Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][C:5]1[CH:13]=[CH:14][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(N2CCNCC2)ccc1OC1CCCCO1
Yield: 85.5 %

Procedure:
A mixture of 2-(4-bromophenoxy)-tetrahydropyran (7.8 g, 30.3 mmol), piperazine (15.7 g, 180 mmol), palladium acetate (136 mg, 0.61 mmol), BINAP (567 mg, 0.91 mmol) and sodium tert-butoxide (3.8 g, 39.4 mmol) in toluene (50 ml) was refluxed under a nitrogen atmosphere for 2 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-[4-(tetrahydropyran-2-yloxy)phenyl]piperazine (6.8 g, yield 85%) as a pale gray powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:24])=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.ClC1C=CC(C(=C)CS(NC2C=CC=CC=2S(N)(=O)=O)(=O)=O)=CC=1.[H][H]>CO.[Pd]>[C:5]1([CH:8]([CH3:24])[CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:11])=[O:12])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: C/C(=C\S(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: C=C(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Solvent: CO
Product: CC(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccccc1
Yield: 32 %

Procedure:
A mixture of 2-[[(E)-2-(4-chlorophenyl)prop-1-enyl]sulfonylamino]benzenesulfonamide and 2-[2-(4-chlorophenyl)prop-2-enylsulfonylamino]benzenesulfonamide (40 mg, 0.11 mmol) was dissolved in methanol (3 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C, 2 runs). The product obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (13 mg, 32%) as a white solid.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.6 %

Procedure:
To a pre-cooled (ice bath) solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (201 mg, 0.37 mmol) and triethylamine (80 μl, 0.55 mmol) in anhydrous CH2Cl2 (4 mL) was added a solution of benzoylchloride (54 μl, 0.46 mmol) in anhydrous CH2Cl2 (0.5 mL) and the reaction mixture was allowed to stir at room temperature for 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL), washed with sat. aqueous NaHCO3 then brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) to give the desired amide (203 mg, 85%) as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)#[N:2].P([S-])(OCC)(OCC)=[S:32].C(=O)([O-])O.[Na+]>C(OC(=O)C)C.Cl>[NH2:2][C:1](=[S:32])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CCOP(=S)([S-])OCC
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(CCC#N)cc(C(F)(F)F)c3)cs2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(CCC(N)=S)cc(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution (13 mL) of the compound (2.8 g, 6.5 mmol) obtained in Example 96b in 4N hydrogen chloride ethyl acetate was added O,O-diethyl dithiophosphate (1.8 g, 9.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (2.0 g, 66%) as a colorless amorphous form.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21])=[O:15].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])=[O:15]
Reactant: COCC(=O)Nc1cccc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(C=O)c1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a mixture of 11.40 g of oxalyl chloride and 200 ml of dichloromethane was added dropwise a solution of 14 ml of dimethyl sulfoxide in 30 ml of dichloromethane at −60° C. for 15 minutes. After stirred at −60° C. for 10 minutes, a solution of 15.88 g of 3-(methoxyacetylamino)benzyl alcohol in 70 ml of dichloromethane was added dropwise at −60° C. for 20 minutes. After stirred at −60° C. for 10 minutes, 24.82 g of triethylamine was added dropwise at −60° C. for 20 minutes. After stirred at room temperature for 45 minutes, 500 ml of water was added to the reaction solution, followed by extraction with 300 ml of ethyl acetate. The organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to obtain 14.93 g of 3-(methoxyacetylamino)benzaldehyde [Compound No. (a)] as a white crystal.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:29].CO>>[ClH:29].[NH:8]1[CH2:11][CH:10]([C:12]2[C:21]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1
Reactant: Cc1cccc(-c2nc3ccccc3nc2C2CN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: CO
Product: Cc1cccc(-c2nc3ccccc3nc2C2CNC2)c1
Yield: 98.8 %

