.C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#Cc1ccc(S(=O)(=O)Oc2ccc(C)cc2)cc1
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Oc3ccc(C)cc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-hydroxy-5-iodobenzoate (58.5 g, 0.2 mol), 4-methylphenyl 4-ethynylbenzenesulfonate (54.4 g, 0.2 mol) and triethylamine (40 g, 0.4 mol) were dissolved in tetrahydrofuran (100 g). The solution was heated to 50° C. and dichlorobis(triphenylphosphine)palladium (0.5 g, 0.72 mmol) and copper(I)iodide (1 g, 5.2 mmol) were) added simultaneously with stirring. The reaction mixture turned dark and triethylamine hydroiodide started to precipitate after about 10 min. After keeping at 45° C. for 45 min, the suspension was poured into dilute hydrochloric acid and the mixture was extracted with toluene. The toluene solution was evaporated to dryness. The residue was triturated with acetonitrile, filtered off and dried. Yield 73 g, (84%). The pooled material from several batches (270 g) was recrystallized from acetonitrile (1.2 l). Yield 250 g.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 112.4 %

Procedure:
Benzoyl peroxide (0.0112 g) was added to a mixture of 4-(4-methylbenzoyl)-nitrobenzene (1.20 g) and N-bromosuccinimide (0.89 g) suspended in carbon tetrachloride (63 mL). The reaction mixture was refluxed under argon for 4 hours while illuminated with an incandescent lamp. The mixture was filtered, and the yellow solution containing the crude product was evaporated, chromatographed on silica gel, eluting with hexane/ethyl acetate, to give 4-(4-bromomethylbenzoyl)-nitrobenzene (1.79 g, 81%) as a white solid, m.p. 112.7-113.1° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]=[O:13])=[CH:5][N:6]2[CH3:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH:12]=[O:13])=[CH:5][N:6]3[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1cc(C=O)c2c(Br)cccc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2c(-c3ccccc3)cccc21
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.
Reaction SMILES: CN(C)C=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:25]N1C(=O)CCC1=O>O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
Into 500 ml of dry dimethylformamide, 50 g (200 mmole) of triphenylamine was dissolved. To the obtained solution, a solution prepared by dissolving 36 g (200 mmole) of N-bromosuccinimide into 100 ml of dry dimethylformamide was added and the obtained solution was stirred at the room temperature for 6 hours. After the reaction was completed, 1 liter of water was added to the reaction mixture and the formed precipitates were separated by filtration. The obtained light yellow solid was washed with water, dried at a reduced pressure and recrystallized from hexane and 38 g (the yield: 59%) of white needle crystals of the subject compound was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[S:12]1[CH2:16][CH2:15][N:14]2[CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=[C:13]12>O>[OH:21][CH2:20][C:18]1[N:19]=[C:13]2[N:14]([CH:17]=1)[CH2:15][CH2:16][S:12]2
Reactant: CCOC(=O)c1cn2c(n1)SCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn2c(n1)SCC2
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Lithium aluminium hydride (280 mg, 7.3 mmol) was suspended in dry, redistilled THF (20 ml) under argon and treated dropwise with a solution (THF, 20 ml), of ethyl 2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate (1.32 g, 6.7 mmol). After 2 h, water was added carefully until effervescence ceased when the mixture was filtered through Celite, the filter pad washed with THF and water and the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was evaporated twice from ethanol to give the title compound as a white solid (1.03 g, 100%); dH (250 MHz; CD3OD) 3.73-3.95 (2H, m), 4.06-4.30 (2H, m), 4.42 (2H, s), 7.04 (1H, s).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].[F:26][C:27]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:37][C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH:25][C:38](=[O:39])[CH2:37][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:27]=2[F:26])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1NC(=O)Cc1cccc(C(F)(F)F)c1F
Temperature: 40 °C

