Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[C:10]([Br:12])[C:9]([F:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:28])[C:24]([O:26]C)=[O:25]>O.CO>[Br:12][C:10]1[C:9]([F:13])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([NH:2][CH:23]([C:24]([OH:26])=[O:25])[CH3:28])[CH:11]=1
Reactant: Nc1cc(Br)c(F)cc1C(=O)O
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(Nc1cc(Br)c(F)cc1C(=O)O)C(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To a mixture of 2-amino-4-bromo-5-fluorobenzoic acid, hydrochloride (D85) (1.5 g, 5.55 mmol) in water (10 mL) was added sodium hydroxide (0.444 g, 11.09 mmol) followed by potassium carbonate (1.533 g, 11.09 mmol). A solution of methyl 2-bromopropionate (0.619 mL, 5.55 mmol) in MeOH (10.00 mL) was added to the mixture and the mixture was then heated at 80° C. for 24 hours. LCMS showed reaction was not complete with remaining significant amount of starting material. Further methyl 2-bromopropionate (0.619 mL, 5.55 mmol) was added to the mixture and the mixture was then stirred for 24 hours at 80° C. 6M aqueous sodium hydroxide (4.62 mL, 27.7 mmol) was added to the mixture and the mixture was then heated at 100° C. for 1.5 h. After cooling to RT, MeOH was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (20 mL). The aqueous layer was cooled to 0° C. and was then acidified with addition of concentrated HCl. The formed precipitate was filtered, washed with water and collected to give title compound (1.78 g). LCMS (A): m/z (M+H)+ 306/308, C10H9BrFNO4 requires 305/307 (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][CH:10]1[NH:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:15]2[CH:10]([CH3:9])[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Solvent: CS(C)=O
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1c1cccc(Br)n1
Temperature: 95 °C
Yield: 39 %

Procedure:
A solution containing 2-bromo-6-fluoropyridine (0.95 mL, 6.65 mmol and tert-butyl 6-methylpiperidin-3-ylcarbamate (750 mg, 3.32 mmol) in methyl sulfoxide 5.0 ml was heated 95° C. 18 h. The reaction was quenched with water then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 30% EtOAc) to give tert-butyl N-[1-(6-bromo-2-pyridyl)-6-methyl-3-piperidyl]carbamate (480 mg) in 39% yield. MS (ESI) m/z: 371.2
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:23]=2[S:24][C:25]=1[CH3:26])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[S:10][C:3]=34)=[CH:27][C:23]=2[S:24][C:25]=1[CH3:26])=[O:20]
Reactant: CNC(=O)c1c(C)sc2cc(O)ccc12
Reactant: Clc1ccnc2cc(CN3CCCC3)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4cc(CN5CCCC5)sc34)ccc12

Procedure:
This material was prepared from 7-Chloro-2-(pyrrolidin-1-ylmethyl)thieno[3,2-b]pyridine 115a, 6-hydroxy-2-methyl-benzo[b]thiophene-3-carboxylic acid methylamide 1d and cesium carbonate in a similar manner as described in example 1. 1H-NMR (DMSO-d6, 400 MHz) δ 8.44 (1H, d, J=5.3 Hz), 8.27 (1H, q, J=4.6 Hz), 7.91 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.6 Hz), 7.43 (1H, s), 7.28 (1H, dd, J=2.3, 8.6 Hz), 6.60 (1H, d, J=5.6 Hz), 3.93 (2H, s), 2.82 (3H, d, J=4.8 Hz), 2.60 (3H, s), 2.54 (4H, bs), 1.72 (4H, s); MS m/z 438 (M+H)+;
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[O:13]=[CH:14][C:15](=[CH2:17])[CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[CH3:17][C:15](=[CH2:16])[CH:14]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:13]
Reactant: C=C(C)C=O
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)C(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To toluene (12 mL) were added dropwise at −78° C. n-butyllithium (2.76 mol/L solution in n-hexane, 4.14 mL, 11.4 mmol) and a solution of 3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (4.0 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (4.0 mL) was added to the resulting suspension. After stirring at −78° C. for 15 minutes, methacrolein (1.03 mL, 12.5 mmol) was added, and the mixture was stirred for 1 hour allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.08 g, 70% yield).
Reaction SMILES: [Br:1]Br.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][O:4]1>ClCCl>[Br:1][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH:3]=[O:4]
Reactant: BrBr
Reactant: c1ccc2c(c1)CCOC2
Solvent: ClCCl
Product: O=Cc1ccccc1CCBr
Yield: 86.3 %

