Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(OC(=O)[NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc(N)nc3)n2n1
Temperature: 145 °C
Yield: 63.6 %

Procedure:
To a mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (75 mg, 0.28 mmol), tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (107 mg, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) and potassium phosphate (58 mg, 0.42 mmol) was added 3:1 acetonitrile/water (2 mL). The resulting mixture was heated at 145° C. (microwave) for 1000 s. The reaction was then filtered and concentrated. The residue was finally purified by preparative HPLC (neutral) to afford 3-(6-aminopyridin-3-yl)-N-butylimidazo[1,2-b]pyridazin-6-amine (50.3 mg, 47% yield) as a yellow solid: 1H NMR (METHANOL-d4) δ: 8.72 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.7, 2.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=9.7 Hz, 1H), 6.58-6.66 (m, 2H), 4.78-4.88 (m, 11H), 3.27-3.33 (m, 3H), 1.62 (d, J=7.1 Hz, 2H), 1.42 (d, J=7.9 Hz, 2H), 0.91-0.97 (m, 3H); LRMS (ESI) m/e 283.4 [(M+H)+, calcd for C15H19N6 283.2].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:8](=[O:23])[C:7]=1[C:24](O)=O)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[BH3-]C#N.[Na+].P([O-])([O-])([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:62]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:8](=[O:23])[C:7]=1[CH2:24][Br:62])=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1CBr
Reaction time: 3 h
Yield: 29.6 %

Procedure:
1-(2,4-Dimethoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 4-ethyl ester (13.2 g, 36.5 mmol) was dissolved in 280 mL of CH2Cl2. Oxalyl chloride (32 mL, 365 mmol) and DMF (3 drops) were added, and the mixture was stirred for 3 h. Solvent and excess oxalyl chloride were removed by evaporation in vacuo, and to the residue was added a solution of NaCNBH3 (4.6 g, 73 mmol) in THF (250 mL). The resulting yellow suspension was stirred at r.t. for 16 h. The reaction mixture was cooled in an ice bath, and then poured into a pre-cooled, vigorously stirring pH 4.9 phosphate buffer (900 mL). The resulting mixture was extracted several times with benzene, and the combined organic layer was washed with ice-cold water and dried over MgSO4. Evaporation of the solvent at reduced pressure gave a viscous oil, which was dissolved in 260 mL of CH2Cl2. The solution was cooled in at ice bath, and triphenylphosphine (10.5 g, 39.9 mmol) and carbon tetrabromide (13.2 g, 39.9 mmol) were added. The mixture was then stirred at r.t. for 16 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-60% EtOAc/hexanes) to give 4.43 g of the title compound as a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=7.35-7.50 (m, 2H), 6.40-6.55 (m, 3H), 5.07 (s, 2H), 4.87 (s, 2H), 4.39 (q, 2H, J=7.0 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 1.41 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].BrC1C=CC=CC=1[C@@H]([N:26]=[C:27]=[O:28])C.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2([CH2:5][C:6]([CH3:8])=[CH2:7])[O:9][C:27](=[O:28])[NH:26][CH2:2][CH2:3]2)=[CH:11][CH:12]=1
Reactant: C[C@H](N=C=O)c1ccccc1Br
Reactant: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)CC1(c2ccc(F)cc2)CCNC(=O)O1
Yield: 65.7 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (3.15 g, 13 mmol), (S)-(−)-1-(-bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in THF (80 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3 x). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give (R)-3-(S)-1-(4-bromophenyl)-ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one (2.13 g, yield: 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(CC)CC)C>CN(C=O)C.ClCCl>[N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:29]1[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A 100-mL 2-necked round bottom flask was fitted with thermometer, magnetic stirrer, and reflux condenser with nitrogen bypass. The flask was charged with 1.23 g (5 mmol) of 2-nitro-4-(methylsulfonyl)benzoic acid, 2 drops of DMF, and 20 mL of dichloromethane. Oxalyl chloride (0.70 g, 5.5 mmol) was added dropwise and the mixture was stirred for 1 hr. A solution consisting of 0.70 g (5 mmol) of 4-nitrophenol, 0.55 g (5.5 mmol) of triethylamine and 5 mL of dichloromethane was added and the mixture was stirred for 1 hr. The mixture was diluted with 100 mL of dichloromethane, washed twice with 100 mL portions of aqueous sodium bicarbonate, once with 100 mL of water, dried with magnesium sulfate, filtered, and volatiles removed under reduced pressure to give the title product as 1.56 g of off-white solid, m.p. 171-173° C. 1H NMR (CDCl3): δ 3.19 (s, 3), 7.47 (m, 2), 8.10 (m, 1), 8.38 (m, 3), 8.69 (m, 1).