Procedure:
A solution of 3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (69) (637 mg, 1.7 mmol) in 4N HCl/MeOH (25 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (70) (523 mg, 1.68 mmol, yield 98.8%).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)CC.Cl[C:35]1[N:36]=[CH:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH:29][C:35]5[N:36]=[CH:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=5)[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: Cl
Solvent: CCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](Nc5cnc(C#N)cn5)C4)n23)cc1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
To a microwave vessel was added (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.500 g, 1.06 mmol), n-propanol (10 mL), 5-chloropyrazine-2-carbonitrile (0.223 g, 1.60 mmol) and DIEA (0.837 mL, 4.79 mmol). The resulting mixture was heated in a microwave at about 150° C. for about 30 min. DCM (100 mL) was added and a solution was formed. The organic solution was washed with water and brine (50 mL each), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a brown solid. The residue was taken up in DCM (30 mL) and adsorbed onto silica gel (5 g). The material was purified by silica gel chromatography (80 g cartridge) eluting with neat EtOAc to give 5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl-amino)pyrazine-2-carbonitrile (0.43 g, 80%) as a light yellow solid: LC/MS (Table 2, Method d) Rt=1.40 min; MS m/z: 500 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:18])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:24]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:16]([Br:24])=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:18])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(Cl)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 70 °C
Yield: 84 %

Procedure:
The product from Step 2 (3 g, 11.6 mmol) was suspended in acetic acid (50 mL) and sodium acetate (1.4 g, 17.3 mmol) and the mixture cooled in an ice bath while bromine (3.6 mL, 69.3 mmol) was added dropwise. After the addition was complete, the mixture was heated at 70° C. under a nitrogen atmosphere for 5 h and then allowed to cool to room temperature. The mixture was poured onto 50 mL of a 10% aqueous Na2S2O3 solution, and the whole reduced in vacuo to approximately 10 mL and then neutralized with 2 N NaOH solution. The organics were extracted with dichloromethane (3×150 mL), washed with water (100 mL) and brine (100 mL) and then dried (MgSO4) and evaporated to a yellow solid. Trituration of the solid with ether and filtration provided an off-white solid of 9-benzyl-8-bromo-2-chloro-9H-purin-6-ylamine (3.3 g, 85%) which was found to be sufficiently pure to be used with no further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[F:21].N>>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)ccc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-3-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 7.78 (dd, J=8.3, 7.5 Hz, 1 H), 8.07 (ddd, J=8.3, 2.0, 0.8 Hz, 1 H), 8.12 (dd, J=9.5, 2.0 Hz, 1 H), 8.55 (dt, J=7.9, 2.0 Hz, 1 H), 8.74 (dd, J=5.0, 1.8 Hz, 1 H), 9.28-9.30 (m, 1 H) ppm; MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1.O.O.Cl[Sn]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(Cl)ccc1N

Procedure:
A mixture of (5-chloro-2-nitro-phenyl)-methyl-amine (59) (500 mg, 2.7 mmol, 1 eq), SnCl2.2H2O (3.0 g, 13.3 mmol, 5 eq) in ethyl acetate (25 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated potassium carbonate solution. The organic phase was concentrated and the crude residue was purified with flash chromatography to give 4-chloro-N2-methyl-benzene-1,2-diamine (60).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[N:17][CH:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.N1C2C3N=CC=NC=3C=CC=2N=C1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[C:53]=1[OH:59]>CN(C=O)C>[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[C:53]=1[O:59][C:2]1[C:3]2[N:4]([CH:16]=[N:17][CH:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2
Reactant: COc1cc2nc(Cl)c3cncn3c2cc1OC
Reactant: Cc1cccc(Cl)c1O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Oc3c(C)cccc3Cl)c3cncn3c2cc1OC

