Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)#[CH:5]
Reactant: CCOC(=O)c1cn2cc(C#C[Si](C)(C)C)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2nc(C(=O)OCC)cn2c1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 500 mg of ethyl 6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in 10 mL of anhydrous tetrahydrofuran, cooled to 0° C. are added dropwise 1.58 mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture is stirred for 30 minutes, 5 mL of water are then added and the resulting mixture is extracted three times with 20 mL of dichloromethane. The product is purified by chromatography on silica, eluting with mixtures of ethyl acetate and hexane (from 1/3 to 1/1). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 280 mg of ethyl 6-ethynylimidazo[1,2-a]pyridine-2-carboxylate in the form of a yellow solid.
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1.[OH-].[Na+].[Cl:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29](Cl)[N:28]=1>CN(C)C=O>[Cl:26][C:27]1[N:28]=[C:29]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][C:12]3[CH:11]=[C:10]([C:9]4[C:4]([NH2:3])=[N:5][C:6]([NH2:23])=[CH:7][CH:8]=4)[O:14][N:13]=3)=[CH:17][CH:18]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cncc(Cl)n4)cc3)no2)c(N)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a methanol (1.5 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 2 N sodium hydroxide solution (89 μL), which was concentrated under a reduced pressure. 2,6-Dichloropyrazine (28 mg, 0.19 mmol) and N,N-dimethylformamide (0.75 mL) were added to the residue, which was stirred for 10 minutes at 100° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, then ethyl acetate) to obtain the title compound (47 mg, 67%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]([F:42])([F:41])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=1.Cl>O1CCCC1.COCCOC>[F:13][C:14]([F:41])([F:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](=[O:36])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][N:38]([C:33]5[N:32]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:39][CH2:40]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1cnc(N2CCNCC2)nc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ncccn2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.97 (M+H+); retention time=0.84 minutes.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:25][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:39][CH2:38][C:36]2[N:37]=[C:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:34][C:35]=2[CH3:51])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C(F)(F)F)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2cccc(C(F)(F)F)c2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-methyl-2-(3-trifluoromethyl-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 2H), 7.50-7.46 (m, 3H), 7.33 (t, 1H, J=8.21 Hz), 7.26-7.24 (m, 1H), 7.17 (d, 2H, J=8.60 Hz), 7.14-7.12 (m, 1H), 7.04-7.01 (m, 1H), 6.81 (d, 2H, J=8.60 Hz), 4.20 (t, 2H, J=5.87 Hz), 3.27 (d, 1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08 Hz), 3.07 (t, 2H, J=5.87 Hz), 2.42 (s, 3H), 1.44 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H27NO5F3 526.1841, found 526.1845.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(NC(N)=[S:25])(=O)C>C(O)C>[SH:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CS)cc2)cs1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a suspension of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (589.7 mg, 2.000 mmol) in ethanol (10 ml) was added 1-acetyl-2-thiourea (472.6 mg, 4.000 mmol), and the mixture was heated under reflux for 19 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 30 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(sulfanylmethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (507.7 mg, 1.736 mmol, yield 86.8%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19]C)=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.041 g, 0.10 mmol) in dichloromethane (1 mL) was treated with BBr3 (0.32 ml, 1.0 M solution in CH2Cl2) and stirred overnight at 20 C. The excess BBr3 is quenched with water and the resulting mixture diluted with ether (50 mL), washed twice with saturated aqueous Na2CO3 (20 mL) and concentrated. Flash chromatography (20% EtOAc in hexanes, silica) resulted in 0.037 g clear oil. MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[C:20]([CH:22]([C:30]#[N:31])[C:23]([CH3:29])([CH3:28])[C:24](OC)=[O:25])#[N:21].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[NH2:21][C:20]1[C:22]2[C:23]([CH3:29])([CH3:28])[C:24](=[O:25])[NH:31][C:30]=2[N:15]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])[N:6]=2)[N:14]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(N)c21

Procedure:
300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide were admixed with 2 ml of tert-butanol, 287 mg (1.38 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 181 mg (1.61 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 72 h. The mixture was concentrated to dryness and the residue was stirred with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theory) of the target compound were obtained.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethanol (0.8 ml), ion-exchanged water (0.2 ml), and potassium hydroxide (28 mg) were added to 2-butyl-4-chloro-1-[2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde (61 mg, 0.13 mmol) as obtained in Example 1, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 1. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). It was then dried in vacuo overnight at 37° C. to give 36 mg of 2-butyl-4-chloro-1-[2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde.
Reaction SMILES: [CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:31]([C:33]1[O:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl>[CH2:1]([N:3]([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:38]([C:36]2[O:37][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[O:39])=[C:9]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CCN(C)CCCc1ccc(N)c(N2CCC(C)CC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)CCCc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCC(C)CC2)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 4-[3-(ethyl-methyl-amino)-propyl]-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step, 32 mg, 0.11 mmol) in DCM (2 mL) at 0° C. was added DIEA (48 μL, 0.27 mmol) followed by 5-cyano-furan-2-carbonyl chloride (as prepared above, 22 mg, 0.16 mmol). The reaction was allowed to warm to RT overnight, at which time it was diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (10% MeOH—CHCl3) afforded 20 mg (45%) of the title compound as an oily amber solid. 1H-NMR (CDCl3; 400 MHz): δ 9.69 (s, 1H), 8.38 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3.6 Hz), 7.05 (d, 1H, J=2.0 Hz), 7.00-6.97 (m, 1H), 6.91 (d, 1H, J=4.0 Hz), 3.01-2.98 (m, 2H), 2.78-2.64 (m, 7H), 2.50 (s, 3H), 2.04-1.98 (m, 2H), 1.89-1.85 (m, 2H), 1.63-1.46 (m, 5H), 1.25 (t, 3H, J=4.6 Hz), 1.10 (d, 3H, J=6.4 Hz), 0.93-0.89 (m, 2H). Mass spectrum (ESI, m/z) calcd for C24H32N4O2, 409.2 (M+H). found 409.3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[N:12].N>CO.[Ni]>[NH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: N#Cc1ccc2ccccc2n1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc2ccccc2n1
Yield: 98 %

