Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:29]([C:31]1([NH:37][C:38]([CH:40]([NH2:48])[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:39])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)#[N:30]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:48][CH:40]([C:38](=[O:39])[NH:37][C:31]2([C:29]#[N:30])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCOCC1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCOCC2)cc1
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
4-Acetamidobenzoic acid (353 mg, 1.98 mmol), EDC (378 mg, 1.98 mmol), and HOBT (268 mg, 1.98 mmol) were combined in 15 mL of DMF and stirred for 20 min. Solid [1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amine hydrochloride (625 mg, 1.98 mmol) was added. The reaction was stirred for 16 hours. The volatiles were removed with a pump and the resulting residue was triturated, with rapid stirring, with 250 mL of saturated aqueous sodium bicarbonate. The resulting solid was collected by filtration and washed with 250 mL of water. The solid was dried in vacuo to give the title compound (250 mg); MS, ml/z 441=M+1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CN(C=O)C>[OH:26]/[C:20](=[CH:1]\[C:2](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)/[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
To a solution of 4-benzyloxyacetophenone 1.1 (20.0 g, 88.4 mmol) in DMF (100 ml) at rt, was added NaH (60% in oil, 4.26 g, 106 mmol). The mixture was stirred at rt for 45 min, cooled to 0° C., and diethyl oxalate (14.4 ml, 106 mmol) was added dropwise, and the suspension warmed to rt and stirred for 17 h. The reaction mixture was poured over a mixture of ice and 1N HCl and the suspension stirred for 30 min, filtered, and the solid rinsed with water and dried to afford 28.9 g of the butenoate 1.2. MS (ESI) 325.2 (MH+).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH2:29][CH3:30])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH2:29][CH3:30])=[CH2:1])[CH:23]=1)[CH3:20]
Reactant: CCC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CC)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Methyl triphenylphosphonium bromide (0.72 g; 2.01 mmol) was added to benzene (15 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.3 ml; 2.03 mmol) was added dropwise. The mixture was stirred for 5 minutes, and Compound 23 (0.40 g; 1.34 mmol) in benzene (5 ml) was added dropwise thereto, followed by heating under reflux for 2 hours. The mixture was brought to room temperature, and poured into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.20 g of the target compound as pale yellow oily matter (yield: 50.5%).
Reaction SMILES: [CH3:1][Mg]I.[OH:4][C@H:5]1[CH2:10][C@H:9]2[CH2:11][C@@:8]32[C@H:12]2[C@H:22]([CH2:23][CH2:24][C@:6]13[CH3:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH:14]=[CH:13]2>C1COCC1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:4][C@H:5]1[CH2:10][C@H:9]2[CH2:11][C@@:8]32[C@H:12]2[C@H:22]([CH2:23][CH2:24][C@:6]13[CH3:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH2:14][C@H:13]2[CH3:1]
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Reactant: C[Mg]I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)C[C@H]4C[C@]43[C@H]12
Temperature: -5 °C
Reaction time: 2 h

Procedure:
80 ml of THF is added to a solution of methylmagnesium iodide (prepared from 2.5 g of magnesium and 6.4 ml of methyl iodide in 80 ml of diethyl ether), it is cooled to −5° C., and 1 g of copper acetate-monohydrate, dissolved in 50 ml of THF, is added. It is cooled to −20° C., and then a solution of 5 g of 17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one in 80 ml of THF is added in drops. After 2 hours, it is poured onto ice water/2N sulfuric acid and extracted with 3×80 ml of ethyl acetate. The organic extract is dried and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethyl acetate 10:1). For further purification, it is recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CCCCCCC>CN(C=O)C>[Si:20]([O:9][CH2:8][C@@H:7]1[C@H:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:10])[CH2:6]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@@H]1CC(=O)C[C@@H]1CO