Procedure:
Bromine (29.6 g, 185.2 mmols) in dichloromethane (20 ml) was added to isochroman (25 g. 186.0 mmol) in dichloromethane (150 ml) over one hour in the presence of a strong light source at such a rate that the reaction temperature was about 35° C. The mixture was left for a further hour in the presence of the light source, keeping the temperature of the mixture below 40° C. The mixture was concentrated under reduced pressure to give a heavy yellow oil. This was then left on an oil bath at 80° C. under nitrogen for one and a half hours. The crude product was dissolved in dichloromethane (150 ml). Washed with water (100 ml). Saturated sodium bicarbonate (30 ml) was made up to 100 ml with water and this was used to wash the organic layer. This layer was again washed with water and then dried (Mg2SO4). Excess solvent was removed under reduced pressure to give a heavy yellow oil of 2(2' -bromoethyl)benzaldehyde 34.07 g (88 9%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([C:35]3[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:32]=[CH:33][CH:34]=2)O1>CN(C)C(=O)C.O.C(=O)([O-])O.[Na+].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>[CH:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:33]3[CH:32]=[C:31]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:30]=[CH:29][CH:34]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1)=[O:12]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: O=Cc1ccn2c(Br)cnc2c1
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: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Trifluoromethanesulfonic acid 2′-cyanobiphenyl-3-yl ester (0.55 g, 1.66 mmol), potassium acetate (0.49 g, 4.98 mmol) and bis(pinacolato)diboron (0.55 g, 2.16 mmol) were dissolved in 1,4-dioxane (10 ml) and the mixture degassed with N2 for 15 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (41 mg, 0.05 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (28 mg, 0.05 mmol) were then added and the mixture heated at 85° C. for 18 h. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to give 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as a black oil (0.51 g, 100%). This oil was dissolved in sufficient N,N-dimethylacetamide to give a 0.5 M stock solution. 3-Bromoimidazo[1,2-α]pyridine-7-carboxaldehyde (0.70 g, 3.11 mmol), potassium phosphate (0.99 g, 4.67 mmol) and 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (1.80 g, 5.90 mmol) were dissolved in N,N-dimethylacetamide (6 ml) and the mixture degassed with N2 for 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) was added and the mixture heated at 80° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water (20 ml) and saturated sodium hydrogencarbonate solution (20 ml), then extracted with ethyl acetate (3×75 ml). The combined organic fractions were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give a black oil. The oil was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-3%). The solid obtained was triturated with diethyl ether which gave the title compound (0.33 g, 29%) as a yellow powder. 1H NMR (400 MHz, CDCl3) δH 7.41 (1H, dd, J 7 and 1), 7.52 (1H, dt, J 8 and 1), 7.58 (1H, d, J 7), 7.62-7.73 (4H, m), 8.81-8.44 (2H, m), 7.98 (1H, s), 8.18 (1H, d, J 1), 8.63 (1H, d, J 7), 10.03 (1H, s); m/z (ES+) 324 (M++H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]1[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: O=CC(Cl)(Cl)Cl
Product: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21

Procedure:
Salicylamide (40.0 g.) and anhydrous chloral (400 ml.) were heated together on a steam-bath for 3 hours, the reaction mixture was cooled, and the excess of chloral was evaporated under reduced pressure. The syrupy product was mixed with concentrated sulphuric acid (500 ml.) and heated on a steam-bath for 1 hour. The mixture was cooled and poured into crushed ice (3 kg.), and the precipitated solid was filtered off, triturated with diethyl ether (300 ml.) and filtered again. The solid product was stirred with water (1 l.), filtered, washed well with water, dried and crystallised from ethanol (400 ml.) to yield 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 175°-177° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[CH:5][C:4]([CH3:9])=[N:3]1.S(Cl)(Cl)=O.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([S:15]([Cl:14])(=[O:17])=[O:16])[C:4]([CH3:9])=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C)nn1C
Solvent: O=S(Cl)Cl
Product: COc1c(S(=O)(=O)Cl)c(C)nn1C
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Into 70 ml of chlorosulfonic acid was added dropwise under cooling at 5° C. or lower 12.6 g (0.1 mol) of 1,3-dimethyl-5-methoxypyrazole. After the addition, the mixture was stirred at 100° C. for 8 hours. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 11.9 g (0.1 mol) of thionyl chloride over 30 minutes. After the dropwise addition, the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled and poured carefully into ice-water, whereby crude 1,3-dimethyl-5-methoxy-pyrazole-4-sulfonylchloride was formed as crystals The crystals were separated by filtration, dissolved in 20 ml of tetrahydrofuran and the resultant solution was added dropwise into 100 ml of aqueous ammonia (28%) at 10° C. or lower. After the addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure to remove low boiling components, whereby crystals were precipitated. The crystals were filtered, washed with water and dried to give 11.5 g of 1,3-dimethyl-5-methoxypyrazole-4-sulfonamide melting at 144°-146° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[N:8]=1
Reactant: COC(=O)c1ccc(C=CCC2CCCCC(=O)N2)o1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CCC2CCCCC(OC)=N2)o1

