Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC>CCOCC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:14]1[CH2:13][CH:12]2[CH:11]=[CH:10]1
Reactant: Fc1cccc(F)c1I
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cccc2c1C1C=CC2C1

Procedure:
A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P, ether (70 mL, 40-60° C.) under N2 and treated with n-BuLi (8.74 mL, 2.5M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous 1N HCl solution and the product was extracted with hexanes (3×50 mL). The combined organic layer was washed with H2O (50 mL), saturated aqueous NaCl solution (50 mL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes Rf0.55). 1H NMR (400 Mhz, CDCl3) δ7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5,8.3,7.0 Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2,1.7,1.7 Hz, 1H), 2.30 (ddd, J=7.2,1.7,1.5 Hz, 1H), GCMS m/e 160 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9](C2C=C3C(=CC=2)CN(S(C2C=CC(C)=CC=2)(=O)=O)CC3)[CH2:8]1.[CH3:32][O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44](Br)[CH:45]=[CH:46][C:39]=2[CH2:38][CH2:37]1)=[O:35].C[C@H]1CCCN1[C@H]1CCNC1>>[CH3:32][O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44]([N:9]3[CH2:10][CH2:11][C@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)[CH:45]=[CH:46][C:39]=2[CH2:38][CH2:37]1)=[O:35]
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1
Reactant: COC(=O)N1CCc2ccc(Br)cc2CC1
Agent: C[C@H]1CCCN1[C@H]1CCNC1
Product: COC(=O)N1CCc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2CC1

Procedure:
This intermediate was synthesized in substantially the same way as intermediate (vi), 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline, by condensation of 7-bromo-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid methyl ester with (2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 65 °C
Yield: 99 %

Procedure:
A mixture of 1-(4-hydroxyphenyl)ethanone (20.4 g, 150 mmol), K2CO3 (62.1 g, 3.0 eq.), and 3-bromo-1-chloropropane (29.6 mL, 2.0 eq.) in CH3COCH3 (200 mL) was heated to 65° C. overnight. The mixture was filtered, washed with acetone, and concentrated to dryness. The crude product was dissolved in 150 mL of CH2Cl2, and washed with saturated NaHCO3, NaCl solution and dried over Na2SO4. Concentration to dryness under vacuum afforded product (31.5 g, 99% yield): MS m/z 213 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH3:31][O:32][CH2:33][C:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>>[CH3:31][O:32][CH2:33][C:34]([C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:41][CH:42]=1)([CH3:36])[CH3:35]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: COCC(C)(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: COCC(C)(C)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Off-white crystalline solid. MS (ESI): 541.19 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(2-methoxy-1,1-dimethyl-ethyl)-phenylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[S:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccsc1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1ccsc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and thiophene-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([N:25](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:16])[NH:17][NH2:25])=[N:6]1
Reactant: CCN(CC)CC
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ncc2c(C(=N)NN)nn(Cc3cccc(F)c3F)c2n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Under an argon atmosphere, 440 mg (1.237 mmol, purity 85%) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 6 ml of ethanol and cooled to 0° C. 500 mg (4.49 mmol) of triethylamine and 85 mg (1.361 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 72 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 421 mg (purity 84%, 90% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][CH2:65][C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@H:66]1[CH2:65][O:64][CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: COC[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-methoxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Br:1]C1C=CC(CC(OCC)=O)=CC=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:15]=1)[C:22](=[O:25])[CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Product: CC1(C)CCC(=O)c2ccc(Br)cc21

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Med Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[C:9](OC(=O)C)(=[O:11])[CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:9]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C(OC(C)=O)C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
First, to a mixture of ethyl pyruvate (315 g, 2.7 mol) and acetic anhydride (554 g, 5.4 mol), p-toluenesulfonic acid monohydrate (8 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 24 hours to obtain a reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (40 to 50 mmHg) was removed from the reaction solution. Thereafter, the residue was purified by reduced pressure distillation (35 to 40 mmHg, 90 to 103° C.) to obtain ethyl α-acetoxyacrylate (250 g, yield 58%).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].CCCCCC.C([Li:21])CCC>C1COCC1>[CH:1]([N-:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[Li+:21]
Reactant: CC(C)NC1CCCCC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[N-]C1CCCCC1
Product: [Li+]
Temperature: -78 °C