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC[C@@H]1CC(=O)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.60 g, 18.3 mmol) in DMF (30 mL) was added imidazole (1.87 g, 27.4 mmol) followed by tert-butylchlorodimethylsilane (3.03 g, 20.1 mmol). After about 4 h, heptane (50 mL) was added. The heptane layer was removed and washed with brine. The brine layer was combined with the DMF layer and extracted with EtOAc/heptane (1:1, 30 mL). The heptane and EtOAc layers were combined, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane (0-30%) to provide (3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone (3.5 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.77 (dd, J=10.5, 4.3 Hz, 1H), 3.64 (dd, J=10.5, 4.0 Hz, 1H), 2.40-2.20 (m, 5H), 2.18-2.02 (m, 1H), 1.65-1.55 (m, 1H), 1.52-1.37 (m, 1H), 0.97 (t, J=7.4 Hz, 3H), 0.87 (s, 9H), 0.43 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (382 mg, 0.884 mmol) and 3-(4-bromophenyl)propanoic acid (243 mg, 1.060 mmol) in toluene (6 mL) and ethanol (6 mL) were successively added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.088 mmol) and potassium carbonate (366 mg, 2.65 mmol). The resulting mixture was stirred at 80° C. for 2 h, then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (25 g), eluting with EtOAc in cyclohexane (10-70%). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (209 mg, 52%) as a white solid. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]12[O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]2>>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[O:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@@H]4CCCC[C@H]4O)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 31 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and cyclohexene oxide instead of 1-oxaspiro[2.4]heptane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)N(CCc2ccccc2)Cc2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CCc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 75-76° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[C:13]1(=[O:23])[N:17]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[O:11][CH3:12])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(C#N)ccc1CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#N)ccc1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
24.4 g (108 mol) of 4-bromomethyl-3-methoxybenzonitrile dissolved in 125 ml of DMF and 20.0 g of potassium phthalimide were stirred at RT for 24 h and then at 50° C. for 1 h. The mixture was poured into water, whereupon the product precipitated as solid. 21.5 g (68%) of the product were obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.O[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(N(CCCOc2ccc(CO)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 5B from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzaldehyde: MS (APCI) m/z 405 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=3)[CH2:34][CH2:33]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCC(N)CC2)nc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)nc1
Temperature: 120 °C
Yield: 43.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (97 mg, 0.324 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 1-(5-Methylpyridin-2-yl)piperidin-4-amine dihydrochloride (86 mg, 0.327 mmol) was added followed by TEA (33 g, 0.324 mmol). The reaction mixture was heated in a microwave reactor for at 120° C. for 25 mins. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3-solution and water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (64 mg, 43.5%). 1H NMR (500 MHz, CDCl3): δ 1.33-1.41 (m, 2H), 1.71-1.74 (m, 1H), 2.17 (s, 3H), 2.38-2.43 (m, 2H), 3.08-3.15 (m, 1H), 3.95-3.99 (m, 2H), 5.23 (d, 1H), 6.51 (d, 1H), 7.26 (dd, 1H), 7.43-7.45 (m, 3H), 7.53-7.55 (m, 2H), 7.96 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 17.51, 27.84, 32.05, 44.64, 50.68, 61.78, 107.10, 107.50, 122.63, 125.39, 128.91, 130.11, 131.90, 134.20, 138.65, 147.86, 157.77, 159.91; Mass Spectrum: M+H+ 455.0.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([CH2:13][S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[CH2:12][CH2:11]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: BrCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](CSCC1CC1)C(=O)O
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a suspension of L-cysteine (100 g) in ethanol (850 mL) under nitrogen was added over 40 min a solution of sodium hydroxide (2.0 eq., 64.6 g) in ethanol (650 mL) (the sodium hydroxide solution was maintained below 40° C. during its preparation, 3 hours for complete dissolution). After the addition, cyclopropylmethyl bromide (1.1 eq., 122.5 g) was added over 20 minutes while maintaining the temperature at 25-30° C. with a cold bath. The resulting white slurry was stirred for another 18 hours and then quenched by adding 2N HCl (0.73 eq., 300 mL) over 20 minutes. The thick suspension was concentrated (100 mbars, 52° C. bath) to about 400 mL (1.5L ethanol/water distilled) and then water (750 mL) was added. The pH (9.6) was adjusted to pH 6.5 with 2N HCl and the mixture was stirred at 4° C. for 2 hours and then filtered. The cake was washed five times with water (100 mL) and then dried in vacuum to afford S-cyclopropylmethyl-L-cysteine (128.2 g, 88.6% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1c(F)cccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1c(F)cccc1Cl