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9]C[CH:7](C#N)[CH2:6]1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:17]([OH:20])(=[O:19])[CH3:18]>O.C(OCC)(=O)C>[CH2:1]([C@H:5]1[CH2:6][CH2:7][CH:18]([C:17]([OH:20])=[O:19])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CCC(C#N)C1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC[C@H]1CCC(C(=O)O)C1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A mixture of 73 mg of (1RS,3S)-3-butyl-1-cyanocyclopentane (prepared in Reference Example 13), 0.6 ml of conc. sulphuric acid, 0.6 ml of acetic acid and 0.6 ml of water was stirred for 1 hr. at 110° C. To the reaction solution, 30 ml of ethyl acetate and 20 ml of water were added. The oily layer which separated was washed with water, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 30 mg of the title compound having the following physical characteristics, in a 36.5% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCOCC1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)CNC(C)C)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In a reactor, 21 g (0.1 mol) of 4-acetylaminophenacyl chloride are introduced into a mixture comprising 100 ml of dioxane, 26 ml (0.3 mol) of isopropylamine and 20 ml of water. The reaction medium is stirred at 30°-40° C. for 2 hours. After the addition of 500 ml of iced water, a precipitate is collected, washed and dried. Recrystallization from ethyl acetate gives 21 g of N-(4-acetylaminophenacyl)isopropylamine, which is in the form of a white powder. Melting point (inst.)=156° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH:16]([C:25]([O:27]C)=[O:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1.CO.O.[OH-].[Li+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH:16]([C:25]([OH:27])=[O:26])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Oc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Oc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Dimethyl 13-cyclohexyl-6,7-dihydroindolo[1,2-d][1,4]benzoxazepine-6,10-dicarboxylate was dissolved in THF:MeOH (1:1) (0.02 M) and to that solution 1.4 eq. of an aq. solution of lithium hydroxide monohydrate (0.1 N) were added. The solution was stirred at RT for 2 h. Volatiles were reduced in vacuo, the residue acidified with 1N HCl (aq) and the resultant precipitate filtered and dried in vacuo to afford the title compound (99%). (ES+) m/z 420 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:22]C(=O)C(C)(C)C)[NH:3]1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO.O>[NH2:22][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(C#C[Si](C)(C)C)cc3c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Yield: 58.5 %

Procedure:
A solution of N-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide (0.24 g, 0.61 mmol) and K2CO3 (0.50 g, 3.6 mmol) in methanol (~ 50 ml) was stirred at reflux for 2.5 hours. The solution was then diluted with water (~ 20 ml) acidified with acetic acid, and the resulting solid filtered and dried at 90° C. under reduced pressure. The solid was resuspended in ethanol (~ 20 ml), filtered, and dried to give 3-amino-9-ethynyl benzo[f]quinazolin-1(2H)-one (0.084 g) as a tan solid. 1H NMR (DMSO-d, 200 MHz) δ: 4.26 (s, 1H, ethynyl CH), 6.63 (br s, 2H, NH2), 7.32 (d, J=9 Hz, 1H, Ar), 7.47 (dd, J=8,2 Hz, 1H, Ar), 7.87 (d, J=8 Hz, 1H, Ar), 8.02 (d, J= 9 Hz, 1H, Ar), 9.78 (s, 1H, Ar), 11.34 (br s, 1H, NH). Mass spectrum (CI-CH4): 236 (M+1, 100%). Anal. Calculated for C14H9N3O: C, 71.48; H, 3.86; N, 17.86. Found C, 71.30; H, 3.92; N, 17.68.
