Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(=O)CC(O)=O)CC1.NN.[CH:12]1([C:15]2[CH2:19][C:18](=[O:20])[NH:17][N:16]=2)[CH2:14][CH2:13]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N+:25]([O-])=[CH:24][CH:23]=1.C([NH:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1)(=O)C>C(O)C.C(OC(=O)C)(=O)C.C(O)(=O)C>[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([S:43][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25]/[C:24](=[C:19]3/[C:15]([CH:12]4[CH2:14][CH2:13]4)=[N:16][NH:17][C:18]/3=[O:20])/[CH:23]=2)=[CH:39][CH:38]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1CC(C2CC2)=NN1
Reactant: [O-][n+]1ccc(Cl)c2ccccc21
Agent: NN
Agent: O=C(O)CC(=O)C1CC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C3CC3)Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 15 h

Procedure:
3-Cyclopropyl-3-oxo-propionic acid (0.5 g, 3.2 mmol) was stirred in ethanol and acetic acid (10:1, 2.2 mL) and treated with hydrazine (0.12 mL, 3.8 mmol). After 15 hrs, the solid was filtered off and washed with a minimum amount of ethanol. Then, the product (3-cyclopropyl-1H-pyrazol-5(4H)-one) (0.4 mmol) and 4-chloroquinoline N-oxide (0.087 g, 0.48 mmol) were stirred in acetic anhydride (1 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and carried out to the next step with out any purification. The resulting (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.076 g, 0.45 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 30 minutes. The mixture was concentrated and purified by LC-MS to give the title compounds of Example 14 and Example 15.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[N:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2ccn[nH]2)cc1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(n2nccc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 5-(4-chloro-phenyl)-1H-pyrazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](N(OC)C)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[Li]>O1CCCC1>[CH2:1]([N:4]([CH2:12][C:13](=[O:14])[C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1cccs1)C(=O)OC(C)(C)C
Yield: 56 %

Procedure:
To a solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (25 g, 96.8 mmol) in tetrahydrofuran (339 mL) at −78° C. is added drop wise 2-thienyllithium (145 ml, 1 M in tetrahydrofuran) over 20 min. The reaction is carefully quenched with aqueous ammonium chloride (20 mL), diluted with water (100 mL), and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (5:1) to give the title compound (15.2 g, 56%). ES/MS (m/e): 182 (M+H-100).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:26][CH3:27])([C:15]2[S:19][C:18]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:17]=3[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:28].[CH2:30]1[CH2:34]OCC1.[CH2:35]([Mg]Br)[CH3:36]>[Cl-].N>[CH2:13]([C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])([CH2:35][CH3:36])[CH2:30][CH3:34])=[C:7]([CH3:28])[CH:8]=1)([C:15]1[S:19][C:23]2[CH:22]=[C:21]([O:24][CH3:25])[CH:20]=[CH:18][C:17]=2[CH:16]=1)[CH2:26][CH3:27])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc2ccc(OC)cc2s1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: N
Agent: [Cl-]
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(OC)cc3s2)cc1C
Yield: 56 %

Procedure:
To a mixture of {4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxy}-acetic acid methyl ester (1.50 g, 3.64 mmol) and THF (20 mL) is added ethyl magnesium bromide (3.0 mL, 9.1 mmol, 3M in THF). The solution is heated at a reflux for 3 h, diluted with saturated ammonia chloride solution (80 mL), extracted with diethyl ether (2×75 mL), dried over MgSO4, filtered, and concentrated. The residue is purified by silica gel chromatography (10% to 30% EtOAc gradient) to give the title compound (0.90 g, 2.04 mmol, 56%). 1H NMR (CDCl3), δ 0.75 (t, J=7.6 Hz, 6H), 0.95 (t, J=7.4 Hz, 6H), 1.68 (q, J=14.8, 7.5 Hz, 4H), 2.13-2.24 (m, 7H), 3.81 (s, 2H), 3.86 (s, 3H), 6.73 (dd, J =8.2 Hz, 1H), 6.89 (dd, J =8.8, 2.6 Hz, 1H), 7.06 (s, 2H), 7.09 (dd, J=8.4, 2.5 Hz, 1H), 7.17 (d, J=2.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H). LC/MS (m/z): calcd. for C27H37O3S (M+H)+: 441.3; found: 441.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[Li]CCCC.[CH:19]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:26]=2[N:27]=1)([CH3:21])[CH3:20].CCOC(C)=O.CCCCCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:32]([C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([NH:22][CH:19]([CH3:20])[CH3:21])[S:24][C:25]=3[CH:31]=2)[OH:33])[S:9][CH2:10][CH2:11][CH2:12][S:13]1
Reactant: Fc1ccccc1C1SCCCS1
Reactant: CC(C)Nc1nc2ccc(C=O)cc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Nc1nc2ccc(C(O)C3(c4ccccc4F)SCCCS3)cc2s1
Reaction time: 2.5 h
Yield: 74 %

