Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(C)[O-].[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH:35]=O)=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1.CO>COCCOC>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH2:35][C:17]#[N:18])=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1
Reactant: Cn1c2cc(Cl)ccc2c2c(C=O)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cn1c2cc(Cl)ccc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
1.27 g (10.96 mmol) of potassium 1,1-dimethylethoxide are added, in small portions, to a solution of 2.14 g (10.96 mmol) of (4-methylbenzenesulphonyl)methyl isocyanide in 50 ml of 1,2-dimethoxyethane, the reaction mixture is stirred for 30 min at −60° C., 2.88 g (8.53 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxaldehyde are added and the reaction mixture is stirred for 3 hours 30 min at −60° C. 9 ml of methanol are added and the reaction mixture is further stirred for 30 min at room temperature and for 1 hour at reflux. The mixture is cooled and concentrated under reduced pressure, water, 5 ml of acetic acid and 200 ml of dichloromethane are added to the residue, the organic phase is separated by settling and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 1.87 g (5.36 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O.[NH2:15][NH2:16]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:15][NH2:16])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc2[nH]ncc2c1
Yield: 93.4 %

Procedure:
A solution of methyl 1H-indazole-5-carboxylate (5.02 g, 28.5 mmol) and hydrazine monohydrate (6.94 mL, 143 mmol) in methanol (50 mL) was heated under reflux for 48 hr. After cooling, the precipitate was collected by filtration, and washed with methanol to give the title compound (4.69 g, yield 93%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CCO.CC(O)=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][N:19]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][NH2:1])=[CH:14][CH:13]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: NCC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NCC(=NNc1ccc(Cl)cc1)c1ccccc1
Yield: 84 %

Procedure:
A mixture of 10.43 g 2-aminoacetophenone and 11.0 g 4-chlorophenylhydrazine in 30 ml EtOH and 10 ml HOAc was refluxed for one hour. The cooled reaction mixture was diluted with water and the precipitate was collected, washed with water, and dried to give 16.83 g solid. Recrystallization from methanol gave 3.48 g solid, m.p. 109°-112° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:22].Br[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: CNC(=O)c1c(-c2ccc(Br)cc2)oc2ccc(O)c(F)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1c(-c2ccc(Br)cc2)oc2ccc(OC(C)C)c(F)c12
Temperature: 50 °C

Procedure:
To a mixture of 4-fluoro-2-(4-bromophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide (0.17 g, 0.467 mmol, 1 eq), 2-bromopropane (0.18 ml, 1.46 mmol, 3.1 eq), and cesium carbonate (0.46 g, 1.41 mmol, 3 eq) in N-methylpyrrolidinone in a sealed tube was heated at 50° C. for 16 h. The reaction mixture was cooled to r.t., and the inorganic was removed by filtration. The filtrate was diluted with water, and the product extracted into EtOAc. The organic was washed with saturated brine solution, filtered, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 0-20% EtOAc in petroleum ether as an eluent Yield: 0.15 g (79.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=4.4 Hz, 1H), 7.78-7.73 (m, 4H), 7.46 (d, J=9.2 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H), 4.53 (m, 1H), 2.82 (d, J=4.4 Hz, 3H). 1.29 (d, J=6.0 Hz, 6H). Column: purospher@star RP-18 (4×55) mm, 3 μm; Mphase A: 20 mM NH4OAc in 90% H2O, 10% MeCN; Mphase B: 20 mM NH4OAc in 10% H2O, 90% MeCN; Flow: 2.5 ML/min; Time: 0; % A: 100; % B: 0; Time: 1.8; % A: 0; % B: 100; RT min: 2.117, wavelength: 220 nm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([F:17])[CH:8]=1.[OH-].[Li+].CO>O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C2OCCCO2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2OCCCO2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.1 %

Procedure:
To a solution of EXAMPLE 22A (1. 9 g) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide (1 g) in water (5 mL). Methanol was added until homogeneous and the solution stirred at ambient temperature for 4 hours. The mixture was concentrated to 5 mL and the residue acidified to pH 2 with 2 N hydrochloric acid. Ethyl acetate and water were added and the organic phase separated, washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.7g, 95%). MS (DCI): m/z 227 (M+H)+.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[CH:56]=[CH:55][O:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[O:54]1[CH:55]=[CH:56][C:52]([C:49]2[CH:50]=[CH:51][C:24]([OH:23])=[C:25]([CH:48]=2)[C:26]([NH:28][C:29]2[CH:41]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[CH:38][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:53]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccoc2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccoc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.5 %