Procedure:
A solution of 0.315 mL of freshly distilled isopropylcyclohexylamine in 2 mL of dry THF was placed in a 25 mL flask. A second solution was prepared by dissolving 0.315 mL of the same amine in 1.5 mL of THF in a 5 mL flask. Both solutions were cooled to -78° C. while stirring under an inert atmosphere and treated with 1.2 mL of a 1.6M hexane solution of n-butyl lithium, dropwise from a syringe over 1.5 minutes in order to form lithium isopropylcyclohexylamide. To the first solution was added, dropwise over 6 minutes, 500 mg of (9) in 1 mL of THF. The reaction was stirred at -78° C. for 5 minutes, then a solution of 0.12 mL of diethylcarbonate in 0.5 mL of THF was added, dropwise over 10 minutes via syringe. After 3 additional minutes, the second solution of lithium isopropylcyclohexylamide was added followed by an additional 0.12 mL of diethyl carbonate. After 20 minutes at -78° C., the reaction was allowed to warm to room temperature and stir for 10 minutes following which it was neutralized with 0.2 mL of acetic acid in 2 mL of H2O. The reaction was partitioned between 100 mL of H2O and 35 mL of ether. The ether phase was separated, dried, filtered, evaporated, and the residue dried under high vacuum to give a yellow oil. It was chromatographed on 60 g of silica gel eluting with 29:1 (v/v) CH2Cl2 :EtOH. Nine mL fractions were collected. Fractions 29-51 were combined and evaporated to give 548 mg (86% yield) of the ester (10) as a clear, pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22](C(F)(F)F)[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:32](N(C(C)C)CC)([CH3:34])[CH3:33].BrC(C)C.[I-].[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:32]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:2]([F:7])([F:6])[F:1])[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12]1)([CH3:34])[CH3:33]
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(c2cc(-c3ccccc3C(F)(F)F)nc(C#N)n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 1; 50 mg) in acetonitrile (1 ml) was added diisopropylethylamine (39 μl) and 2-bromopropane (15.5 μl). The resulting solution was subjected to microwave heating at 150° C. for 5 mins. Sodium iodide (2 mg) was added and the reaction mixture was subjected to further heating at 180° C. for 30 mins. Reaction mixture was concentrated in vacuo and the residue was dissolved in methanol and purified using the prep-HPLC to give 4-(4-isopropyl-piperazin-1-yl)-6-(trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (10 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1O)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.CO>[CH3:13][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (1.0 g) in ether (5 mL) and methanol(5 mL) was treated with excess trimethylsilyldiazomethane. After stirring 30 min at room temperature the reaction was treated with magnesium sulfate, filtered and concentrated to a brown solid. The title compound was obtained by purification on silica gel to give a colorless solid (670 mg). NMR (CDCl3); δ 7.75 (s,2H), 3.85 (s,3H), 2.30 (s,6H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:10][Si:9]([CH3:11])([C:5]([CH3:8])([CH3:7])[CH3:6])[O:4][CH2:1][C:2]#[CH:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCO[Si](C)(C)C(C)(C)C

Procedure:
A solution of propargyl alcohol (8.7 ml), t-butyldimethyl silyl chloride (25. g) and 4-dimethylaminopyridine (0.73 g) in methylene chloride (45 ml) was cooled to 0°. Triethylamine (25.1 ml) was added dropwise over 5 mins with stirring. After 18 h the mixture was diluted with methylene chloride (50 ml) and extracted with water (2×75 ml). The aqueous solutions were combined and then extracted with methylene chloride (25 ml). The organic phases were combined and washed with water and saturated aqueous ammonium chloride, dried and evaporated to give an oil (24.9 g). Distillation under reduced pressure afforded the title compound as an oil (20.8 g); bp 60°-62° (24 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)ccc3Cl)cc2)c1C
Yield: 33.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 33%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][C@H:9]1[CH2:16][O:17][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](N(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethyl pyrrolidine (180 mg, 0.73 mmol), methyl 4-hydroxybenzoate (114 mg, 0.75 mmol), and Ph3P (296 mg, 1.13 mmol) in THF (10 ml) was added DIAD (227 mg, 1.13 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) to MeOH—CH2Cl2(5:95, v/v) as eluent to give methyl 4-[trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl]methoxybenzoate (180 mg, 68%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.46 (s, 9H), 1.80–1.95 (m, 1H), 2.20–2.23 (m, 1H), 2.24 (s, 6H), 2.90–2.95 (m, 1H), 3.10–3.30 (m, 1H), 3.50–3.65 (m, 1H), 3.88 (s, 3H), 3.95–4.35 (m, 3H), 6.93–6.95 (m, 2H), 7.96–7.98 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: NCCCCO
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN(CCCCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
To a three-neck flask fitted with a mechanical stirrer, a thermometer, and a condenser is added 124.0 g (1 mole) of 4-fluorobenzaldehyde, 89.14 g (1 mole) of 4-amino-1-butanol, and 276.4 g (2 moles) of potassium carbonate, and dimethylsulfoxide The reaction mixture is then heated at 95° C. for about 3 hours until TLC indicates no more 4-fluorobenzaldehyde is present After cooling to room temperature, the solution is chilled to -10° C., and 141.9 g (1 mole) of iodomethane is added dropwise with stirring. After 2 hours at -10° C. the solution is poured into a four-fold excess (relative to dimethylsulfoxide) of ice water, and the solid product is collected by filtration and recrystallized from water.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2].CO.[OH-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethylacetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol 40/1) to give the title compound (0.61 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:4].[S:25]1[CH:29]=[C:28]([CH:30]=O)[N:27]=[CH:26]1.CN(C)C=O.ClCCCl.C(Cl)Cl>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:2]([NH:1][CH2:30][C:28]2[N:27]=[CH:26][S:25][CH:29]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=2)=[O:4])=[CH:23][CH:22]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cnc(-c2ccncc2)s1
Reactant: O=Cc1cscn1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2ccncc2)s1)[C@H](Cc1ccc(F)cc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a mixture of (S)-2-amino-3-(4-fluorophenyl)-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide (0.090 g, 0.20 mmol), thiazole-4-carbaldehyde (0.022 g, 0.20 mmol), N,N-dimethylformamide (0.014 g, 0.20 mmol) and 1,2-dichloroethane (0.020 g, 0.20 mmol) was added Reactant 3 (0.19 g, 0.89 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was directly purified HPLC to give 56 mg of (S)-3-(4-Fluorophenyl)-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide 5.2. 400 MHz 1H NMR (CD3OD) δ: 9.09 (d, J=4.0 Hz, 1H), 8.78 (d, 2H), 8.34 (d, J=8.0 Hz, 2H), 7.80 (d, 1H), 7.74 (s, 1H), 7.24 (dd, J=8.0, 4.0 Hz, 2H), 7.04 (, J=12, 8.0 hz, 2H), 4.54 (d, J=16 Hz, 1H), 4.50 (d, J=16 Hz, 1H), 4.40 (dd, J=12.0, 8.0 Hz, 1H), 3.47 (dd, J=16.0, 8.0 Hz, 1H), 3.26 (dd, J=16.0, 8.0 Hz, 1H). LCMS (ES+) m/z 440.