Procedure:
To a solution of 2-(2-fluorophenyl)-1,3-dithiane (0.820 g, 3.83 mmol) in THF (25 mL) was added n-BuLi (1.6 M in hexane, 2.3 mL, 3.68 mmol) at −10° C. over 10 min. The resulting solution was stirred at −10° C. for 30 min before a solution of 2-(isopropylamino)benzo[d]thiazole-6-carbaldehyde (0.385 g, 1.75 mmol) in THF (5 mL) was added. The mixture was stirred at between −10° C. and 5° C. for 2.5 hr, and then quenched with saturated NH4Cl solution (25 mL). This was extracted with AcOEt (3×20 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The title compound (0.563 g, 74% yield) was isolated as a pale yellow solid by silica gel chromatography (35% AcOEt/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:10]([CH:28]([CH3:30])[CH3:29])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:33].Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[CH2:47]([NH2:51])[CH:48]([CH3:50])[CH3:49]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:31]=[CH:32][C:2]([NH:1][C:35]([NH:51][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:36])=[C:3]([F:33])[CH:4]=3)[CH2:9][C@@H:10]2[CH:28]([CH3:29])[CH3:30])[CH:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)[C@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN
Solvent: ClCCl
Product: CC(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)[C@@H](C(C)C)C2)cc1F
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a stirred solution of (S)-3-((4-(4-amino-3-fluorobenzoyl)-2-isopropylpiperazin-1-yl)methyl)-N-tert-butylbenzamide (40 mg, 0.088 mmol) in dichloromethane (2 mL) at room temperature was added 4-nitrophenyl chloroformate (18.62 mg, 0.092 mmol). The reaction mixture was stirred for 1 hour before the addition of isobutylamine (6.44 mg, 0.088 mmol). After 2 hours stirring, the reaction mixture was applied to a silica carbonate column (2 g). The eluant was concentrated under vacuum and redissolved in methanol. Purification by HPLC gave the title compound (3 mg). MS (ESI) m/z 554.3 [M+H]+
Reaction SMILES: CS([O:5][C@@H:6](C)[C:7]([C:15]1C=CC=CC=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O)(=O)=O.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([Al](CC)CC)C>C(Cl)Cl.P([O-])([O-])([O-])=O.C(OCC)(=O)C>[C:24]1([C:6](=[O:5])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:15])[CH:23]=[CH:22][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](OS(C)(=O)=O)C(O)(c1ccccc1)c1ccccc1
Reactant: CCCCCC
Agent: CC[Al](CC)CC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol (153 mg, 0.5 mmol) present in 5 ml of CH2Cl2 in Referential example 3 was added a hexane solution of triethylaluminum (0.6 mmol, 0.7 ml) slowly at -78° C. The color of the solution changed to yellow. After stirred further for 30 minutes, the reaction was stopped with three drops of phosphate buffer solution having a pH value of 7. The suspension obtained was diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated. Oily residue was subjected to the chromatography treatment with Florisil column to obtain 1,2-diphenyl-1-propanone (100 mg, 96%).
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[CH2:30]([Mg]Br)[CH3:31]>O1CCCC1>[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][C:17]1[O:18][C:14]2[CH:15]=[CH:27][C:11]([C:7]3[CH:6]=[C:5]([C:4](=[O:28])[CH2:30][CH3:31])[CH:10]=[CH:9][CH:8]=3)=[CH:12][C:13]=2[CH:16]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The product from Example 145 (20 mg, 0.05 mmol) was dissolved into tetrahydrofuran (900 μL), cooled to 0° C., and treated with 1.0 M ethylmagnesium bromide in tetrahydrofuran (150 μL, 150 μmol). The reaction mixture was then stirred at room temperature overnight, quenched by the addition of saturated aqueous NH4Cl, and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc, and the combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.] to provide the title compound (44% yield). MS (ESI APCI) m/z 362 (M+H)+; HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.21 (t, 3 H), 1.39-1.53 (m, 1 H), 1.74-1.87 (m, 2 H), 1.95-2.09 (m, 1 H), 2.24-2.37 (m, 1 H), 2.42-2.61 (m, 2 H), 2.94-3.18 (m, 4 H), 3.20-3.35 (m, 2 H), 6.63 (s, 1 H), 7.50-7.52 (m, 2 H), 7.58 (dd, 1 H), 7.77-7.79 (m, 1 H), 7.87 (ddd, 1 H), 7.96 (ddd, 1 H), 8.22 (dd, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]([CH2:27][CH3:28])[N:19]=2)=[CH:14][CH:13]=1)=[O:11].CI.[C:31]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:27]([N:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([C:2]3[N:1]([CH3:31])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:11])=[CH:17][CH:16]=2)=[N:19]1)[CH3:28]
Reactant: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)c2ncccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A suspension of 1H-benzimidazol-2-yl[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl]methanone (147 mg), MeI (0.037 mL), and K2CO3 (111 mg) in DMF (1.5 ml) was stirred overnight at 40° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (139 mg).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>CN(C)C=O>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1cccnc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2ncccc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a mixture of 2-fluoro-nicotinonitrile (400 mg, 3.3 mmol) and 1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N,N-dimethylformamide (30 mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction was stirred overnight at rt. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (8:1) to give the title compound (210 mg, 29%). MS (DCI/NH3) m/z 218 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: COc1ccnc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccnc(-c2ccc(Cl)c(N)c2)c1
Yield: 98.1 %

