Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[N:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>Br.O>[N:21]1[N:22]2[CH:9]=[CH:8][N:27]=[C:23]2[N:24]=[CH:25][CH:26]=1
Reactant: Nc1nccnn1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cnn2ccnc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 4.7 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (8.88 ml, 57.24 mmol) in concentrated hydrobromic acid (1.7 ml) and water (1.7 ml) was heated at reflux for 20 min, then poured into 1,2-dimethoxyethane (12.5 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added [1,2,4]triazin-3-ylamine (5.00 g, 52.03 mmol) and neutralised again with solid sodium hydrogencarbonate. The mixture was stirred at 80° C. for 20 h. After allowing to cool, silica gel was added to the mixture, the solvent was removed in vacuo and the residue was purified by chromatography (silica gel 5% MeOH/CH2Cl2) to give 0.292 g (5%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 8.01 (1H, d, J 1.4 Hz), 8.38 (1H, d, J 1.4 Hz), 8.59 (1H, d, J 2.1 Hz), 8.68 (1H, d, J 1.8 Hz); MS (ES+) m/z 121 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]OC(=O)CC1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 95.0 mg, 0.34 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 90.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[OH:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)=[O:18].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[CH:20]12[CH2:25][CH:23]([CH:22]=[CH:21]1)[CH2:24][CH:19]2[C:17]([O:16][CH2:15][CH2:14][O:13][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)=[O:18]
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Reactant: O=C(OCCO)C1CC2C=CC1C2
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: C[SiH]1O[SiH](C)O[Si](C)(OCCOC(=O)C2CC3C=CC2C3)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl-5-norbornene-2-carboxylate. The resulting mixture was stirred for 24 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[CH:8][C:7]([Cl:21])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:21][C:7]1[CH:8]=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=3)=[N:10]2)=[CH:5][C:6]=1[O:22][CH3:23]
Reactant: COc1cc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)cc1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1cc2c(O)cc(-c3nc(C(C)C)cs3)nc2cc1Cl
Yield: 70 %

Procedure:
Compound 43g was synthesized from compound 42g as a yellow solid in 70% yield, according to the procedures as described for compound 43a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:25][N:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[S:25][N:24]=[CH:23][N:22]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncns2)=NC1c1ccc(F)cc1Br
Yield: 40 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1,2,4-thiadiazol-5-yl)-1,4-dihydropyrimidine-5-carboxylate (5.7 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.7 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].[CH3:26][C:27]([C:30]([NH2:32])=[NH:31])([CH3:29])[CH3:28].Cl.C([O-])(=O)C.[Na+]>CN(C=O)C>[C:27]([C:30]1[N:32]=[C:17]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:4]([C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:6])=[C:1]([CH3:2])[N:31]=1)([CH3:29])([CH3:28])[CH3:26]
Reactant: CC(C)(C)C(=N)N
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)NCCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)C)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide was dissolved in 5 ml of DMF. 54.5 mg (0.399 mmol) of t-butyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate were added at room temperature and stirred at 80° C. for one day. After DMF was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:37]\[C:38]([NH2:40])=[O:39])=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][CH:33]1[CH2:32][C:31]2[C:35](=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)/[C:34]/1=[CH:37]/[C:38]([NH2:40])=[O:39]
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.4 %

