Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(F)cc1
Yield: 21.9 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-fluorophenyl)-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (8.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(1-naphthyl)imidazole-4-carboxylate (3.3 g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(1-naphthyl)imidazole-4-carboxyic acid (2.4 g), melting point 175° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH2:25]([SH:27])[CH3:26]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:27][CH2:25][CH3:26])=[C:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCS
Reactant: CCCC1=CC(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Solvent: CO
Product: CCCC1=C(SCC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Temperature: 0 °C

Procedure:
To a suspension of 2-(4-methoxybenzyl)-3-methyl-5-propyl-4,7-benzofurandione (from Preparation 28) (0.988 g, 3.05 mmol) in MeOH (23 mL) was added ethanethiol (2.5 mL). After a few minutes, the yellow quinone passed into solution giving a reddish colour. The reaction was cooled to 0° C. and solid FeCl3 (2.5 g) was added. The reaction was quenched 10% HCl and extraction with CH2Cl2 afforded the crude product which was chromatographed on silica gel (5% EtOAc/hexane) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)C(C)c1ccccn1

Procedure:
Using General Procedure A, reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine and 2-bromomethyl-5-cyano-benzoic acid methyl ester in CH3CN with DMAP, KI, and DIPEA gave 5-cyano-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoic acid methyl ester as an amber oil. 1H NMR (CDCl3) δ 1.26 (t, 1H, J=7.3 Hz), 1.58 (d, 3H, J=6.7 Hz), 1.73 (s, 1H), 2.04 (s, 1H), 2.09 (s, 3H), 3.73-3.94 (m, 1H), 3.87 (s, 3H), 4.08-4.19 (m, 4H), 6.92-6.98 (m, 1H), 7.14-7.20 (m, 1H), 7.23 (d, 1H, J=8.0 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.48-7.53 (m, 1H), 7.64-7.69 (m, 2H), 7.92 (d, 1H, J=1.6 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.57 (d, 1H, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1.[H-].[Na+]>C1COCC1>[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[N:12]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(COc2cncc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.9 %

Procedure:
To a solution of (6-fluoro-pyridin-2-yl)-methanol I-3d (368 mg, 2.89 mmol) and 2,6-dichloro-pyrazine (431.2 mg, 2.89 mM) in THF (14.7 mL) at room temperature was added 60% NaH in mineral oil (174 mg, 4.34 mmol). The resulting mixture was stirred at ambient temperature for 19 h and concentrated. The residue was purified by column chromatography (ethyl acetate/hexanes=1:4)) to afford 560 mg of the title compound (I-3e).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])#[N:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]#[N:30])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C#N)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 17D (1.38 g, 4.38 mmol) in anhydrous dichloromethane (25 mL) was added triethylamine (0.9 mL) followed by 3-cyanobenzoyl chloride (0.727 g, 4.38 mmol) and the mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (50 mL) and H2O (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers dried (Na2SO4), filtered, and concentrated to an oil which was chromatographed on a Biotage 40M eluting with 10% hexane/90% ethyl acetate to provide the titled compound. MS (ESI) m/e 445 (M+H)+, 443 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 1.39 (s, 6 H) 1.45 (s, 3 H) 1.65 (m, 1 H) 2.53 (m, 2 H) 3.05 (m, 1 H) 3.19 (m, 2 H) 3.46 (m, 2 H) 3.78 (m, 2 H) 4.61 (m, 3 H) 7.66 (t, 1 H) 7.89 (d, 1 H) 8.11 (d, 1 H) 8.17 (s, 1 H).
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(S(F)(F)[F:35])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:35][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2.5 h
Yield: 15.3 %

