Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:50])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:50])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 108.9 %

Procedure:
To a stirred solution of (2R,5R)-4-{2-[6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.572 g, 0.97 mmol) and triethylamine (0.22 mL, 0.157 g, 1.55 mmol) in DCM (10 mL) at −10° C. under nitrogen was added a solution of methanesulfonyl chloride (0.09 mL, 0.133 g, 1.2 mmol) in DCM (5 mL). Mixture was stirred at 20° C. for 18 h then partitioned between saturated aqueous NaHCO3 (50 mL) and DCM (3×30 mL) and combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (0.576 g) as an oil, used without further purification. MS: [M+H]+=545.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: CC(C)(O)CN
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 6.8 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 1-amino-2-methylpropan-2-ol (5.85 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.2 min) to provide (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (2 mg, 2.99 μmol, 6.83% yield): LCMS=574.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.50-7.79 (7 H, m), 5.11 (1 H, s), 3.48-3.58 (2 H, m), 3.14-3.22 (2 H, m), 2.48 (2 H, t, J=6.71 Hz), 1.16 (3 H, s), 1.16 (3 H, s); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])=[CH2:2].[C:23]([OH:26])(=[S:25])[CH3:24].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:23]([S:25][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:26])[CH3:24]
Reactant: C=Cc1cccc(-c2cccc(C(=O)OC)c2)c1C(=O)OC
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1cccc(-c2cccc(CCSC(C)=O)c2C(=O)OC)c1
Yield: 47.2 %

Procedure:
To a solution of 3-ethenyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.85 g, 2.9 mmol) in benzene (10 mL) was added thioacetic acid (2.1 mL, 29.4 mmol) followed by AIBN (0.053 g, 0.32 mmol). The solution was deoxygenated for 30 min by bubbling nitrogen through the solution and then heated at reflux for 4 h. Saturated aqueous NaHCO3 (20 mL) was added to the solution and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (1:12 EtOAc/hexanes) to give 3-[2-(acetylthio)ethyl]-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.51 g, 48%) as an off white solid: 1H NMR (CDCl3) δ2.35 (s, 3H), 2.93 (m, 2H), 3.14 (m, 2H), 3.62 (s, 3H), 3.93 (s, 3H), 7.29 (dd, J=7.6, 0.9 Hz, 1H), 7,35 (dd, J=7.5, 0.8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 1), 7.55 (dt, J=8.0, 1.5 Hz, 1H), 8.03 (dt, J=7.9, 1.5 Hz, 1H), 8.07 (t, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].Br.[Br:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18].P([O-])([O-])([O-])=O>CO>[Br:10][C:11]1[S:15][C:14]([N:16]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Agent: Br
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: Cc1ccc(C)n1-c1nc(C(F)(F)F)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1261 %

Procedure:
Add hexane-2,5-dione (3.5 mL, 3.4 g, 30 2 mmol) to a solution of 5-bromo-4-trifluoromethyl-thiazol-2-ylamine hydrobromide (9.0 g, 27.4 mmol) in methanol (60 mL). Stir at room temperature overnight. Add phosphate buffer (50 mL, pH=7). Collect the resulting precipitate by filtration, washing with water. Dissolve the filter cake in CH2Cl2 and dry over sodium sulfate. Filter and concentrate under vacuum to obtain the title compound (8.2 g, 92%). 1H NMR (400 MHz, CDCl3) δ 5.91 (s, 2H), 2.27 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:16](=O)[CH3:17])[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7](=O)[CH3:8])C.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:3][C:4]([C:5]1[CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:8])=[N:21][NH:22][C:16]=1[CH3:17])=[O:19]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C(C(C)=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NN=C(C)C1c1ccccc1

Procedure:
19 g (75 mmols) of 2-acetyl-4-oxo-3-phenyl-pentanoic acid ethyl ester were heated to the boil together with 3.75 g (75 mmols) of hydrazine hydrate in 100 ml of ethanol under nitrogen for 10 hours. The solvent was then distilled off in vacuo and the residue was recrystallised from isopropanol.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH2:13][CH3:14])[C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1>CCO>[CH2:13]([C@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CNC[C@@H]1CC
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.4 %