Procedure:
N-Bromosuccinimide (22.57 g, 126.8 mmoles, Aldrich) and benzoyl peroxide (1.89 g, 7.8 mmoles, Aldrich) were added to a suspension of (E)-2-(6-fluoro-1-indanylidene)acetamide (21.00 g, 109.8 mmoles) in carbon tetrachloride (400 mL) and benzene (400 mL). The mixture was refluxed under a calcium chloride drying tube while shining an infrared lamp on it for two hours, after which time an orange solution formed. The heat and light were removed, and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered, and the solids were washed with ethyl acetate. The washings and filtrate were combined and evaporated in vacuo. The residue was dissolved in ethyl acetate (800 mL) and washed with water (3×200 mL) and brine (200 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting first with hexane:ethyl acetate (2:1) gradually increasing the polarity to hexane:ethyl acetate (1:1). The fractions containing the major spot were combined and evaporated in vacuo to give a yellow solid which was dried in a vacuum at 70° C. for 18 hours to give 1.022 g (3%) of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide as a yellow solid, mp 162-163° C. 1H-NMR
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:26]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[N:17]([CH3:26])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)c(F)cc1Cl
Reactant: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CSC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-1-methyl-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.35 ppm (d, 1H), 5.23 ppm (m, 1H), 4.24 ppm (m, 2H), 4.09 ppm (m, 2H), 3.45 ppm (s, 3H), 1.36 ppm (d, 6H),
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:6])=[CH2:5].[CH3:8][O:9][C:10](=[O:13])[CH2:11][SH:12].N1CCCCC1.C[O-].[Na+]>CO>[CH3:8][O:9][C:10]([CH:11]1[C:3](=[O:2])[CH:4]([CH3:6])[CH2:5][S:12]1)=[O:13]
Reactant: C=C(C)C(=O)OC
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C1SCC(C)C1=O

Procedure:
100 g (1 mole) of methacrylic acid methyl ester are added dropwise to 106 g of thioglycolic acid methyl ester and 1 ml of piperidine. The reaction mixture is added dropwise to a solution of 40 g of sodium methylate in 200 ml of methanol. The mixture is stirred for a further half an hour, poured onto water, acidified and extracted with methylene chloride and the organic phase is washed with water and dried with sodium sulfate. After distillation, 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester is obtained (bp. 110° to 115°/14 Pascal).
Reaction SMILES: N1(CC(N)=O)C=CC=N1.[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([O:30]CC)=O)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C>>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([NH:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:30])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: NCCN1CCCC1
Agent: NC(=O)Cn1cccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCN1CCCC1

Procedure:
By a procedure substantially similar to that of Example 13, 6.67 g of 4.5-diphenyl-N-2-(1-pyrrolidinyl)ethyl-]1H-pyrazole-1-acetamide, mp 80°-84° C., was prepared from 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 9 mL (0.072 mol) of N-(2-aminoethyl)pyrrolidine and 62 mL (0.36 mol) of diisopropylethylamine.
Reaction SMILES: C(O[CH:5]([CH:19]([CH3:21])[CH3:20])[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)=[O:7])(=O)C.Cl.OC(C(C)C)C(C1C2C(=CC=CC=2)C(F)=CC=1)=O.OC(C1C2C(=CC=CC=2)C(F)=CC=1)C(=O)C(C)C.[N:59]#[C:60][NH2:61]>C(O)C>[NH2:61][C:60]1[O:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)=[C:5]([CH:19]([CH3:21])[CH3:20])[N:59]=1
Reactant: N#CN
Reactant: CC(=O)OC(C(=O)c1ccc(F)c2ccccc12)C(C)C
Agent: CC(C)C(=O)C(O)c1ccc(F)c2ccccc12
Agent: CC(C)C(O)C(=O)c1ccc(F)c2ccccc12
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(N)oc1-c1ccc(F)c2ccccc12
Temperature: 110 °C
Yield: 6 %

Procedure:
A mixture of 2-acetoxy-3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one (4.8 g), IMS (100 ml) and hydrochloric acid (1M; 70 ml) were boiled under reflux for 4 hours. The mixture was cooled, evaporated in vacuo and partitioned between dichloromethane and brine. The organic layer was separated, dried with sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography in 66-100% dichloromethane in petroleum ether to afford a mixture of 2-hydroxy-3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one and 1-hydroxy-3-methyl-l-(4′-fluoronaphth-1-yl)butan-2-one (3.2 g). Cyanamide (0.65 g) and anhydrous ethanol (10 ml) were added and the resulting mixture was boiled under reflux for 48 hours. After cooling the volatiles were removed in vacuo and the residue heated at 110° C. for a further 48 hours. The mixture was cooled, triturated with chloroform (100 ml) and filtered. The filtrate was washed with water, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (0.25 g; m.p. 141° C., softens from 125° C.) was obtained following silica gel column chromatography of the residue in 50% ethyl acetate in petroleum ether.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-methoxyaniline (61.6 mg, 0.50 mmol) as described in General Procedure X to afford Iag (26 mg, 37.7%) as an ivory colored solid, tlc Rf=0.6 (5% MeOH/CH2Cl2-0.2% Et3N), m/z obs=404 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.62 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.48 g, yield: 62.8%). mp: 80-82° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.19 (t, J=7.3 Hz, 3H), 2.59 (s, 3H), 3.34 (dq, J=6.1 and 7.3 Hz, 2H), 5.72 (s, 1H), 6.60-6.85 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([CH3:16])[C:5]=2[N:4]=[CH:3]1.[OH:17]O>>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[N+:7]([O-:17])=[C:6]([CH3:16])[C:5]=2[N:4]=[CH:3]1
Reactant: OO
Reactant: Cc1nc2ccc(F)cc2c2c1ncn2C
Product: Cc1c2ncn(C)c2c2cc(F)ccc2[n+]1[O-]

