Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:25]2[CH2:26][CH2:27][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24]2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(-c2ccc(CC=O)cc2OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(-c2ccc(CCN3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)cc1
Reaction time: 16 h

Procedure:
A solution of Example 491C (400 mg, 1.41 mmol) and tert-butyl 1-piperazinecarboxylate (289 mg, 1.55 mmol) in 1,2-dichloroethane (5 mL) at room temperature was treated with sodium triacetoxyborohydride (329 mg, 1.55 mmol), and stirred for 16 hours. The solution was purified by flash column chromatography on silica gel with 90:10:0.25 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:34]([O:33][C:5]([CH3:32])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)[C:4]([OH:38])=[O:3])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-Butoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with 1N HCl, extracted, dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.22 (t, 1H, J=8.0 Hz), 7.07 (d, 2H, J=8.5 Hz), 6.83-6.79 (m, 3H), 6.72 (d, 2H, J=8.5 Hz), 4.38, 4.30 (ABq, 2H, J=15.1 Hz), 3.95 (t, 2H, J=6.0 Hz), 3.78 (s, 3H), 3.69-3.62 (m, 1H), 3.60-3.54 (m, 1H), 3.50-3.45 (m, 1H), 3.50-3.45 (m, 1H), 3.40 (t, 1H, J=9.0 Hz), 3.03-3.00 (m, 1H), 3.01, 2.95 (ABq, 2H, J=14.6 Hz), 2.85 (s, 3H), 2.26-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.62-1.55 (m, 2H), 1.48 (s, 3H), 1.42 (m, 2H), 0.93 (t, 3H, J=7.0 Hz). MS [EI+] 499 (M+H)+, [EI−] 497 (M−H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:17])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Reaction time: 20 h
Yield: 56.6 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (112KK03) (0.123 g, 0.47 mmol), 4-butylpiperidine (0.074 g, 0.52 mmol), NaI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were purified by cation exchange CC followed by purification by flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (112KK07) (0.097 g, 57%). 1H NMR (CD3OD) δ 7.20-7.09 (m, 2H), 3.91 (t, J=7.2 Hz, CH2), 2.90-2.82 (m, 4H), 2.59-2.55 (m, 2H), 2.38-2.34 (m, 2H), 1.97-1.91 (m, 2H), 1.82-1.75 (m, 2H), 1.66 (d, J=9.8 Hz, 2H), 1.28-1.16 (m, 9H), 0.87 (t, J=6.7 Hz, CH3); 13C NMR (CD3OD) δ 172.1, 150.4 (q, J=243.2 Hz, J=13.2 Hz), 146.9 (q, J=243.2 Hz, J=12.6 Hz), 137.3 (q, J=8.1 Hz, J=2.9 Hz), 124.9 (q, J=5.8 Hz, J=3.9 Hz), 117.6 (d, J=18.7 Hz), 106.4 (d, J=22.6 Hz), 56.8, 55.0, 41.8, 37.4, 36.8, 33.1, 32.4, 30.1, 25.5, 25.3, 23.9, 14.4.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5]([CH3:14])=[C:6]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.Br.CC(C)=O>C(O)(=O)C>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[CH3:14]
Reactant: CC(=O)Cc1cccc(F)c1C
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1c(F)cccc1CC(=O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
Analogously to the procedure described in H. Y. Choi et al., Org. Lett. 5 (2003), 411, a solution of bromine (8.46 g, 52.95 mmol) in acetic acid (12 ml) was added at 0° C. to a solution of 1-(3-fluoro-2-methyl-phenyl)-propan-2-one (4.00 g, 24.07 mmol) in acetic acid (4 ml) and a 33% solution of hydrogen bromide in acetic acid (4 ml). The mixture was warmed to room temperature and stirred for 12 h. Then acetone was added and the mixture was stirred for 24 h. After evaporation under reduced pressure, the residue was extracted several times with DCM. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative HPLC to give 4.10 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])[CH:18]=1
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)c(OC)c1
Yield: 68.2 %

