Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cccc2nc3ccc4c(OCc5ccccc5)cccc4c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (80 mg), sodium hydroxide (34 mg) and benzyl bromide (100 μL) in ethanol (2 mL) was heated to reflux for 4 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with dilute acid, dried (MgSO4) and the solvent removed in vacuo to yield the crude title compound as a brown solid (50 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.CCN(CC)CC.C(Cl)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.[N+](C1C=CC(OC(=O)[NH:71][C:72]2[CH:77]=[CH:76][C:75]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[CH:74][CH:73]=2)=CC=1)([O-])=O.C(NCC)C>C(Cl)Cl>[N:78]1([C:75]2[CH:74]=[CH:73][C:72]([NH:71][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]6[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]6)=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:77][CH:76]=2)[CH2:79][CH2:80][O:81][CH2:82][CH2:83]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCNCC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-[7-(3-piperazin-1-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.05 mmol), prepared as described in Example 118, was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.05 mmol) followed by FMOC-Cl (0.1 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), as prepared by the method outlined in Example 66a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain the pure product. This was dissolved in anhydrous DCM (1 mL) and diethylamine (0.25 mL) was added and the mixture was stirred at rt overnight. It was then concentrated in vacuo and purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain 2.8 mg (10%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.13 (s, 1H), 8.05 (d, 1H), 7.35-7.23 (m, 4H), 6.88 (d, 2H), 6.35 (s, 1H), 4.32-4.14 (m, 4H), 3.90-3.80 (m, 4H), 3.75-3.60 (m, 1H), 3.20-2.91 (m, 10H), 2.75-2.55 (m, 6H), 2.18-1.85 (m, 7H). LC/MS (ESI): 560.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:11]2[CH2:13][CH2:12]2)[CH:9]=O)[C:3]=1[CH3:14].N1CCC[CH2:17][CH2:16]1.C(O)(=O)C.C([C:27](CC)([C:31]([O-:33])=O)[C:28]([O-:30])=[O:29])C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:4]([C:3]=1[CH3:14])=[C:8]([CH:11]1[CH2:13][CH2:12]1)[CH:9]=[C:27]([C:28]([O:30][CH2:16][CH3:17])=[O:29])[C:31]2=[O:33]
Reactant: Cc1c(Cl)ccnc1C(C=O)C1CC1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Temperature: 100 °C

Procedure:
1.31 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropylethanal (XII) was dissolved in 45 ml of anhydrous ethanol, and 1.48 ml of piperidine, 1.48 ml of acetic acid and 4.75 ml of diethylmalonate were added thereto and the resulting mixture was heated at 100° C. for 5 hours. The solvent was distilled off under reduced pressure, and thereafter, the resulting mixture was diluted with ether and the resulting organic layer was washed with water and saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. 30 ml of Dowtherm A was added to the resulting residue, which was heated at 240° C. for 30 minutes. The reaction solution was purified directly by silica gel column chromatography (eluent; hexane hexane:ethyl acetate=1:1) to obtain 1.45 g of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (XIII).
Reaction SMILES: [OH2:1].[PH2]([O-])=O.C([NH+](CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]#N)[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1>[Ni].ClCCl.CO>[Cl:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:1])[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C#N)cc1Cl)CC2
Reactant: O
Agent: [Ni]
Agent: CC[NH+](CC)CC
Agent: O=[PH2][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C=O)cc1Cl)CC2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a hydrogenation reactor under an argon atmosphere, triethylammonium hypophosphite hydrate (2.2 mL, 12 mmol) is added at 10° C. to a suspension of Raney nickel (8 g, 93 mmol) in 75 mL dichloromethane and 75 mL methanol. After the release of gas has died away N-[1-(2-chloro-4-cyanophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide (PCT/EP05055021) (2.7 g, 5.6 mmol) is added and the mixture is stirred for 3 h at 55° C. The reaction mixture is filtered and the filtrate is evaporated down. The residue is purified on silica gel with dichloromethane/methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(O)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 77.1 %

Procedure:
6,7-Dimethoxy-quinazolin-4-ol (1.00 g, 4.85 mmol, 1 eq.), phosphorous oxychloride (4.07 mL, 43.6 mmol, 9.00 eq.) and triethylamine (6.08 mL, 43.6 mmol, 9 eq.) were refluxed for 2 hours. Stripped then restripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 to 3:1 Hexanes/EtOAc. Obtained 0.84 g of off-white solids as product. LCMS detects (M+H)+=225.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.O>C(Cl)Cl>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([OH:6])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.8 %

Procedure:
A methylene chloride solution of boron tribromide (18.5 ml, 18.5 mmol) was added to a solution of 5-methoxy-1H-indazole (1.24 g, 8.40 mmol) in methylene chloride (84 ml) at 0° C. and stirred at room temperature for 10 hours. Then, water was poured into the reaction solution in an ice-water bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=96/4) to obtain 1H-indazol-5-ol (877 mg, 71%).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:25](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:26].[CH3:38][C:39]1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([N:15]([CH2:38][CH3:39])[C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reaction time: 22 h
Yield: 15 %