Procedure:
The product of Example 177 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:15]=[N:16][N:17]([C:2]2[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]3[CH:10]=[CH:9][NH:8][C:7]=23)[CH:18]=1
Reactant: COc1cnc(Br)c2[nH]ccc12
Reactant: Clc1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(-n2cc(Cl)cn2)c2[nH]ccc12
Temperature: 100 °C
Yield: 72.3 %

Procedure:
To a sealable flask containing 7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine (1 g, 4.40 mmol) was added 4-chloro-1H-pyrazole (0.903 g, 8.81 mmol), potassium carbonate (2.435 g, 17.62 mmol), copper(I) iodide (0.419 g, 2.202 mmol), and trans-1,2-bis(methylamino)cyclohexane (0.626 g, 4.40 mmol). The mixture was diluted with 1,4-Dioxane (15 mL) and was sealed and heated to 100° C. for 3 h. The mixture was cooled to rt and was filtered through a pad of celite to remove any solids. The organic solution as concentrated under reduced pressure, and the residue was purified by flash chromatography to give 7-(4-chloro-1H-pyrazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridine (0.79 g, 3.18 mmol, 72.1% yield) as an off-white solid. LCMS: m/e 249.12 (M+H)+, ret time 2.851 min (method 4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Yield: 47.3 %

Procedure:
A mixture of methyl 3-cyano-4-hydroxybenzoate (D22; 120 mg, 0.677 mmol), (bromomethyl)cyclopropane (Aldrich; 0.099 ml, 1.016 mmol), and potassium carbonate (140 mg, 1.016 mmol) in dry N,N-dimethylformamide (DMF) (2 ml) was heated under microwave irradiation at 150° for 90 mins. The cooled mixture was partitioned between water (30 ml) and ethyl acetate (3×25 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a light brown crystalline solid which was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (74 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]=2[CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37]CC)=[O:36])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]=2[CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([OH:37])=[O:36])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccccn3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccccn3)cc12
Temperature: 23 °C
Yield: 86 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(pyridin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (98 mg, 0.17 mmol) in THF (1 mL), MeOH (1 mL), and 6M aqueous NaOH (0.75 mL) is heated at 50° C. for 3 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is partitioned between CH2Cl2 and brine then the organics are collected and dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (80 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH3:17][CH2:18]O>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-4-hydroxyphenylacetic acid (1.19 g, 5 mmol, 1 eq.) in EtOH (15 mL), thionyl chloride (0.73 mL, 10 mmol, 2 eq.) was added. The reaction mixture was stirred at r.t. during 1 h 30. The mixture was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and sat. aq. NaHCO3 soln. (50 mL). The layers were separated and the aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a pale yellow oil. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:9]12[CH2:16][NH:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2>>[Cl:8][C:6]1[CH:7]=[C:2]([N:11]2[CH2:12][CH:13]3[CH:9]([CH2:16][NH:15][CH2:14]3)[CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: C1NCC2CNCC12
Reactant: Clc1cncc(Cl)c1
Product: Clc1cncc(N2CC3CNCC3C2)c1

Procedure:
3,5-Dichloropyridine (1 eq.), 3.7-Diazabicyclo[3.3.0]octane (1 eq.) and palladacycle (0.2%) [Herrmann W A, Brossmer C, Öfele K, Reisinger, C-P, Priermeier, T, Beller M, and Fischer, H; Angew. Chem. Int. Ed. Enql. 1995 34 1844] is stirred at 160° C. for 24 hours. Workup-procedure A/B.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C@@H:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8]([OH:10])=[O:9]>C(O)(=O)C>[C:8]([O:10][C@@H:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8]([OH:10])=[O:9])(=[O:9])[CH3:7]
Reactant: COCC[C@H](N)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC[C@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.8 %