Procedure:
A parr shaker was charged with PdOH2 on carbon (2.243 g, 3.19 mmol) and (cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (16.7 g, 63.9 mmol) followed by EtOH (100 mL). The reaction mixture was degassed and purged with hydrogen gas and shaken on the parr shaker at 60 psi for about 4 days at ambient temperature. The reaction mixture was degassed and purged with nitrogen. The suspension was filtered through a pad of Celite® washing with EtOH (˜900 mL). The solvent was removed under reduced pressure to afford (cis)-ethyl 4-ethylpyrrolidine-3-carboxylate (8.69 g, 79%) as an oil: LC/MS (Table 1, Method a) Rt=1.11 min; MS m/z: 172 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:34][OH:35])=[N:17][N:18]3[CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[O:32][CH3:33])=[CH:14][CH:13]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39].Cl>O1CCCC1.CN(C)C=O>[CH:3]1([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:34][O:35][C:38](=[O:39])[N:37]([CH3:41])[CH3:36])=[N:17][N:18]3[CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[O:32][CH3:33])=[CH:14][CH:13]=2)=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)c1ccc(Cn2nc(CO)c3ccc(C(=O)NCC4CCCC4)cc32)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(COC(=O)N(C)C)c3ccc(C(=O)NCC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
To a suspension of 60% sodium hydride dispersion (13 mg) (petroleum ether washed) in tetrahydrofuran (1 ml) at 0° was added a solution of methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-hydroxymethylindazol-1-ylmethyl]-3-methoxybenzoate (151 mg) in 7:1 dimethylformamide:tetrahydrofuran (8 ml). After stirring for 45 minutes, dimethylcarbamoyl chloride (0.033 ml) was added. The reaction was stirred for 15 minutes and was allowed to warm to room temperature. After 3 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried (MgSO4). Evaporation and flash chromatography over 15 g silica gel, eluting with 2:8 ethyl acetate:methylene chloride (50 ml) and 4:6 ethyl acetate:methylene chloride, afforded methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(dimehylcarbamoyloxymethyl)indazol-1-ylmethyl]-3-methoxybenzoate as a colorless solid (40 mg, 23%); mass spectrum (chemical ionization) 523 (M+H). NOTE: Still further Examples of compounds of the invention are provided by the benzoic acid starting materials for formula I (M=CO2H) described in connection with Examples 6, 8 and 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.CCN(CC)CC.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a mixture of 10.0 g (37.9 mmol) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of Et3N in 200 mL of dry THF at room temperature and under a nitrogen atmosphere was added 33.0 g of piperazine. The mixture was stirred at room temperature for 22.5 hours and then refluxed for 5.5 hours. It was then cooled to room temperature, poured into 250 mL of 5% aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (2→5% MeOH saturated with ammonia in CH2Cl2) to yield the title compound as a glass.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=[O:11])[NH:3][CH:2]=1.OS(O)(=O)=O.[CH3:18]O>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:18])=[O:11])[NH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccnc2[nH]cnc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc2[nH]cnc12
Reaction time: 10 h
Yield: 80 %

Procedure:
Absolute methanol (30 ml) is added to acid x177 (2.0 g). Concentrated H2SO4 (4 ml) is added to the obtained suspension at 0° C. The reaction mixture is refluxed under protection from the air moisture and vigorous stirring for 10 h. After 3 h the solid is completely dissolved. The next morning the reaction mixture is evaporated to half-volume in the vacuum of a rotary evaporator and neutralized under cooling with ice with aqueous ammonia to pH 8-9. The formed precipitate is quickly separated by filtration, washed with ice-cold water (2×30 ml), and dried over P2O5 overnight to afford 1.74 g of methyl 3H-imidazo[4,5-b]pyridine-7-carboxylate x179.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH2:11][CH2:12][CH:13]([CH3:17])[C:14](O)=[O:15])([O:9][CH3:10])=[O:8]>C(Cl)Cl>[C:7]([CH2:11][CH2:12][CH:13]([CH3:17])[C:14]([Cl:4])=[O:15])([O:9][CH3:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCC(C)C(=O)O
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)Cl

Procedure:
9.64 g of oxalyl chloride are added to the solution of 6.1 g of 4-carbomethoxy-2-methylbutanoic acid (U.S. Pat. No. 4,052,511) in 50 ml of methylene chloride. The mixture is refluxed for two hours and evaporated, to yield the 4-carbomethoxy-2-methylbutanoyl chloride, which is used as such without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=CC([N:42]2[CH:46]=[CH:45][CH:44]=[N:43]2)=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N:42]4[CH:46]=[CH:45][CH:44]=[N:43]4)=[CH:29][CH:30]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccc(-n3cccn3)cc2)c1=O

Procedure:
Title compound 21 was prepared by the methods used in the preparation of compound 17, except that 1-(4-bromomethyl-phenyl)-1H-pyrazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.90 (d, J=2.5 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51-7.58 (m, 3H), 7.43-7.37 (m, 3H), 7.22 (d, J=7.8 Hz, 1H), 6.47 (t, J=2.1 Hz, 1H), 5.43 (s, 1H), 5.14-5.30 (ABq, J=41.2, 16.4 Hz, 2H), 5.05 (s, 2H), 3.32-3.40 (m, 2H), 2.96 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.66 (s, 2H). MS (ES) [m+H] calc'd for C27H28N7O2, 482.2; found 482.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[CH3:31][CH2:32][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1.ClCCl>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]([OH:28])[CH2:31][CH3:32])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CC[Mg+]
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(O)c1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cn1CC
Temperature: -15 °C
Yield: 46 %

