Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([N:7]2[CH:6]([CH3:22])[C:5]3[C:9](=[CH:10][C:2]([C:32]4[CH:31]=[N:30][N:29]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][O:23]5)[CH:33]=4)=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2C)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Combine 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (64 g, 177 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 g, 295 mmol), potassium carbonate (70 g, 506 mmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (9 g, 11 mmol), dioxane (800 mL), and water (212 mL) under nitrogen and heat to 70-75° C. for 16 hours. Add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 g, 54 mmol) and heat to 80-85° C. for 2 hours. Concentrate under reduced pressure to 200 mL, add ethyl acetate (500 mL) and water (500 mL), stir for 30 minutes, and filter the solids. Combine the solids and the organic layer and evaporate under reduced pressure. Dissolve the residue in dichloromethane and filter through a pad of silica gel. Wash the silica gel pad with dichloromethane/ethyl acetate (1:0) and then (2:1) and evaporate to dryness under reduced pressure. Slurry the solid in a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30° C. and filter to collect the solid to give the title compound as an off-white solid (68 g, 89%). ES/MS m/z: 432 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([N:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(C)c2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reaction time: 2 h
Yield: 6.8 %

Procedure:
Anhydrous potassium carbonate (0.204 g, 14.8 mmol), and methyl iodide (0.209 g, 14.8 mmol) were added to a stirred solution of 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (0.250 g, 5.94 mmol) in acetonitrile (10 mL) under a nitrogen atmosphere at room temperature. After 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude reaction mixture was subjected to purification by column chromatography on silica gel. Elution with an ethyl acetate-hexane mixture (20:80) gave 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-N-(methyl)benzenesulfonamide (0.175 g) as a white colored solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([N:15](C(OCC(Cl)(Cl)Cl)=O)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][NH:34]1)[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][N:34]1[C:18](=[O:20])[C@@H:16]([NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:17])[CH3:30]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)O
Reactant: CCOC(=O)COc1ccc(C(=O)C=C2CN[C@H](C(=O)OCC)C2)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)C=C2C[C@@H](C(=O)OCC)N(C(=O)[C@H](C)N[C@@H](CCc3ccccc3)C(=O)OCC)C2)c(Cl)c1Cl

Procedure:
The acid chloride of N-((1S)-1-ethoxycarbonyl-3phenylpropyl)-N-(2,2,2-trichloroethoxycarbonyl)alanine (Example 7A) is dissolved in CH2Cl2 and added dropwise to a solution of 4-(2,3-dichloro-4-((ethoxycarbonyl)methoxy)benzoyl)methylene proline ethyl ester and triethylamine in CH2Cl2. Further reaction and purification as in example 7A gives the desired amide.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:21]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:19])[F:20])=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.1 h
Yield: 55.3 %

Procedure:
4-Phenyl-8-trifluoromethyl-quinoline-3-carboxylic acid (0.110 g, 0.347 mmol), whose preparation is described in Scheme 2, p-toluidine (0.074 mL, 0.693 mmol), EDCI-HCl (0.110 g, 0.520 mmol), and DMAP (0.084 g, 0.520 mmol). are dissolved in 1,2-dichloroethane (3 mL) in a 5 mL microwave tube. After stirring in the microwave reactor for 6 min at 70° C. the cooled solution is poured into 2 N aq HCl and extracted with methylene chloride, washed with water, brine, and dried with magnesium sulfate. The combined extracts are concentrated and the residue is chromatographed in 1:9 ethyl acetate:hexanes to afford the title amide as a white solid (0.078 g, 56%). mp 203-205° C.; MS (ES) m/z 405.2; HRMS: calcd for C24H17N2F3O+H, 407.13712; found (ESI, [M+H]+), 407.1376.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20](O)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25].[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCCl>[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20]([C:31]1[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=2)[NH:33][CH:32]=1)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2C#N)c(F)c1
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cc(F)cc23)C2CC2C#N)c(F)c1