Procedure:
A solution of 2-acetoxypropionyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by column chromatography to give the desired product in 68.2% yield. (m.p. 179-180° C.)
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=2[S:6][C:5]=1[S:18][CH3:19])([OH:3])=[O:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:2][C:1]([C:4]2[C:9](=[O:10])[C:8]3[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=3[S:6][C:5]=2[S:18][CH3:19])=[O:3])=[CH:24][CH:23]=1
Reactant: CSc1sc2c(F)c(F)c(F)cc2c(=O)c1C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC(=O)c2c(SC)sc3c(F)c(F)c(F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a suspension of 50 mg (0.163 mmol) of the compound of Example 112 in 0.2 ml of chloroform were added 30.7 mg (0.196 mmol) of p-methoxybenzyl chloride, 16.5 mg (0.163 mmol) of triethylamine and 29.4 mg (0.196 mmol) of sodium iodide, and the mixture was stirred for 5 hours at room temperature, which was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water and with saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (CHCl3) to obtain 22.5 mg (0.0528 mmol) of title compound (yield 32%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl.CO>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([S:12][CH3:13])[CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2cc(SC)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Yield: 92 %

Procedure:
A solution of 50 mg of ethyl 4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxylate in 200 μL of 4-chlorobenzylamine is heated at 190° C. under argon for 16 h, then cooled and diluted with CHCl3 and MeOH. The solution is washed with dil. HCl, dried (Na2SO4), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 2-4% MeOH in CH2Cl2 affords 62.4 mg (92%) of N-(4-chlorobenzyl)-4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxamide.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:16][CH3:17])=[O:2]
Reactant: O=C(O)CSCCCCC1=CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CSCCCCC1=CCCC1=O

Procedure:
In the manner described in Example 23, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[CH3:17]
Reactant: O=Cc1cccc(Br)c1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=Cc1cccc(Br)c1

Procedure:
In analogy to example 74, step 1, from 3-bromobenzaldehyde and ethyl cyanoacetate was prepared the title compound as a white solid, MS (EI+): m/z=279 ([M]+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(F)c1CCl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3c(F)cccc3F)c2c1