Procedure:
Thioanisole (1.6 mL) and trifluoroacetic acid (5.2 mL) were added to tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate (0.14 g), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and dioxane was added to the residue. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solid substance was collected by filtration to obtain 0.020 g of 2-(5-(furan-3-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][CH:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:32][CH:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: Nc1cc(OCc2ccccc2)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccccc2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
A solution of 4-amino-5-chloro-2-(phenylmethoxy)benzoic acid (2.78 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 11.5 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of 3-aminoquinuclidine (1.84 g, 14.6 mmol) in anhydrous tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo and rinsed with water in order to remove the remainins imidazole by-product. The residue was dried azeotropically with toluene, then taken up in tetrahydrofuran and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether/petroleum ethers (30°-60° C.), and recrystallized from ethyl acetate/hexane to afford 3.18 g (82%) of colorless solid; mp 170°-171° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12](O)=[O:13].[BH4-].[Na+].CS(O)(=O)=O.Cl>O1CCCC1.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CCO)cccc1[N+](=O)[O-]
Temperature: 67.5 °C
Yield: 97.6 %

Procedure:
A solution of 2-Methyl-3-nitro phenylaceticacid (160 g) in Tetrahydrofuran (480 ml) is added to Sodium borohydride (75 g) and Tetrahydrofuran (160 ml). Further, Methanesulfonicacid (53 ml) is added to reaction mixture at ambient temperature and stirred at 60-75° C. until the completion of reaction. 3N Hydrochloric acid (384 ml) is added to reaction mixture followed by addition of water (1420 ml). Reaction mixture is extracted twice with Dichloro methane (1×800 ml and 1×400 ml) and organic layer is separated. The combined organic layer is washed with NaHCO3 solution and brine solution. Dichloromethane is distilled out under vacuum at 40-50° C. to obtain 2-Methyl-3-nitro phenyl ethyl alcohol as dark brown oil (˜145 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:23])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][CH2:10]OC)=[CH:7][C:6]([O:13]C)=[C:5]([O:15][CH2:16]OC)[C:4]=1[CH:19](O)[CH2:20][C:21]1[C:26]([O:27][CH2:28]OC)=[C:25]([O:31]C)[CH:24]=[C:23]([O:33][CH2:34]OC)[C:22]=1[O:37]C.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+].O=O>FC(F)(F)C(O)=O.CO.C(OCC)(=O)C.CCCCCC>[CH2:19]([C:4]1[C:3](=[O:2])[C:8]([O:9][CH3:10])=[CH:7][C:6](=[O:13])[C:5]=1[O:15][CH3:16])[CH2:20][C:21]1[C:22](=[O:37])[C:23]([O:33][CH3:34])=[CH:24][C:25](=[O:31])[C:26]=1[O:27][CH3:28]
Reactant: COCOc1cc(OC)c(OCOC)c(CC(O)c2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC1=CC(=O)C(OC)=C(CCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Yield: 67.4 %

Procedure:
Under ice-cooling conditions, 302 mg of 1,2-bis[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethanol was dissolved in 5 ml of trifluoroacetic acid, then 0.4 ml of triethylsilane was added to the solution. This mixture was stirred under ice-cooling conditions for 2 hours. After concentrated the reaction mixture, benzene was added and the mixture was further treated under a reduced pressure. The residue thus obtained was dissolved in 5 ml of methanol, and a catalytic amount of sodium hydrogen carbonate was added thereto, and oxygen gas was blown into the reaction mixture. 2 Hours later, the reaction mixture was filtered, and the filtrate was concentrated under a reduced pressure. The residue obtained was treated by means of a thin layer chromatography (adsorbent: silica gel, manufactured by E. Merck A. G., size: 20 cm×20 cm, thickness: 2 mm, 2 plates were used, developping solvent: 30% ethyl acetate-n-hexane) to obtain 132 mg of 2,2'-ethylenebis(3,6-dimethoxy1,4-benzoquinone). Yellow oily substance.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[Br:6][C:7]1[C:8]([CH2:17]Br)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11]>C1COCC1>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:9]2[C:8]=1[CH2:17][N:2]([CH3:1])[C:10]2=[O:11]
Reactant: CN
Reactant: COC(=O)c1cccc(Br)c1CBr
Solvent: CCO
Solvent: C1CCOC1
Product: CN1Cc2c(Br)cccc2C1=O
Reaction time: 2 h

Procedure:
An 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2 h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2,3-dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3×100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74%). 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]([C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]2[CH2:21][C@@H:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]2)=[O:14])=[CH:4][CH:3]=1.N1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[CH:2]=[CH:3][CH:4]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:17]1)=[O:14]
Reactant: COCCCCn1c(Br)ccc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccn1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCCn1cccc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 124.8 %