Reaction SMILES: [H-].[Na+].[Br-].[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1.Cl>CN(C)C=O>[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49](/[CH:50]=[CH:11]\[CH2:10][CH:5]2[O:4][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:52][CH:53]=1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C\CC2OCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Sodium hydride (60% in oil, 0.78 g) was added in limited amounts, at room temperature, to a solution of [2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (8.9 g) in N,N-dimethylformamide (100 ml). The mixture was stirred for 30 minutes at the same temperature range, to which was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g). The mixture was stirred for 15 minutes at room temperature, then for 5 hours at 70° C. The reaction mixture was poured into ice-water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The residue was purified by means of a silica gel column chromatography. From the fractions eluted with hexane-ethyl acetate (3:1), (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane (5.1 g, 77%) was obtained as an oily product.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1>CCO.C(#N)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1
Reactant: CN
Reactant: Clc1cc(COCC2CC2)nc(Cl)n1
Solvent: CCO
Solvent: CC#N
Product: CNc1cc(COCC2CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanamine (0.124 mL, 0.99 mmol) in EtOH was added to a solution of 2,4-dichloro-6-((cyclopropylmethoxy)methyl)pyrimidine (77 mg, 0.33 mmol) in acetonitrile (6 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was concentrated and the residue was purified by preparative HPLC give the title compound, 42 mg (56%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])#[N:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13].C1(O)C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:3]2[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=2[O:10][S:12](=[O:14])(=[O:13])[N:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1c(O)cccc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Product: NC1=NS(=O)(=O)Oc2cccc(F)c21
Temperature: 50 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
8.0 g (58.3 mmol) of 2-cyano-3-fluorophenol are dissolved in 100 ml of anhydrous toluene. With exclusion of moisture and under protective argon gas, a solution of 8.489 g (60 mmol) of chlorosulphonyl isocyanate is added dropwise, in the course of which slight exothermicity occurs. The mixture is stirred at 50° C. for 16 hours; phenol is no longer detectable by thin-layer chromatography. The mixture is heated under reflux for 16 hours; no further evolution of HCl gas takes place. The mixture is concentrated under reduced pressure, taken up in acetonitrile and admixed with aqueous acetonitrile. After stirring at room temperature for 1 hour, the mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 13 g of a reaction mixture are obtained, which is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 1.3 g of a fraction are isolated, which consists of two components at log P=0.76 and 1.06. After separating this mixture by means of HPLC, 0.8 g of 4-amino-5-fluoro-1,2,3-benzoxathiazine 2,2-dioxide is obtained as a white solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:23])[C:8]1[CH:22]=[CH:21][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15]=2[CH3:20])=[CH:10][CH:9]=1.[CH3:24][N:25]([CH3:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:23][N:7]([CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15]=2[CH:20]=[CH:30][C:29]2[CH:32]=[CH:33][C:26]([N:25]([CH3:34])[CH3:24])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Cc1n(C)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C=Cc2n(C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1

Procedure:
0.66 g of 1-[[p-(dimethylamino)benzylidene]-amino]-2,3-dimethylimidazolium tetrafluoroborate, 0.45 g of p-(dimethylamino)benzaldehyde and 0.34 g of piperidine are suspended in 30 ml of toluene, whereupon the suspension is heated to boiling under reflux for about 70 hours on a water separator filled with toluene which contains 5% piperidine. The precipitated material is removed by filtration under suction, washed with toluene, twice with diethyl ether and twice with water and recrystallized from methanol. There is obtained colorless 1-[[p-(dimethylamino)benzylidene]amino]-2-[p-(dimethylamino)styryl]-3-methylimidazolium tetrafluoroborate of melting point 235°-238°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([C:15]1[N:16](S(C)(=O)=O)[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[CH:18]=2)([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].Cl>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:24]#[N:25])=[CH:20][CH:21]=4)[NH:16][C:15]=3[C:12]([CH3:13])([CH3:14])[C:5]=2[CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1C(C)(C)c1cc2ccc(C#N)cc2n1S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