Procedure:
To a suspension of 1-chloro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg) in ethanol (6 ml) and water (0.6 ml) were added iron powder (206 mg) and ammonium chloride (28 mg), and the mixture was refluxed for 3 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-chloro-5-(4-methoxypyridin-2-yl)aniline (174 mg).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Li]CCCC.Cl[CH2:17][CH2:18][CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([CH2:19][CH2:18][CH2:17][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: [Li]CCCC
Product: Fc1ccc(C2(CCCN3CCc4ccccc4C3)OCCO2)cc1
Yield: 16 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline, n-BuLi, and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane were allowed to react under conditions analogous to Example 1, Method C. Flash chromatographic purification provided 4A (16% yield) as a yellow oil. 1H NMR(300 MHz, CDCl3, δ): 7.44-7.39 (m, 2H), 7.15-6.98 (m, 6H), 4.08-3.96 (m, 2H), 3.83-3.71 (m, 2H), 3.57 (s, 2H), 2.87 (t, 2H, J=6 Hz), 2.67 (t, 2H, J=6 Hz), 2.47 (t, 2H, J 7 Hz), 1.96-1.91 (m, 2H), 1.69-1.59 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)(Cl)Cl>[F:19][C:20]([F:27])([F:26])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: NCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cc(-c2cccs2)[nH]c1-c1cccs1)C(F)(F)F
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution containing 100 mg (0.36 mmol) of 3-(2-aminoethyl)-2,5-dithienylpyrrole (XXII), 2 mL of ethyl trifluoroacetate, and 5 mL of CHCl3 was allowed to stand at ambient temperature overnight. The CHCl3 solvent was removed in vacuo, and the product XXIII isolated by preparative SiO2 -TLV plates (20×20×1000u) eluted with a 9:1 toluene-dioxane solvent mixture. Sixty mg of compound XXIII was obtained (45% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36](=[O:43])[CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CN(C=O)C.O>[O:43]=[C:36]([CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NCC(=O)Cc1cccs1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)Cc3cccs3)nc12
Reaction time: 48 h
Yield: 16.7 %