Procedure:
Diethyl 1,4-dihydro-2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (0.1 g, 0.25 mmoles) in dry methylene chloride (5 ml) was added to a stirred solution at -60° of diethylaminosulphur trifluoride (0.068 ml, 0.55 mmoles) in dry methylene chloride (10 ml) over 10 minutes. The reaction mixture was allowed to reach room temperature over 2.5 hours, poured into aqeuous sodium bicarbonate (15 ml) and the aqueous layer extracted with methylene chloride (2×). The organic extracts were washed with water, dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures to give the title compound (0.015 g); identical with that prepared in Example 94.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[CH3:29][C:18]1[N:19]=[C:20]2[N:21]([CH2:24][CH2:25][CH2:26][CH:27]2[OH:28])[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (formula-10) (0.3 grams) taken in a mixture of methanol (1.5 ml) and dichloromethane (3 ml) added sodium borohydride (0.008 grams) and stirred for 1 hour at 30° C. The solvent was distilled off under reduced pressure. Methanol (1.5 ml) was added to it and heated to reflux for 30 min. the reaction mixture was cooled to 20° C. and stirred for 1 hour. Filtered the solid, washed with methanol and dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:34]([C:7]1[CH:8]=[C:9]2[C:14]([CH2:13][CH2:12][CH:11]([NH:17][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH:10]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:15][CH:16]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.58 h

Procedure:
8-(3,4-Dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (250 mg, 0.475 mmol), zinc cyanide (139 mg, 1.187 mmol) and tetrakistriphenyl palladium (82 mg, 0.071 mmol) in dimethylformamide (5 mL) were heated in the microwave at 120° C. (100 W) under stirring for 35 min. The solvent was evaporated in vacuo and the crude product was partitioned between ethyl acetate (40 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate one more time (20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product (460 mg) was purified by flash chromatography (dichloromethane to dichloromethane:methanol=100:1, silica gel). Yield: 109 mg (0.270 mmol, 57%, colorless solid).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:20]=2[O:19][CH2:18]1>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]3([C:29]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[N:7]=4)=[O:30])[CH2:27][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(N)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (71 mg, 0.50 mmol) and Et3N (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (110 mg, 0.50 mmol) in dichloromethane (2 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N aqueous HCl (1×5 mL) and saturated aqueous NaHCO3 (1×5 mL). The organic layer was dried over sodium sulfate and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide (120 mg, 71% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.94-7.91 (m, 1H), 7.79-7.77 (m, 1H), 7.09 (m, 1H), 7.00-6.88 (m, 2H), 6.06 (s, 2H), 2.25 (s, 3H), 1.47-1.44 (m, 2H), 1.13-1.10 (m, 2H) ESI-MS m/z calc. 330.1. found 331.5 (M+1)+. Retention time 1.99 minutes.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Yield: 78 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added phenyl chloroformate (45.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give 112 mg (78% yield) of the title compound as an off-white oil. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])([OH:16])[CH2:17][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:11][CH:10]=1
Reactant: Clc1ccccc1C1(c2ccc(-c3ccccc3)cc2)CO1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccc(-c2ccccc2)cc1)c1ccccc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
3.5 g (0.065 mol) of sodium methylate are dissolved in 20 ml of methanol, and 7.5 g (0.11 mole) of imidazole are added. A solution of 15 g (0.05 mol) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated to 80° C. for 1.5 hours. Thereafter, it is poured onto water and the crystals which form are filtered off and dried. 14.7 g (79% of theory) of 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-imidazol-1-yl-ethanol of melting point 222° C. are obtained.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH:20][C:11](=[O:13])[CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[S:18][CH:19]=1
Reactant: O=C(O)Cc1cccc2nccn12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1cccc2nccn12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide was synthesized from 2-(imidazo[1,2-a]pyridin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=7.958, method [6], MS(ESI) 403.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.46 (b s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.08-7.96 (m, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.16 (s, 1H), 4.64 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H-].[Na+].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[C:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([C:13]2[CH:17]=[N:16][N:15]([CH2:22][C:23]#[N:24])[CH:14]=2)[C:3]([CH3:18])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cn[nH]c1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 1-[5-chloro-2-methoxy-4-methyl-3-(1H-pyrazol-4-yl)phenyl]ethanone (0.13 g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 0.014 g, 0.59 mmol) at 0° C. The mixture was stirred for 1 hour at room temperature, followed by the addition of chloroacetonitrile (0.037 mL, 0.59 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour, quenched with water and extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to afford the desired product (0.1 g, 67%). LCMS calculated for C15H15ClN3O2 (M+H)+: m/z=304.1. found: 304.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylene chloride (700 μL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (35 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (40.4 mg, 64%) as a pink solid: mp 200–202° C.; EI-HRMS m/e calcd for C18H21FN2O3S2 (M+) 396.0978, found 396.0976.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([S:29]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)(=[O:30])=[O:31])[CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: O=S(=O)(c1cccc(B(O)O)c1)N1CCCC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(S(=O)(=O)N5CCCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(pyrrolidinylsulfonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 33 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.78 min (Method A); M+H=503 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.16-8.11 (m, 2H), 8.02-7.96 (m, 1H), 7.94-7.89 (m, 1H), 7.83-7.78 (m, 1H), 7.77-7.71 (m, 2H), 7.69-7.65 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.21-3.14 (m, 4H), 1.95 (s, 3H), 1.70-1.63 (m, 4H))
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:14][C:13](=[O:15])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1)[CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a mixture of 2.28 g of 2-(p-isobutylphenyl)propionic acid sodium salt in 20 ml of dimethylformamide was added 2.52 g of benzyl chloride and the whole was heated at 90° C. for 3 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether and the extract was dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.57 g of 2-(p-isobutylphenyl)propionic acid benzyl ester as a colorless oil, boiling at 108°-110° C./0.1 mmHg. Analysis-Calculated for C20H24O2 : C, 81.04; H, 8.16. Found: C, 80.92; H, 8.02.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7].CN(C)[CH:19]=[O:20]>>[CH:19]([C:12]1[C:11]2[C:15](=[CH:16][C:8]([CH:6]=[O:7])=[CH:9][CH:10]=2)[NH:14][CH:13]=1)=[O:20]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc2cc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(C=O)c[nH]c2c1
Reaction time: 1 h
Yield: 87 %