Procedure:
A solution of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 50 ml dimethylformamide was treated with 0.05 g (0.001 mol) sodiumhydride(55%) for 15 minutes at room temperature. Then 0.22 g (0.001 mol) ethyl-p-toluenesulfonate were added and stirring was continued for 22 hours. Addition of sodiumhydride and p-toluenesulfonate was repeated three times. After each addition stirring was continued at 50° C. for 20 hours. Saturated aqueous sodiumbicarbonate was added and the mixture was extracted with dichloromethane. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 96/4 gave 0.05 g (15%) diethyl-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as yellow oil. MS m/e (%): 343 (M+, 59), 314 (100), 300 (73), 104 (51).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17](B5OC(C)(C)C(C)(C)O5)[CH:16]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1.Br[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.ClCCl.CO.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:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([C:31]5[C:32]([C:33]#[N:34])=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: CC1(C)OB(c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)OC1(C)C
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1
Temperature: 80 °C
Yield: 39 %

Procedure:
A degassed mixture of crude 6-(furan-3-yl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3H-imidazo[4,5-b]pyridine (85 mg), 2-bromobenzonitrile (54 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg) and potassium phosphate (85 mg, 0.4 mmol) in N,N-dimethylformamide (1.5 ml) was heated at 80° C. for 16 hours. The reaction was cooled to ambient temperature, diluted with dichloromethane (10 ml) and methanol (10 ml) and pre-adsorbed onto silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/concentrated ammonia (96:3.5:0.5) furnished the title compound as a cream-coloured solid (31 mg). This was converted to its oxalate salt and crystallised from hot ethanol; δH (400 MHz, d6-DMSO) 7.16-7.17 (1H, m), 7.66 (1H, td, J 8 and 1), 7.70-7.72 (1H, m), 7.78-7.81 (3H, m), 7.87 (1H, td, J 8 and 1), 8.02 (1H, dd, J 8 and 1), 8.17-8.19 (1H, m), 8.25-8.26 (1H, m), 8.36 (1H, s), 8.51 (1H, d, J 2), 8.78 (1H, d, J 2), 9.02 (1H, s); m/z (ES+) 363 (M++H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=3[OH:31])[CH2:18][CH2:17]2)[CH:10]=1.[C:32](Cl)(=[O:34])[CH3:33].O>ClCCl>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=3[O:31][C:32](=[O:34])[CH3:33])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3O)CC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1N1CCN(c2cc(C)cc(C)n2)CC1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
Triethylamine (1.0 mL, 7.17 mmol) was added to a solution of 2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-phenol (500 mg, 1.52 mmol) in dry dichloromethane (20 mL) followed by the dropwise addition of acetyl chloride (0.2 mL, 2.80 mmol). After stirring for 15 min water was added and the mixture warmed to room temperature. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phases were successively washed with water (2×30 mL) then brine (2×30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with 5% dichloromethane in petroleum ether (2×20 mL) to afford acetic acid 2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-phenyl ester (365 mg, 65%) as a pale brownish-yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][O:14][C:12]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]([CH:13]=1)[C:3]([OH:25])=[O:2]
Reactant: COC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
500 mg 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalic acid dimethyl ester were dissolved in 50 ml of MeOH:water/3:1. Then 1 g of lithium hydroxide monohydrate was added the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT and then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethylacetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: C[CH:2]([OH:8])[C:3](=[CH2:7])[CH:4](C)[OH:5].Cl[C:10]1[CH:11]=[C:12]([CH2:18][OH:19])[C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1>>[CH2:7]=[C:3]([CH2:2][OH:8])[CH2:4][OH:5].[C:12]1([CH2:18][OH:19])[C:13]([CH2:16][OH:17])=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: OCc1ccc(Cl)cc1CO
Reactant: C=C(C(C)O)C(C)O
Product: C=C(CO)CO
Product: OCc1ccccc1CO