Procedure:
A mixture of 4-chloro-7,8-dimethoxyimidazo[1,5-a]quinoxaline, prepared as described in U.S. application Ser. No. 09/097,338, “Imidazoquinoxaline Protein Tyrosine Kinase Inhibitors,” filed by Joel C. Barrish et al. concurrently herewith (20 mg, 0.076 mmol), potassium carbonate (52 mg, 0.38 mmol) and 2-chloro-6-methylphenol (13 mg, 0.091 mmol) in 0.5 mL of dry DMF was heated at 80° C. overnight. Upon cooling, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 9.0 mg of the title compound as a tan solid. HPLC Ret. time=4.075 min (HPLC Conditions: 0% B to 100% B; 4 minute gradient; 2 minute hold; 4 mL/min.; 254 nm; YMC S5 C18 Rapid Resolution column 4.6×50 mm; A: 90% H2O −10% MeOH−0.2% H3PO4; B: 10% H2O−90% MeOH−0.2% H3PO4).
Reaction SMILES: [Na].Cl[C:3]1[CH:14]=[C:13]([CH:15]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)[OH:16])[C:6]2[O:7][C:8]([CH3:12])([CH3:11])[O:9][CH2:10][C:5]=2[CH:4]=1.[Cl-].[NH4+].CO>N.C1(C)C=CC=CC=1>[CH3:11][C:8]1([CH3:12])[O:7][C:6]2[C:13]([CH:15]([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[OH:16])=[CH:14][CH:3]=[CH:4][C:5]=2[CH2:10][O:9]1
Reactant: CC1(C)OCc2cc(Cl)cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)OCc2cccc(C(O)c3c[nH]cn3)c2O1
Yield: 33.6 %

Procedure:
5.75 g (0.25 mole) of sodium are added piece by piece to a suspension of 21.46 g (0.04 mole) of alpha-(6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-1-triphenylmethyl-1H-imidazole-4-methanol (prepared in Example 1.C.3.) in 2 liters of ammonia and 200 ml of toluene. stirring is maintained for 40 minutes, then the reaction mixture is decomposed by the addition of 6.42 g (0.12 mole) of ammonium chloride. 500 ml of toluene containing 10% of methanol are added thereto, the ammonia is evaporated and 500 ml of water are added thereto. The toluene phase is decanted off, dried over anhydrous sodium sulfate and then distilled. The residue, containing triphenylmethane, is partly dissolved in 50 ml of water containing 3.3 ml of concentrated hydrochloric acid and the suspension obtained is extracted with diethyl ether. The aqueous phase is subsequently adjusted to pH 8 by the addition of sodium bicarbonate, then extracted with dichloromethane. Subsequently, the solvent is removed by distillation to give 3.5 g of alpha-(2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-1H-imidazole-4-methanol. Yield: 33% of theory. The product formed a hydrochloride (recrystallizable in a 1:1 v/v ethanol-diethyl ether mixture) which has a glassy appearance and which does not have a sharp melting point.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15]>CN(C)C=O>[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:12][C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)=[O:13])#[N:15]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cccc2[nH]c(C(=O)O)cc12
Solvent: CN(C)C=O
Product: Cc1cccc2[nH]c(C(=O)OCc3cccc(C#N)c3)cc12
Yield: 75 %