Procedure:
A reaction vial was charged with acetic acid 2-[6-(2-acetoxy-ethylamino)-5-amino-1-oxo-1H-isoquinolin-2-yl]-ethyl ester (100.00 mg, 0.00028788 mol), 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (76.74 mg, 0.0003454 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (274 mg, 0.000720 mol), N,N-diisopropylethylamine (0.125 mL, 0.000720 mol) and methylene chloride (3 mL, 0.05 mol) and the reaction heated at 40° C. for 5 h. The solvent was removed and the residue purified by flash chromatography to obtain the product as an off white solid. MS m/z=552.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[N:35][CH:34]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[N:35][CH:34]=3)=[N:11][N:10]=2)=[CH:47][CH:48]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cncc(N6CCN(C)C(=O)C6)n5)c4c3)s2)cc1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one (70 mg, 0.103 mmol) in THF (2 mL) followed by 1 M KOH (500 μL, 0.500 mmol). The mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then cooled to RT. The mixture was diluted with H2O, and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one. MS (ESI, pos. ion) m/z: 527 (M+1). A glass microwave reaction vessel was charged with the above crude compound (54 mg, 0.103 mmol) in TFA (1 mL). The reaction was stirred and heated in a 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 4-(6-(5-(5-amino-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyrazin-2-yl)-1-methylpiperazin-2-one (10.0 mg, 0.025 mmol, 24%) as a light yellow solid. MS (ESI, pos. ion) m/z: 407 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (1H, br. s.), 8.73 (1H, s), 8.48 (1H, s), 8.28 (1H, d, J=2.5 Hz), 8.05 (1H, s), 7.74 (1H, dd, J=8.5, 1.5 Hz), 7.53 (1H, d, J=8.4 Hz), 7.26 (3H, s), 4.23 (2H, s), 4.06 (2H, t, J=5.4 Hz), 3.60 (2H, t, J=5.5 Hz), 3.28 (1H, s), 2.96 (3H, s)
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[N+:11]([O-:13])=[O:12])[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile (7.12 g, 29.55 mmol) and morpholine (3.09 g, 35.45 mmol) in CH2Cl2 (98 mL) was added triethylamine (8.97 g, 88.64 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (40 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-(morpholinomethyl)-3-nitrobenzonitrile (5.84 g, 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.83 (br s, 2H), 3.84 (s, 2H), 3.67 (t, 4H, J=4.6 Hz), 2.45 (t, 4H, J=4.6 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1
Reactant: OCc1ccsc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccsc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.0 g of 3-thiophenemethanol was dissolved in 6 ml of dimethylformamide, and under ice cooling, 0.36 g of 60% oily sodium hydride and 1 ml of ethyl bromoacetate were added. The mixture was stirred at room temperature for 15 hours, and then worked up in a customary manner. The product was purified by silica gel column chromatography [hexane/ethyl acetate=6/1] to give 0.9 g of ethyl 3-thienylmethoxyacetate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccc(C#N)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(C#N)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(4-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N+:16]([O-])([OH:18])=[O:17].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of the acetamide from step (a) above (8.46 g, 30 mmol) in concentrated sulfuric acid (32.5 mL) was added dropwise concentrated HNO3 (4.1 mL, 90%. J. T. Baker) with stirring at 0° C. The resulting solution was stirred at room temperature for 3 h and poured into crushed ice (80 mL). The mixture was carefully neutralized with solid NaHCO3 and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (25% EtOAc/hexane) to give the title compound as a yellow solid. MS (ESI, neg. ion) m/z: 325.0 (M−1).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[CH2:1]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CCCCCCCCC
Product: CCCCCCCCCCc1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
General procedure G was used to couple 1-decene (8.1 mmol) to 4-bromobenzaldehyde (5.4 mmol) to yield 1.25 g (5.1 mmol) of the title product after column chromatography. Spectral data was consistent with previously reported compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:15]([CH3:16])[C@@:14]3([O:25][CH3:26])[CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19](=O)[CH:20]=[C:13]3[O:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:28]([NH2:30])[CH3:29]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:15]([CH3:16])[C@@:14]3([O:25][CH3:26])[CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19](=[N:30][O:28][CH3:29])[CH:20]=[C:13]3[O:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CON
Reactant: CCCC1=C[C@@]2(OC)C(=CC1=O)O[C@H](c1ccc(OC)c(OC)c1)[C@@H]2C
Agent: Cl
Solvent: c1ccncc1
Product: CCCC1=C[C@@]2(OC)C(=CC1=NOC)O[C@H](c1ccc(OC)c(OC)c1)[C@@H]2C

Procedure:
(2S,3S,3aS)-2-(3,4-Dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-methoxyiminobenzofuran was prepared from (2S,3S,3aS)-2-(3,4-dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-oxobenzofuran and methoxylamine hydrochloride in pyridine at room temperature for 3 days. The product was purified by flash column chromatography on silica gel (hexane-ethyl acetate, 9:1, v/v) followed by HPLC to afford (2S,3S,3aS)-2-(3,4-dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-methoxyiminobenzofuran, n.m.r. (CDCl3): δ0.98 (t, J 7.5 Hz, CH2CH2CH3), 1.11 (d, CH3 --3), 1.64 (m, CH2CH2CH3), 2.52 (m, CH2CH2CH3), 3.0 (s, OCH3), 3.84 (s, Ar--OCH3), 4.04 (s, NOCH3), 5.07 (s, H-2), 5.72 (s, H-7) 6.48 (s, H-4), 6.87-7.12 (m, Ar--H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1([CH3:34])[CH2:32][NH:31][C:30](=[O:33])[NH:29]1>>[CH3:27][C:28]1([CH3:34])[N:29]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]5)[CH2:12][CH2:11]3)[CH:3]=2)[C:30](=[O:33])[NH:31][CH2:32]1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: CC1(C)CNC(=O)N1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NCC5(C)C)c4)CC3)cccc2n1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 4,4-dimethyl-2-imidazolidinone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[Br:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:20][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2CCNC2)cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(6-amino-5-bromopyridin-3-yl)pyrrolidine-1-carboxylate (65 mg, 0.171 mmol) in DCM (2.4 mL) was added TFA (0.6 mL, 7.79 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was evaporated in vacuo after dilution with toluene. The crude product was used for next step without purification. The crude yield was quantitative. LCMS (m/z): 242.1/244.1 (MH+), 0.214 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)[C:34]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as yellow solid. MS; m/e=489.1 [M+H+].