Procedure:
The titled compound (20 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,6-difluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].CC(=O)OCC>O>[OH:13][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4.27 g 5-amino-2-methylbenzoic acid (see below), 6 ml concentrated sulfuric acid and 10 ml water, 50 ml ice are added, and a solution of 2.1 g sodium nitrite in 15 ml water is added drop wise, maintaining a temperature of the reaction mixture below 7° C. After stirring this mixture for further 30 min, it is added drop wise to a refluxing mixture of 20 ml concentrated sulfuric acid and 20 ml water. The resulting mixture is held under reflux for further 10 min and stirred over night allowing the temperature to cool down to RT. The mixture is portioned between water and EA, the phases are separated, the organic phase is dried over MgSO4, and the solvent is removed under reduced pressure. For further purification the remaining crude product is solved in diethyl ether, and the organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure, resulting in 5-hydroxy-2-methylbenzoic acid as the product, which is used for the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=[O:21]>C1C=CC=CC=1>[OH:21][CH2:20][N:13]1[CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Reactant: C=O
Solvent: c1ccccc1
Product: OCN1CCN=C1CC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 0.75 g of 2-(2,2-diphenyl ethyl)-2-imidazoline, 0.3 g of paraformaldehyde and 5 ml of benzene was refluxed about 2 hours to give 1-hydroxymethyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 161° to 163° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OC)[CH:11]=[CH:10][C:9]=1[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C.[C:22](O)(C(F)(F)F)=[O:23]>C1COCC1>[CH2:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[C:10]([O:23][CH3:22])[CH:11]=[CH:12][CH:13]=2)[CH3:19]
Reactant: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1cc2c(OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of [5-methoxy-2-(2-oxo-butyl)-phenyl]-carbamic acid t-butyl ester 73b (1.36 g, 4.65 mmole) in 10 ml THF was added 4 ml TFA. The reaction mixture was stirred at room temperature for 5 h, quenched with 50 ml H2O and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10–15% EtOAc in hexane) to give pale yellow solid (1.36 g, 73%). 1H NMR (CDCl3) δ 7.75 (1H, bs), 7.49 (1H, d, J=8.6 Hz), 6.81 (1H, s), 6.73 (1H, d, J=8.6 Hz), 3.83 (3H, s), 2.75 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz). ESIMS (MH+): 272.10.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:32][CH:27]4[CH2:26][C:25]5[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=5)[CH2:28]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H31Cl2N3O (m/e) calcd 471.1844, obsd 472.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>>[OH:36][C:37]([CH3:42])([CH3:41])[C:38]([N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)=[O:39]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)C(C)(C)O)CC3)cc1OCC2
Yield: 42.7 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (350 mg, 0.71 mmol), 2-hydroxyisobutyric acid (111 mg, 1.07 mmol), EDCI (327 mg, 1.7 mmol, HOBt (230 mg, 1.7 mmol) and DIPEA (0.36 mL, 2.13 mmol) was stirred at RT for 5 h before the addition of saturated aqueous sodium bicarbonate. The resultant mixture was extracted with DCM (2×30 mL), the combined extracts washed with brine then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) then freeze dried to give 227 as a white solid (141 mg, 43%). 1H NMR δ (ppm) (DMSO-d): 8.31 (1H, d, J=8.29 Hz), 7.82 (1H, s), 7.78 (1H, s), 7.03 (1H, d, J=8.38 Hz), 6.90 (1H, s), 5.85-5.77 (1H, m), 4.69 (2H, d, J=13.25 Hz), 4.48 (4H, t, J=7.99 Hz), 2.91-2.74 (4H, m), 1.85 (2H, d, J=13.04 Hz), 1.63-1.49 (2H, m), 1.49 (6H, d, J=6.64 Hz), 1.37 (6H, s). LCMS: RT=3.92 min, M+H+=465
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH:13]12[CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[CH2:20][OH:21].[I:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[I:22][C:23]1[CH:28]=[CH:27][C:26]([O:21][CH2:20][CH:14]2[CH2:15][CH:16]3[CH2:19][CH:13]2[CH:18]=[CH:17]3)=[CH:25][CH:24]=1
Reactant: OCC1CC2C=CC1C2
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccc(OCC2CC3C=CC2C3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
Diethylazodicarboxylate (8.7 g) was added dropwise to a solution of 5-norbornene-2-methanol (6.2 g, 0.05 mol), 4-iodophenol (11.0 g, 0.05 mol) and triphenylphosphine (13.1 g, 0.05 mol) in 100 mL of anhydrous tetrahydrofuran. After completion of the addition, the resulting solution was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the oily residue was extracted three times with hot hexane. Combined hexane extracts were evaporated under reduced pressure to give 8 (15.0 g, 97%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
A mixture of (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 93.1, 60 mg, 0.110 mmol), pyrimidin-5-ylboronic acid (21 mg, 0.164 mmol), 2M Na2CO3 (0.2 mL, 0.4 mmol) and DME (4 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=0.88 min, m/z=445.0 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[NH:20][C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
DIPEA (102 mg, 0.14 mL, 0.79 mmol) was added to a stirred solution of 5-phenyl-1H-pyrrole-2-carboxylic acid (37 mg, 0.19 mmol) in DMF (4 mL). HOBT (30 mg, 0.22 mmol) and EDCI (57 mg, 0.29 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (83.6 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 69 mg (72% yield) of 5-phenyl-1H-pyrrole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 89.78%. 1H NMR (DMSO-d6): δ 11.7 (s, 1H), 8.2-8.1 (bs, 1H), 7.9-7.7 (s, 4H), 7.7-7.6 (s, 1H), 7.6-7.5 (s, 1H), 7.45-7.3 (t, 2H), 7.3-7.2 (t, 1H), 6.9-6.8 (s, 1H), 6.6-6.5 (s, 1H), 4.28-4.04 (d, 2H), 3.84-3.5 (bs, 4H), 3.5-3.4 (s, 2H), 3.2-3.0 (d, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[C:8]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: Nc1ccc(CCO)cc1
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Nc3ccc(CCO)cc3)c21
Yield: 41.3 %

Procedure:
Following general procedure H, 2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.200 g, crude) was reacted with 2-(4-aminophenyl)ethanol (0.034 g, 0.25 mmol) to afford the title compound (0.040 g, 20%) as a white solid. MW=387.50. 1H NMR (DMSO-d6, 500 MHz) δ 8.57 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.62 (t, J=5.5 Hz, 1H), 3.70-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.93 (t, J=6.5 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.37-2.29 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.54 (m, 6H); APCI MS m/z 388 [M+H]+.