Procedure:
0.41 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.14 g 1,1′-carbonyl-diimidazole in 11 ml DMF were stirred at room temperature for 16 hours. 0.16 g 1-amino-3-thiophen-2-yl-propan-2-one hydrochloride and 0.23 ml triethylamine were added and stirring was continued for two days at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 3:7–7:3 to yielded 0.06 g (18%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-3-thiophen-2-yl-propyl)-amide as a yellow solid; MS (ISP): m/e=432 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C(OCC)(=O)C.O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A solution of (S)-2-hydroxy-3-(4-hydroxy-phenyl)-propionic acid (3.00 g, 16.47 mmol) in ethanol (50 mL) was treated with benzyl chloride (4.20 g, 33.18 mmol) and potassium carbonate (4.60 g, 33.28 mmol) and the resulting mixture heated at reflux overnight. The mixture was cooled and treated with water (50 mL), and the resulting mixture stirred for 1 h. At this time ethyl acetate was added and the mixture acidified with 1N aqueous hydrochloric acid. The layers were separated and the aqueous phase extracted with ethyl acetate (3×). The organic phases were combined and concentrated in vacuo to an approximate volume of 10 mL. The resulting mixture was filtered and the isolated solid washed with diethyl ether and dried to afford (S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (3.00 g, 67%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]([O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:25]([C@@H:27]1[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][N:29]([C@H:38]([CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[C:39]([O:41]CC2C=CC(OC)=CC=2)=[O:40])[CH2:28]1)=O>>[CH2:8]([NH:15][C:16]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C@@H:27]2[C@@H:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][N:29]([C@H:38]([CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[C:39]([OH:41])=[O:40])[CH2:28]2)[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCc1ccccc1)OC1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1)OC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 63.7 %

Procedure:
The title compound was prepared from 4-((N-benzylcarbamoyl)oxy)-piperidine trifluoroacetate (35 mg, 0.1 mmol, from Step B) and (R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.05 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 17 mg (64%) of the title compound. ESI-MS: 534.5 (M+H); HPLC A: 2.16 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[OH:22][C:23]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:24]=1[CH:25]=[O:26]>C1COCC1.O>[OH:26][CH:25]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1)[C:24]1[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:23]=1[OH:22]
Reactant: Cc1cc(C)c(C=O)c(O)c1
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)c2ccc(C(C)C)cc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 1-bromo-4-isopropylbenzene (3.32 g, 16.7 mmol) in THF (30 mL) was added dropwise n-butyllithium (a 1.59 M hexane solution, 9.2 mL, 14.7 mmol) under argon atmosphere at −78° C. The reaction solution was stirred for 30 minutes, a solution of 2-hydroxy-4,6-dimethylbenzaldehyde obtained in Reference Example 146 (1.0 g, 6.7 mmol) in THF (10 mL) was added dropwise thereto at −78° C., and the mixture then was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1.64 g (yield 91%) of the title compound. Melting point: 103-104° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[NH2:25][C:26]1[N:31]=[C:30]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:15][CH:16]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)c3ccccc3Nc3ccc(F)cc3)cc2)n1
Temperature: 150 °C

Procedure:
A mixture of 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide (157 mg, 486 μmol), 2-amino-4-chloropyrimidine (60 mg, 463 μmol), and cesium carbonate (302 mg, 926 μmol) in DMSO (2316 μl, 463 μmol) was placed in a microwave pressure vial, the vial was sealed, and the vial (reaction mixture) was heated in a Biotage Microwave to 150° C. for 12 minutes. LCMS analysis indicated that the reaction was complete. Reaction was diluted with EtOAc and washed with sat NaHCO3 (aq). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a brown color oil. The oil was taken up in minimal amount of DMSO and purified by Gilson HPLC {10-80% (0.1% TFA in CH3CN) in H2O over 20 min} to afford pure N-(4-(2-aminopyrimidin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide. MS Calcd for C23H18FN5O2=415. Found: [M+H]+=416.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].CS(C)=[O:22].O>CS(C)=O.O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([OH:18])(=[O:22])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CS(C)=O
Solvent: O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)O)c(C(C)C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 30.2 g (0.1 mol) of commercially available 2,4,6-triisopropylbenzenesulfonyl chloride were added 30 g of dimethyl sulfoxide and 30 g of water. Using an oil bath, the mixture was heated and stirred at 80° C. for 3 hours. The dimethyl sulfoxide-water solution was ready for use in the subsequent step of anion exchange reaction.