(Method 2) To the THF (5.6 ml) solution of 2-[1-(6-cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-benzoic acid methyl ester (Compound AA4, 138 mg, 0.324 mmol), tetrabutylammonium fluoride (514 mg, 6 eq.) was added, and the mixture was stirred at room temperature overnight. Thereafter, 2 M aqueous solution of sodium hydroxide (5.6 ml) was added to the mixture, which was then stirred for 4 hr, added with 1 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were dissolved in ethyl acetate (10 ml) and added with e 4 M HCl and ethyl acetate solution (10 ml) followed by stirring at room temperature for 30 min. The residues obtained after concentration of the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (89.2 mg, 62%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]([F:17])([F:18])[F:19])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A solution of N-ethoxalyl-4-chloro-2-trifluoromethylaniline in concentrated sulphuric acid (125 ml) was added to a stirred mixture of 100% nitric acid (120 ml) and concentrated sulphuric acid (240 ml). The temperature was kept between 8°-10° C. during the addition. After the addition was completed, the solution was stirred for additionally 20 min. without external cooling, whereafter it was poured onto icewater. This afforded precipitation of the title compound as an oil, which crystallized as light yellow crystals upon standing. The crystals were filtered off and washed extensively with water. M.p. 100°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:8][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 17 ml DCM and 0.5 ml pyridine, 1.5 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C-:16]#[N:17].[K+].C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:16]#[N:17])=[C:4]([I:14])[C:5]=1[O:11][CH2:12][CH3:13])(=[O:10])[CH3:9]
Reactant: [C-]#N
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Temperature: 40 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (7.3 g, 21 mmol) in N,N-dimethylformamide (80 mL)was treated with potassium cyanide (2.1 g, 32 mmol) and stirred at 40° C. for 5 h. The reaction mixture was diluted with ethyl acetate and poured into saturated sodium bicarbonate solution/water (1:1). The organic layer was separated, washed with saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated to give a crude brown oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product (6.1 g, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 3.93 (q, J=7.0 Hz, 2H), 2.61 (s, 3H), 1.47 (t, J=7.0 Hz, 3H). LCMS for C11H10ClINO2 (M+H)+: m/z=349.9; Found: 349.9.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Br:7])[N:6]=1.S(Cl)(Cl)=O.CN(C)C=O.C(N(CC)CC)C.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>ClCCl.O>[CH2:27]([NH:30][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:10])[CH:28]=[CH2:29]
Reactant: O=C(O)c1sc(Br)nc1Br
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To a solution of 2,4-dibromo-1,3-thiazole-5-carboxylic acid (25.0 g, 87.1 mmol) in dichloromethane (600 mL) at 0° C. was added thionyl chloride (66.1 mL, 906 mmol) followed by N,N-dimethylformamide (7.02 mL, 90.6 mmol). The mixture was allowed to warm to room temperature and stir for 2 hours. The solvent was evaporated and the excess thionyl chloride was removed by azeotroping with toluene. The residue was dissolved in dichloromethane (600 mL) and cooled to 0° C., then added triethylamine (63.2 mL, 453 mmol) was added followed by 2-propen-1-amine (23.8 mL, 317 mmol) and N,N-dimethylaminopyridine (1.11 g, 9.06 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was then diluted with dichloromethane and water and the layers were separated. The aqueous phase was then extracted with dichloromethane twice, then the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (14.3 g, 50%). LCMS: (FA) ES+, 327. 1H NMR (400 MHz, d4-methanol) δ: 5.97-5.85 (m, 1H), 5.32-5.24 (m, 1H), 5.20-5.14 (m, 1H), 4.02-3.95 (m, 2H).