Procedure:
Phosphorous oxychloride (48.2 ml) was added dropwise to stirred N,N-dimethylformamide (72.8 ml) at 0° (internal temperature). Stirring was continued for about 1 hour, and a solution of 6-formylindole (32.7 g) (see Example 12, part b) in N,N-dimethylformamide (444 ml) was added dropwise, while maintaining the internal temperature at 0°. The cooling bath was removed and the mixture stirred for 18 hours before water (1 liter) was added and the mixture heated under reflux for 15 min. The mixture was cooled in an ice bath; and the precipitated product isolated by filtration, washed with water and dried under vacuum to give 3,6-diformylindole (33.97 g, 87%); mp 200°-203°; NMR (250 MHz, DMSO-d6): 7.75(dd, J=8.25, 1.25 Hz, 1H, H5 -indole), 8.10(s, 1H, H2 -indole), 8.24(d, J=8.25 Hz, 1H, H4 -indole), 8.57(s, 1H, H7 -indole), 10.00(s, 1H, CHO), 10.06(s, 1H, CHO); 12.61(br s, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([OH:44])=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([O:44][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)OCC(c1cccc(F)c1)C2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2cccc(F)c2)C3)nc1

Procedure:
2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 125 mg of 3-(3-fluorophenyl)-chroman-7-ol. The product was recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.0, 2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, 1H, J 10.6, 4.3 Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1.Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=1[O:23][CH3:24]>>[NH2:1][C:2]1[C:7]([C:8]([C:18]2[C:19]([F:21])=[CH:20][CH:15]=[C:16]([O:23][CH3:24])[C:17]=2[F:22])=[O:10])=[CH:6][N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1
Reactant: CCSc1ncc(C(=O)O)c(N)n1
Reactant: COc1c(F)cc(F)cc1Br
Product: CCSc1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanylpyrimidine-5-carboxylic acid, Example 1, and 2-bromo-4,6-difluoroanisole (Astatech), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 326.