Procedure:
The starting material was 4-methyl-1H-indole-2-carboxylic acid. Alkylation with 3-cyano-benzylbromide (analogously to example 19/1, but the solvent was dimethylformamide instead of tetrahydrofuran) gave 4-methyl-1H-indole-2-carboxylic acid 3-cyano-benzyl ester. Yield: 75%. MS: 291.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[SH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](=[O:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10][CH2:18][C:19]([CH3:20])=[O:21]
Reactant: CC(=O)CBr
Reactant: Fc1cc(S)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CSc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-Bromo-4,5-difluorobenzenethiol (900 mg, 4.00 mmol) and potassium carbonate (1.11 g, 8.00 mmol) were suspended in DMF (20 mL), and bromoacetone (0.403 mL, 4.80 mmol) was added thereto, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: BrCC#CC[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].N1C=CN=C1.[Na]>CN(C)C=O>[C:7]1(=[O:16])[C:8]2[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:11])[NH:6]1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCBr
Agent: [Na]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A mixture of 27.8 g. of N-(4-bromo-2-butynyl)phthalimide, 9.0 g. of sodium imidazole and 150 ml. of dimethylformamide is heated at 80° C. for 3 hours and then concentrated to remove the solvent. The residue is extracted with 500 ml. of hot toluene and the toluene layer is concentrated to a viscous oil which is further purified by HPLC, developed with ethyl acetate to obtain 2-[4-(1H-imidazol-1-yl)-2-butynyl)]-1H-isoindole-1,3(2H)-dione, m.p. 139°-141° C.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].O/[N:12]=[C:13](\Cl)/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>CO>[CH2:9]([O:8][C:2]([C:3]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:12][O:5][C:4]=1[CH3:6])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: O/N=C(\Cl)c1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)noc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a suspension of sodium (2.67 g, 116 mmol) in methanol (100 mL) was added ethyl acetoacetate (12.8 g, 11.9 mL, 110 mmol) at room temperature over 15 minutes and then a a solution of (E)- and/or (Z)—N-hydroxy-3-chloro-benzenecarboximidoyl chloride (19.0 g, 100 mmol) in methanol (100 mL) was added over 20 minutes and the resulting mixture allowed to stir for 4 h at room temperature. The mixture was then poured onto water and cooled to 5° C., filtered and evaporated. Purification by recrystallisation from ethanol afforded the title compound (10.1 g, 40%) which was obtained as a white solid. Mp: 71-73° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([CH3:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[CH3:35])=[O:22])[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([CH3:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:25]([CH3:35])=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][C:33]=2[CH3:34])=[O:22])[CH2:11]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of methyl 4-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-2-methyl-benzoyl]amino]-3,5-dimethyl-benzoate (0.40 g, 0.76 mmol) in THF (10 ml) is added Bu4NF 1.0 M in THF (0.39 g, 1.52 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 1 hour, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 4% MeOH in dichloromethane to afford the title compound as a light brown solid (0.30 g, 96%). Mass spectrum (m/z): 411.5 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:11]1[CH:10]=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(OCCCC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc(Br)c(OCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
80 g of 1,3-dibutoxybenzene (0.36 mol) are dissolved at room temperature in 100 ml of carbon tetrachloride. 64.25 g of N-bromosuccinimide (0.36 mol) are introduced in portions over 30 minutes such that the temperature can be maintained between 20° C. and 30° C. When the addition is complete, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered over kieselguhr and the solvent is removed completely by concentration. The crude product (110 g) is fractionated on a 10 cm Vigreux column at 10-1 mbar. In this way, 65 g of 1-bromo-2,4-dibutoxybenzene with a boiling point of 112° C. at 10.1 mbar are obtained as a yellowish oil in 60% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>N1C=CC=CC=1CO>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([O:3][CH2:1][C:2]4[CH:7]=[CH:8][CH:9]=[CH:4][N:5]=4)=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: OCc1ccccn1
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccn3)[nH]c(=O)c2nn1C
Temperature: 110 °C
Yield: 91 %

Procedure:
A mixture of the title compound of Example 78 (100 mg, 0.2 mmol), potassium bis(trimethylsilyl)amide (210 mg, 1.1 mmol) in pyridine-2-methanol (1 ml) was heated to 110° C. for 18 hours. The cooled mixture was partitioned between ethyl acetate (10 ml) and water (10 ml), and the phases separated. The aqueous layer was extracted with ethyl acetate (2×5 ml) and dichloromethane (10 ml), the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using methanol:ethyl acetate (10:90) as eluant, and triturated with ether, to afford the title compound (49 mg, 43%) as a solid.