Procedure:
Combine quinoline-2-carbonitrile (0.2 g, 1.29 mmol), Raney® 3201 nickel (slurry in water, 0.05 g), 2N ammonia in methanol (10 mL) and hydrogenate at 50 psi for 15 min. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.2 g, 98%). MS (ES+) m/z: 159 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]=[C:12]([CH3:13])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3.05 g of 3-hydroxybenzaldehyde, 2.3 ml of bromoacetone and 30 ml of dimethylformamide was added 4.15 g of potassium carbonate, and this was heated and stirred at 70° C. for 30 minutes. After cooled to room temperature, insolubles were filtered and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and then extracted with ethyl acetate. The organic layer washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 0.76 g of oily 3-(2-oxo-propoxy)benzaldehyde [Compound No. (o)].
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([CH3:40])[C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[C:35]([CH3:40])=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=4[Cl:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(Cl)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-dichloro-6-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=644.6)=85%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1([CH3:32])[CH2:31][O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:28][C:29]([OH:30])([CH3:32])[CH3:31])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)O)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 2,2-dimethyloxirane (2.5 mL), cesium carbonate (1.83 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.92 g, 76%).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:32]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[C:33]([CH:41]=[CH:42][CH:43]=2)[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:14]=1.[F:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:46]([CH2:45][CH2:44][C:32]1[C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[CH:14]=[C:9]([C:54]3[CH:53]=[CH:52][CH:51]=[C:50]([F:49])[CH:55]=3)[CH:10]=2)=[CH:43][CH:42]=[CH:41][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])([OH:48])=[O:47]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(C)c1ccc(-c2cc(Br)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3cccc(F)c3)c2)cc1
Temperature: 90 °C

Procedure:
In a reaction vessel charged with 4 mL of toluene and 1 mL of water, was added 45 mg (0.072 mmol) of 4-[3-[6-(5-bromo-4′-dimethylamino-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid, 3-fluorophenylboronic acid (20 mg, 0.144 mmol), and potassium phosphate (35.9 mg, 0.144 mmol). This mixture was put under an atmosphere of nitrogen and 4.16 mg of tetrakis(triphenylphosphine)palladium(0) was added. This mixture was stirred and was heated overnight at 90° C. At this time, analysis of an aliquot by LC-MS, indicated the formation of the desired product. To the reaction mixture was added 2N HCl to effect pH=˜6. The aqueous phase was thrice extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide a solid which was purified by preparative HPLC to provide 46 mg of product. Example 57 was characterized by low resolution mass spectrometry where signals corresponding to the following were observed: ES(+)=598+Na, ES(−)=597. Example 57 was also characterized by high resolution mass spectrometry where signals corresponding to the following were observed: m/e calculated for C37H39FO6 598.273068; found compatible with (M+Na)1+=621.2624.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH:28]=[CH:29][CH2:30]Cl>CC(=O)CC>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH2:30][CH:29]=[CH:28][Cl:27])=[O:10])=[CH:4][C:3]=1[N:12]1[C:13](=[O:20])[C:14]([CH3:19])=[C:15]([CH3:18])[C:16]1=[O:17]
Reactant: ClC=CCCl
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(Cl)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)OCC=CCl)c(Cl)cc2F)C1=O

Procedure:
A mixture of 3 g of N-(2-fluoro-4-chloro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide, 4.5 g of potassium carbonate, 1 ml of 1,3-dichloropropene and 50 ml of 2-butanone is heated under reflux for 16 hours. The precipitate is separated off and the filtrate is concentrated by evaporation. 3.3 g of N-[2-fluoro-5-(3-chlorallyloxycarbonyl)-4-chlorophenyl]-2,3-dimethylmaleic acid imide are obtained in the form of an oil. Refractive index nD24 1.5640.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][O:25][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(CCO)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
4-[4-(2,4-Dihydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (3.75 g, 9.9 mmol), tosyl chloride (2.07 g, 10.8 mmol), dichloromethane (38 ml) and triethylamine (2.75 ml, 19.7 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.16 ml, 1.0 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→40:60) to afford the title compound as a colorless oil (4.69 g, 89%).