Procedure:
347 mg (1.57 mmol) of indium(III) chloride and 0.18 ml (2.35 mmol) of trifluoroacetic acid were added to 268 mg (1.31 mmol) of the compound from Example 166A and 405 mg (1.57 mmol) of the compound from Example 87A with a purity of 88% under argon in 10 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 358 mg (66% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([NH2:38])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H]1CC[C@H](N=[N+]=[N-])[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@H](N)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H2O (0.04 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16](Cl)[N:15]=[C:14]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH2:34][CH2:35][CH2:36][OH:37]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:37][CH2:36][CH2:35][NH2:34])[N:15]=[C:14]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cn1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 1.0 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 2-aminoethanol to give 950 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrmidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.00 min, (M+1]+=509.53, [M−1]−=507.57.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:3]1.[CH2:18]([Li])CCC.CI>O1CCCC1>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][C:12]=2[CH3:18])=[N:3]1
Reactant: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step (i) (9.5 g) in tetrahydrofuran (40ml) at -60° C. was added n-butyllithium (17 ml of a 2.5M solution in hexanes) dropwise. The mixture was stirred at -65° C. for 1 hour and methyl iodide (12 ml) was added. The mixture was stirred at room temperature for 1 hour and quenched with brine. The organic phase was dried (MgSO4) and evaporated. Yield 9.56 g. Used directly in the next step.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38]>CN(C=O)C>[CH2:38]([O:5][C@@H:4]1[C@@H:6]([CH2:7][OH:8])[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@@H:2]1[OH:3])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Adenosine (20 g, 74.84 mmol) was dried over P2O5 under high vacuum at 40° C. for two days. It was then suspended in DMF under inert atmosphere. Sodium hydride (2.5 g, 74.84 mmol, 60% dispersion in mineral oil), stirred at room temperature for 10 minutes. Then allyl bromide (7.14 mL, 82.45 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. DMF was removed under vacuum and residue was washed with ethyl acetate (100 mL). Ethyl acetate layer was decanted. Filtrate obtained contained product. It was then placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get the title compound (15.19 g, 66%). Rf 0.4, 0.4a ((10% MeOH in CH2Cl2)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl.Br[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1ccncc1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1C=O

Procedure:
3-formyl-4-methoxybenzeneboronic acid (393 mg, 2.19 mmol) is coupled to 4-bromopyridine hydrochloride (400 mg, 2.19 mmol) using Method A to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:50]=[CH:51][CH:52]=2)[O:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][NH:19][C:23]([NH:49][CH2:48][CH2:47][CH2:46][O:45][C:44]2[CH:50]=[CH:51][CH:52]=[C:42]([CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:43]=2)=[O:24])[CH3:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.42 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=577 ([M+H]+, 12), 229 (99), 109 (100); IR (KBr): 1640 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/ether/petroleum ether; m.p.: 68° C. (isopropanol/ether/petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[N:20]1[CH2:25][CH:24]=[C:23]([C:26]#[N:27])[CH2:22][CH2:21]1.Cl.C(O)=[O:30]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[N:20]1[CH2:21][CH:22]=[C:23]([C:26](=[O:30])[NH2:27])[CH2:24][CH2:25]1
Reactant: O=CO
Reactant: Cc1cc(N2CC=C(C#N)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Agent: Cl
Product: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 96% formic acid (5 mL) was dissolved 8-(2,4-dichlorophenyl)-2-methyl-4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)quinoline (1.0 g), and hydrogen chloride gas was bubbled into the solution under ice-cooling to saturate the solution therewith. The reaction mixture was stirred at room temperature for 4 hours and then distilled under reduced pressure to remove the solvent. The residue was separated with chloroform and a saturated aqueous sodium hydrogen-carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform-methanol=10:1) and then recrystallized from tetrahydrofuran to obtain the title compound (174 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3ccc(Cl)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 284. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.67 (d, 2H, J=8.56 Hz), 7.54 (d, 1H, J=8.55 Hz), 7.46 (d, 2H, J=8.55 Hz), 7.42-7.40 (m, 2H), 6.47 (d, 1H, J=3.0 Hz), 4.18 (t, 2H, J=7.02 Hz), 1.73 (p, 2H, J=7.18 Hz), 1.24 (h, 2H, J=7.47 Hz), and 0.88 ppm (t, 3H, J=7.33 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[C:25]([O-])(=[O:27])[CH3:26].[Na+]>C(O)(=O)C>[C:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[C:20]2[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]2=[O:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CC(=O)[O-]
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(C)=O)n1