Procedure:
Example 15 was repeated except for using 12.76 g (110 mmoles) of 1,3-dimethyl-2-methylene-1,3-propanediol and 8.62 g (50 mmoles) of 4-chloro-o-xylylene glycol, instead of 9.69 g (110 mmoles) of 2-methylene-1,3-propanediol and 6.91 g (50 mmoles) of o-xylylene glycol respectively, to obtain 8.34 g of spiro[7-chloro-1,5-dihydro-2,4-benzodioxepin-4'6'-dimethyl-5'-methylene-3,2'-[1,3]dioxane].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([NH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].C(N(CC)CC)C.O>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([NH:23][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[C:16]([O:15][CH2:13][CH3:14])=[O:24])[CH3:22]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(NC(=O)c1cc(F)ccc1Cl)C(=O)OCC
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 24.4 g of 2-chloro-5-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise to a solution of 26.8 g of aminomalonic acid diethyl ester hydrochloride and 38.6 ml of triethylamine in 50 ml of dichloromethane with cooling in an ice bath. The reaction mixture was stirred for 2 h while the temperature was maintained at 0-5° C. Then 100 ml of water were added slowly. The phases were separated, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 39.3 g of the crude title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.Cl.[NH2:14][C:15]1[CH:47]=[CH:46][C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]3[N:27]=[C:26]([CH2:28][O:29][C:30]4[CH:43]=[CH:42][C:33]([CH2:34][CH:35]5[S:39][C:38](=[O:40])[NH:37][C:36]5=[O:41])=[CH:32][CH:31]=4)[N:25]([CH3:44])[C:24]=3[CH:45]=2)=[CH:17][CH:16]=1>CN(C)C=O>[O:40]=[C:38]1[NH:37][C:36](=[O:41])[CH:35]([CH2:34][C:33]2[CH:42]=[CH:43][C:30]([O:29][CH2:28][C:26]3[N:25]([CH3:44])[C:24]4[CH:45]=[C:20]([O:19][C:18]5[CH:46]=[CH:47][C:15]([NH:14][C:8](=[O:10])[CH3:9])=[CH:16][CH:17]=5)[CH:21]=[CH:22][C:23]=4[N:27]=3)=[CH:31][CH:32]=2)[S:39]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.36 ml) and acetyl chloride (0.06 ml) were added to a solution of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) in anhydrous N,N-dimethylformamide (8 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=4:1→1:0→ethyl acetate:methanol=10:1 as the eluant to afford the title compound (320 mg, white amorphous, mp 92-95° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[CH:11][N:10]([CH3:25])[CH:9]=2)=[CH:4][CH:3]=1.[F:26][S:27]([O:30][CH3:31])(=[O:29])=[O:28]>C(Cl)(Cl)Cl>[F:26][S:27]([O-:30])(=[O:29])=[O:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N+:10]([CH3:25])[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:13]=2[O:14][CH3:31])=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)F
Reactant: Cn1cc(-c2ccc(Cl)cc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: ClC(Cl)Cl
Product: COc1c(-c2ccc(Cl)cc2)c[n+](C)cc1-c1cccc(C(F)(F)F)c1
Product: O=S(=O)([O-])F
Reaction time: 48 h

Procedure:
To a solution of 2.0 g. of 3-(4-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone in 15 ml. of chloroform was added 5.0 ml. of methyl fluorosulfonate and the mixture was allowed to stand at room temperature for 2 days. The solvent was removed in vacuo and the residue was dissolved in chloroform and the solution washed with water. The chloroform was removed and the residue was crystallized from chloroform-hexane to obtain 0.4 g. of product, m.p. 224°-227°.
Reaction SMILES: BrCC1C=CC([Cl:9])=C(C(F)(F)F)C=1.[C-]#N.[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>CS(C)=O>[ClH:9].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cl
Product: NCCc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
A mixture of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (3.94 g, 14.4 mmol) and sodium cyanide (1.06 g, 21.6 mmol) in dimethyl sulfoxide (12 mL) was heated at 50° C. for one hour. The reaction mixture was then poured on ice water and extracted four times with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated, leading to (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (3.19 g, 14.4 mmol) as a dark red oil. This crude material was transformed into the title compound in accordance with the general method of example H2. White solid, MS (ISP) 224.1 (M−Cl)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[CH3:1][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=1[NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(F)c1NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a suspension of caesium carbonate (1.3 g, 4.0 mmol) in DMF (5.0 ml) was added 2-tert-butoxycarbonylamino-3-fluorobenzoic acid from Example 19A (890 mg, 3.5 mmol) and iodomethane (230 μl, 3.8 mmol). The mixture was stirred for 18 h and evaporated in vacuo. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc;pet. ether 25:75) to give a white solid; yield 680 mg, 72%.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Br:19]Br>CC(O)=O>[Br:19][C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Solvent: CC(=O)O
Product: Cc1c(Br)oc2ccc(C=C3SC(=O)NC3=O)cc12
Temperature: 25 °C
Yield: 66 %

Procedure:
In a 25 ml 3 neck flask was placed 5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione (100 mg, 0.39 mmol) (example 68) and Br2 (20 ul, 1 eq.) in 2 ml of AcOH at 0° C. The mixture was allowed to warm to room temperature. After 2 h at room temperature another equivalent of Br2 was added. After 3 h the reaction was filtered off to obtain a yellow product being the title compound (87 mg, 66%).
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3](OCC)=[O:4].[BH4-].[Na+]>C(O)C>[F:14][C:2]([F:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccccn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Ethyl difluoro(pyridin-2-yl)acetate (G) obtained in step 1 (20 g) and 120 mL of ethanol were added, and 4 g of sodium borohydride was added to the reaction mixture over a period of 30 minutes at 0-5° C. The reaction mixture was stirred for 1 hour at 0-10° C. After completion of the reaction, the RM was quenched by adding saturated ammonium chloride solution at 0-5° C. and the volume of reaction mixture was reduced to half by distilling under vacuum. The solution was basified with 50% NaOH solution and extracted with MTBE. The organic layer was washed with a brine solution, dried over sodium sulphate and distilled under vacuum. The crude material was dissolved in 40 mL MTBE, 70 mL of n-hexane at 0-10° C. was added, and the RM was stirred for 30 minutes. The solid obtained was filtered and washed with hexane, resulting in pure product. (Yield=11 g).