Yield: 2.5 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-6-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-fluoro-biphenyl-2-carboxylic acid (3 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.28-8.38 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.39-7.57 (m, 3H), 7.33 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:7]([CH3:9])[CH3:8])([Cl:6])Cl)[CH3:3].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][CH:7]([Si:4]([CH:2]([CH3:1])[CH3:3])([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[Cl:6])[CH3:9]
Reactant: CCCCCCCCO
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCO[Si](Cl)(C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Alternatively, di(2-propyl)octyloxychlorosilane was prepared as follows. To a 1000 ml three-neck round-bottom flask fitted with a stirrer, drying tube, thermometer and dropping funnel was added di(2-propyl)dichlorosilane (28.3 g, 153 mmol) and dry toluene (200 ml). The reaction mixture was then stirred and cooled to -5° C. A solution of dry octanol (10.0 g, 76 mmole) and dry pyridine (6.5 g, 82 mmole) in dry toluene (100 ml) was added dropwise for 60 minutes. The reaction mixture was suspended overnight at room temperature, filtered under a "nitrogen blanket" and fractionated.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][CH2:14][OH:15].[NH2:16][C:17]1[CH:24]=[C:23](F)[C:20]([C:21]#[N:22])=[CH:19][N:18]=1>C1COCC1>[NH2:16][C:17]1[CH:24]=[C:23]([O:15][CH2:14][CH2:13][O:12][CH3:11])[C:20]([C:21]#[N:22])=[CH:19][N:18]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of KHMDS in THF (1 M, 48.1 ml, 48.1 mmol) was added to a solution of 2-methoxy ethanol (1.68 g, 21.88 mmol) in THF (90 ml) at room temperature. After 2 minutes 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.00 g, 21.9 mmol) was added and the reaction mixture stirred for 16 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined EtOAc layers were washed with brine, dried over MgSO4 and evaporated. The residue was triturated with EtOAc and the title compound obtained by filtration as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 6.91 (s, br, 2H), 6.03 (s, 1H), 4.19-4.13 (m, 2H), 3.34-3.28 (m, 2H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].C[Si]([N:45]=[N+:46]=[N-:47])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:35]1([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]3[NH:47][N:46]=[N:45][N:2]=3)=[CH:4][CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCCCCCc1ccccc1)CCc1ccc(C#N)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCCCCCc1ccccc1)CCc1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 128 mg (0.24 mmol) of ethyl (7E)-6-[2-(4-cyanophenyl)ethyl]-8-{2-[(5-phenylpentyl)oxy]phenyl}oct-7-enoate in 10 ml of toluene is mixed with 0.47 ml (3.57 mmol) of trimethylsilyl azide and 88.9 mg (0.36 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by preparative HPLC. 62 mg (0.11 mmol, 44.8% of theory) of a colorless foam are obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=2)=[C:13]([CH3:26])[CH:12]=1)(=[O:3])[CH3:2].[BH4-].[Na+].CC(C)=O>CO>[C:1]([O:4][C@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=2)=[C:13]([CH3:26])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CCC[C@@H]1Oc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1CCC[C@@H]1Oc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(1R,2R)/(1S,2S)-2-((3′-Formyl-2,6-dimethylbiphenyl-4-yl)oxy)cyclopentyl acetate 17c (71 mg, 0.20 mmol) was dissolved in 10 mL of methanol, followed by addition of sodium borohydride (15 mg, 0.40 mmol). The reaction solution was stirred for 2 hours. The resulting solution was mixed with 6 mL of acetone and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (1R,2R)/(1S,2S)-2-((3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl)oxy)cyclopentyl acetate 17d (61 mg, yield 85.2%) as a colorless slime.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH:13]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH2:41][CH3:42].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:40][CH2:41][CH3:42])[CH:13]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)CCN3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCCN1CCN(S(=O)(=O)c2cccc(Cl)c2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
To a solution of [4-(3-chloro-benzenesulfonyl)-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (100 mg) in acetone (4 mL) was added cesium carbonate (82 mg), followed by 1-bromopropane (21 μL). The reaction mixture was stirred at reflux overnight. Water was added and the reaction mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded [4-(3-chloro-benzenesulfonyl)-1-propyl-piperazin-2-yl]-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam (75 mg), MS: 519.3 ([M+H, 1Cl]+).