Procedure:
A mixture comprising 4.35 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5 g of rhodanine-3-acetic acid, 2.7 g of sodium acetate and 50 ml of acetic acid was heated under reflux for 2 days. The reaction mixture was then worked up as in Example 1, to give the desired compound as a yellow powder.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([O:20][CH3:21])[CH:18]=[C:17]([C:22](O)=O)[CH:16]=2)=[CH:11][CH:10]=1.C(#[N:27])C>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([O:20][CH3:21])[CH:18]=[C:17]([C:22]#[N:27])[C:16]=2[C:6]#[N:5])=[CH:11][CH:10]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC#N
Reactant: COn1cc(C(=O)O)cc1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COn1cc(C#N)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 18 %

Procedure:
Chlorosulfonyl isocyanate (8.1 g, 0.0572 mol) is added dropwise to a 50° C. stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-3-carboxylic acid (6.0 g, 0.0238 mol) in acetonitrile and dimethylformamide. The reaction mixture is stirred at room temperature for 20 hours, cooled to 0° C., treated with dimethylformamide (9.2 mL), heated to 50° C. for 1 hour, cooled to room temperature for 3 hours, diluted with water and extracted with chloroform. The combined chloroform extracts are washed sequentially with water, saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a gum. The gum is chromatographed using silica gel, and methylene chloride as eluent to give 2 products as a mixture. Crystallization from chloroform gives 2-(p-chlorophenyl)-1-methoxypyrrole-3,4-dicarbonitrile (1.1 g, 18%), as a yellow solid, mp 193°-194° C. The filtrate from the above crystallization is chromatographed using silica gel, and 30% ethyl acetate in heptane as eluent to give the title compound as a yellow solid (0.93 g, 15%), mp 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC1C=C(C2N=CC(CCC(N3CCCCC3)=O)=CC=2)C=CC=1.[H-].[Na+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C>[C:47]([O:51][C:52](=[O:55])[CH2:53][NH:14][C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: Nc1ccc(-c2ccc(F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C(CCc1ccc(-c2cccc(F)c2)nc1)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CNc1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 300 mg (1.59 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ylamine (prepared analogously as described in Example 76(a) and (b)) and 104 mg (2.39 mmol) of sodium hydride (55% in mineral oil) in DMF were stirred at room temperature for 30 min. Then 466.4 mg (2.39 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 2 h at room temperature and for 5 h at 100° C. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried and evaporated. Yield: 480 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Yield: 62.6 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (81 mg, 0.21 mmol) and N-bromosuccinimide (40 mg, 0.23 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-15% EtOAc/hexanes+1% AcOH) to give 62 mg of the title compound as a light yellow solid. MS: (−) m/z 469.20, 471.15 (M−1, 7″81Br).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Br[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].[Cl-].[NH4+].O1CCCC1>[Zn]>[CH3:18][C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([CH3:19])[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(C)=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.62 h

Procedure:
To a suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.40 g, 0.0130 mol), 4-bromo-2-methyl-2-butene (3.00 mL, 0.0260 mol) in 15.0 mL sat'd. ammonium chloride and tetrahydrofuran (3.00 mL, 0.0370 mol) was added zinc (1.70 g, 0.0260 mol) at rt. Soon after stirring was started, gas and heat were released. After 30 to 45 min., the resulting light grey mixture was filtered through celite. The filtration was extracted with EtOAc. The organic layeres were combined, washed with brine, dried (NaSO4) and concentrated in-vacuo. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na) 278.2.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:23]1.N1CCCCC1>C(O)C>[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33](/[CH:37]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:34][C:35]=2[CH3:36])[CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (184 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange-red solid.