Procedure:
Using the method of Example 74, 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinoline (from Example 140) was reacted with hydrogen peroxide to provide 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinolin-5-oxide, m.p. 245°-248° C. Analysis: Calculated for C12H10FN3O: %C, 62.3; %H, 4.4; %N, 18.2; Found: %C, 62.7; %H, 4.3; %N, 18.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2cccs2)cc1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27, 0.3 g (2.3 mmol) of thiophene-2-boronic acid and 0.3 g (2.3 mmol) of potassium carbonate in 7 mL of dioxane and 2 mL of water was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to 100° C. for 16 hours cooled to ambient temperature, diluted with 5 mL of water and extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from ethyl ether, filtered and dried in vacuo to afford 0.2 g (47%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: CS(=O)(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 7 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-Hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-methanesulfonamide following a procedure analogous to that described in Example 1. Yield: 7% of theory; LC (method 1): tR=2.07 min; Mass spectrum (ESI+): m/z=411 [m+H]+.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1S(C)(=O)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>O>[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nc2ccn(Cc3ccccc3)c(=O)c2n1Cc1ccccc1
Reactant: C1CNCCN1
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(ccn1Cc1ccccc1)nc(N1CCNCC1)n2Cc1ccccc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 5.5 %

Procedure:
660 mg (11 mmol) of glacial acetic acid were added dropwise to 860 mg (10 mmol) of piperazine with cooling, then 180 mg of 3,5-dibenzyl-2-methanesulphonyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one (crude product from Example 3 h) were added and the mixture was stirred for 24 hours at 150° C. After cooling approx. 10 ml of water were added, the mixture was made alkaline with concentrated ammonia solution and the mixture was extracted three times with 5 ml of dichloromethane. The extracts were dried over sodium sulphate and concentrated by evaporation. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 20–60% ethyl acetate).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][O:21][C:22](=O)[O:23]N1C(=O)CCC1=O>ClCCl>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:22]([O:21][CH2:20][CH2:19][Si:18]([CH3:33])([CH3:32])[CH3:17])=[O:23])[CH2:7][OH:8]
Reactant: COC(=O)[C@@H](N)CO
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.2 %

Procedure:
To a mixture of 1.25 g serine methyl ester hydrochloride, 2.25 ml triethylamine and 10 ml dichloromethane was added at 0° C. a solution of 2.22 g carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-trimethylsilanyl-ethyl ester [R. E. Shute, D. H. Rich, Synthesis, 1987, 346]. After stirring for 24 h at rt the reaction mixture was washed two times with 1N potassium hydrogen sulfate, once with saturated sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.29 g of a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C)C=O>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH3:17]
Reactant: OCC1CCCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of 3-piperidinemethanol (2 g) and potassium carbonate (6 g) in dry N,N-dimethylformamide (15 ml) was added iodoethane (1.53 ml). The reaction became warm and was cooled back to ambient temperature using a cold water bath. After 2 hours, the solvent was stripped, the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and evaporated to give the title compound as a clear oil, yield 1.53 g, 61%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[C:4]([CH2:5][N:6]2[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:17])[F:15])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:7]2)[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(F)cc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of the compound from Example 103A were reacted with 28 mg (0.18 mmol) of 2-chlorophenylboronic acid. This gave 34 mg (54% of theory) of the target compound.