Procedure:
A mixture of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25 mmol) in THF (5 mL; anhydrous) was stirred and cooled to −15° C. To this was added an excess of EtMgBr (3.1 eq; 0.25 mL of 3.0 M solution in hexane), dropwise. The mixture was stirred at −15° C. for one hour. The reaction was worked up by carefully adding 1.0 mL of saturated aqueous ammonium chloride solution, diluting with dichloromethane (30 mL) and washing with water. The organic phase was dried over MgSO4, filtered and evaporated. Two products were separated from the crude mixture by chromatography on silica gel. The column was eluted with a chloroform/methanol mixture on a gradient (9:1 through 7:3). The more polar product was isolated and crystallized from ethyl acetate/hexane to give the title product as white crystals, 0.05 g (46% yield), mp 115-121° C.; MS (ES) m/z 434.2; [M−H]−
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCCBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCCN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3-dione (1.0 g, 3.66 mmol) in anhydrous THF (18 ml) were added DBU (0.82 mL, 5.49 mmol) and methyl 4-bromobutanoate (0.6 mL, 5.49 mmol). After stirring at rt for 2 hrs, the reaction mixture was quenched with water (60 mL) and HCl (IN, 10 mL). Extraction with EtOAc (3×50 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (chexanes/Et2O (1/3)) gave the title compound as an orange powder (1.10 g, 71%) in 90.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]1[C:42]([CH2:43][NH2:44])=[CH:41][N:40]=[CH:39]1>C(Cl)Cl>[CH3:37][N:38]1[C:42]([CH2:43][NH:44][C:27]([N:11]2[CH2:12][CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[CH3:15])[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:28])=[CH:41][N:40]=[CH:39]1
Reactant: Cn1cncc1CN
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)NCc2cncn2C)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(SR)-1-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-pyrrolidine-1-carbonyl chloride (30 mg, 0.064 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 mL, 0.11 mmol) and C-(3-Methyl-3H-imidazol-4-yl)-methylamine (commercially available) (8 mg, 0.070 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH 98/2) to yield 14 mg (40%) the title compound as a white solid. ES-MS m/e: 542.2 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=1[NH:21][C:22](=[O:26])OCC)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)C=O>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:12](=[O:13])[C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=2[NH:21][C:22]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c2s1
Temperature: 150 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A mixture of ethyl (3-{[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]carbonyl}-5-ethyl-2-thienyl)carbamate (0.35 g) and N,N-dimethylformamide (5 mL) was stirred at 150° C. for 1 day. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.14 g, 45%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:14]1[CH:13]=[CH:12][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCCCl)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Aluminum chloride (26.7 g) is added to nitrobenzene (20 ml) and 4-chlorobutyric acid chloride (15.5 g) is added dropwise to the mixture with ice-cooling. Naphthalene (12.8 g) is slowly added to the mixture with ice-cooling and stirring is continued at the same temperature for 30 minutes. After stirring at room temperature for additional 2 hours, the reaction mixture is poured into ice-hydrochloric acid and extracted with chloroform. The chloroform extract is washed with water, saturated aqueous sodium bicarbonate, water and then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The dried solution is distilled. A fraction having b.p. 187°-191° C./1.6 mmHg is separated and purified by silica gel column chromatography. The product thus obtained is crystallized from hexane and then further recrystallized from hexane-petroleum ether to obtain 2-(4-chlorobutyryl)naphthalene (4.2 g) as colorless flakes, m.p. 43°-44° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)(=O)OC.[CH:24]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([CH:24]=[CH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)=[CH:27][N:28]=1
Reactant: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reactant: Cc1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCCC3)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-6 (5.5 g, 16.2 mmol), 5-formyl-2-methylpyrimidine (1-6a, 1.8 g, 14.7 mmol; for preparation, see J. Heterocyclic Chem., 28, 1281 (1991)) in 40 mL DMF was added K2CO3 (4.07 g, 32 mmol). The mixture was stirred at ambient temperature for 15 hr, and concentrated to a paste. The residue was diluted with water, extracted with ethyl acetate, and dried over magnesium sulfate. Following concentration, the residue was chromatographed on silica gel (70 chloroform/25 ethyl acetate/5 methanol) to give 1-7 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
4-Nitrophenol (2.0 g, 14.4 mmol) was dissolved in DMF (50 mL) and potassium carbonate (6.0 g, 43 mmol) and bromomethylcyclopropane (1.51 mL, 16 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous solution of sodium chloride (2×50 mL). Drying (MgSO4) and concentration afforded 2.23 g (75%) of 1-cyclopropylmethoxy-4-nitrobenzene as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2ncccc2c1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 22.9 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methylquinolin-8-amine (Intermediate 31) (70 mg, 0.44 mmol), benzenesulfonyl chloride (0.07 ml, 0.53 mmol) gave the title compound (30 mg, 23%) after purification by column chromatography with DCM as the eluent.