Procedure:
A mixture of tert-butyl (3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (220 mg), pyridin-2-ylboronic acid (65 mg), sodium carbonate (370 mg), tetrakis(triphenylphosphine)palladium (40 mg), ethanol (2 ml), toluene (2 ml) and water (2 ml) was stirred at 80° C. for 12 hr. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate-water, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (240 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC([O-])(C)C.[K+].[CH3:27][N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1>C1COCC1>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([CH2:34][CH:30]2[CH2:31][CH2:32][CH2:33][N:28]([CH3:27])[CH2:29]2)[CH:2]=[CH:3]3)=[O:11])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C)C2)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(ccn3CC3CCCN(C)C3)c2)CC1
Yield: 96.5 %

Procedure:
A mixture of 1.06 g (3.9 mmol) (1H-indol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone (intermediate 1); 0.484 g (4.3 mmol) KOtBu and 1.33 g (4.7 mmol) toluene-4-sulfonic acid 1-methyl-piperidin-3-ylmethyl ester (intermediate 6) in 20 mL THF was shaken at 60° C. for 3 h. After evaporation of all volatiles a mixture ethyl acetate was added and washed with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a solvent mixture formed from DCM, methanol NEt3. The combined product fractions were evaporated to yield 1.44 g (91%) of the title compound as light yellow gum. MS(m/e): 383.5 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:43]>C1COCC1.CCOCC>[ClH:43].[NH:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:25](=[O:26])[C:24]2[CH:41]=[CH:42][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1CCNCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of example 29 (0.125 g, 0.222 mmol) in THF (1 ml), ether saturated with HCl (1.5 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as light yellow solid (0.105 g, 95%). M.P.: 220-224° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.14 (d, J=3.6 Hz, 1H), 8.90 (m, 3H), 8.72 (d, J=8.7 Hz, 1H), 8.67 (d, J=7.4 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.28 (m, 3H), 8.11 (dd, J=8.7, 1.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.89 (dd, J=8.3, 4.8 Hz, 1H), 6.29 (s, 2H), 4.11 (m, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.01 (m, 2H), 1.99 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](N)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.N(OC(C)(C)C)=O.[I:23]I>C(Cl)(Cl)(Cl)Cl>[I:23][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: II
Reactant: COc1ccc(-c2cnc(N)cn2)cc1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc(I)cn2)cc1
Temperature: 0 °C

Procedure:
In a light protected flask, 4.10 g (20.4 mmol) 5-(4-methoxyphenyl)-pyrazin-2-amine are added to 140 mL carbon tetrachloride. After cooling down to 0° C. 4.12 mL (34.6 mmol) tert-butyl nitrite and 6.72 g (26.5 mmol) iodine are added sequently. Then cooling is removed and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with DCM and washed sequently with aq. Na2S2O5 solution and water. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is triturated with TBME and purified by column chromatography (silica gel, PE/EtOAc 6/4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][C:7]=2[CH:8]=O)[CH2:3][CH2:2]1.[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][C:7]=2/[CH:8]=[CH:22]/[C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: COc1cc(OCC2CC2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC2CC2)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1

Procedure:
The title compound was prepared by condensing 2-cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-32B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 187–191° C. 1H-NMR (DMSO-d6) δ 8.22 (d, 2H), 8.19 (s, 1H), 7.01 (m, 4H), 7.62 (d, 1H), 7.47 (d, 1H), 7.09 (t, 1H), 6.76 (s, 1H), 4.06 (d, 2H), 3.94 (s, 3H), 1.34 (m, 1H), 0.62 (q, 2H), 0.38 (q, 2H). MS m/z=434 ([M]+, 82%), 363 (100%). 10%. Anal. for C25H22O5S. HRMS m/z: calc. 435.1266, found 435.1266.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(C(C)C)C(C)C.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([NH:11][CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:13][CH:12]=1)=[O:23]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitrophenethylamine hydrochloride (50 g, 0.247 mole), DIEA (128 mL, 0.74 mole, 3 eq.) and CH2Cl2 (500 mL) in a 1 L round bottom flask equipped with a magnetic stirrer was added (CF3CO)2O (52.5 mL, 0.37 mole, 1.5 eq) dropwise at 5-10° C. (with ice/water bath). After stirring for another 1 h after the addition at RT, the reaction was quenched with water (200 mL) and transferred into a separatory funnel. The organic layer was separated, washed with water and sat. NH4Cl, dried over Na2SO4, filtered, concentrated to give a brown oil. The crude was triturated with water (300 mL), filtered and dried on vacuum overnight to give the desired 2,2,2-trifluoro-N-[2-(4-nitro-phenyl)-ethyl]-acetamide as a yellow solid. This can be used for next step without further purification. An analytical sample was obtained through recrystallization from CH3OH/H2O as a yellow solid.