Procedure:
Sodium nitrate (4.93 g, 57.98 mmol) was added portionwise to (S)-2-amino-4-methoxybutanoic acid (CAS no. 3311-01-1) (3.86 g, 29.0 mmol) in acetic acid (88 mL) at room temperature (with intermittent cooling with an ice bath to keep the temperature near to room temperature). Once the addition was complete, the mixture was left to stir at room temperature for 24 h. The solvent was then removed in vacuo, the residue was dissolved in ether (250 mL), and the ethereal solution was washed with water (3×100 mL). The organic layer was extracted with saturated NaHCO3 solution (3×100 mL). The aqueous extracts were then acidified with 2N HCl and extracted with ether (3×100 mL). The combined organic layers were dried (MgSO4) and reduced in vacuo to give crude (S)-2-acetoxy-4-methoxybutanoic acid (0.600 g, 11.8%) which was used without further purification.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[OH:19].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[OH:19])[NH:18][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(Nc1ccc(O)c(Cl)c1)c1ccccc1O
Yield: 97.6 %

Procedure:
Salicylic acid (1.38 g.) and 2-chloro-4-aminophenol (1.44 g.) were dissolved in acetonitrile (130 ml.), to which with stirring was added as a dehydrating agent dicyclohexyl carbodiimide (1.88 g.) and stirring was continued for about an hour. The precipitated dicyclohexylurea was filtered off, rinsed with warm acetone (90 ml.), and the filtrate and the rinse were combined and evaporated to dryness under reduced pressure. A light brown powder (2.57 g.) of 3'-chloro-2,4'-dihydroxybenzanilide was obtained which was purified through column chromatography using silica-gel (Mallinkrodt Co., U.S.A.) and an ethyl acetate-methanol mixture as the elution solvent system to give needle-like crystals (0.18 g.) of 3'-chloro-2,4'-dihydroxybenzanilide. Yield: 7%. The melting point: 172.5° 173.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 78 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 78%). 1H NMR (300 MHz, CDCl3): δ 2.44-2.47 (m, 3H), 3.19-3.26 (m, 4H), 3.78 (s, 3H), 4.12 (s, 4H), 6.87 (d, J=8.9 Hz, 2H), 7.01-7.11 (m, 1H), 7.22-7.26 (m, 3H), 7.52-7.61 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([N+:15]([O-])=O)=[C:6]([C:10](Br)=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=O.[OH-].[Na+]>[Pd]>[CH3:13][C:12]1[C:4]2[NH:3][CH:1]=[N:15][C:5]=2[C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: Cc1cc(Br)c(C(=O)O)c([N+](=O)[O-])c1NC=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)c2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 3-(Formylamino)-6-bromo-4-methyl-2-nitrobenzoic Acid (21) (1.055 g, 3.68 mmol) and palladium on carbon (10% Pd/C, 0.228 g) in aqueous NaOH (0.294 g, 7.35 mmol of solid NaOH in 100 mL of H2O) is hydrogenated under hydrogen pressure (40 psi) for about 16 hours. The reaction mixture is cooled to ambient temperature and filtered through a pad of Celite. The filtrate is acidified with HCO2H (about 25 mL) and heated to reflux for about 2 hours. The reaction mixture is cooled and concentrated in vacuo to give a beige solid. The solids are triturated in hot methanol (50 mL), cooled slowly to ambient temperature, and filtered to give 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22), as beige solid (0.495 g, 81% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=C=N.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH:23]=[C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:16]=1>C(Cl)Cl>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH:23]=[C:24]2[CH2:25][CH2:26][N:27]([C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:28][CH2:29]2)[N:16]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C(O)Cc1ccccc1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1cccc(C#CC=C2CCN(C(=O)Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of phenylacetic acid (61.5 mg, 0.452 mmol) in 10 mL di CH2Cl2 was added PS-carbodiimide 1.25 mmol/g (480 mg, 0.6 mmol), while gently stirring at r.t. After 20 min., the Compound of Example 3 (64 mg, 0.301 mmol) was added. A very slow stirring was maintained overnight. Filtration, followed by washing the resin with CH2Cl2 and evaporation afforded a crude which was purified by flash chromatography (CHCl3-1.4 N MeOH/NH3 100:0.2) yielding the title product (80 mg).