Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ncc(F)cn1

Procedure:
The title compound, MS: m/e=314.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-fluoro-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:7]([F:17])=[CH:6][C:5]=2Br.[OH-].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:7]([F:17])=[CH:6][CH:5]=2
Reactant: [H][H]
Reactant: Cc1cc2c(N3CCOCC3)c(F)cc(Br)c2[nH]1
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Yield: 65.7 %

Procedure:
To a solution of 24 g of 2-methyl-4-morpholino-5-fluoro-7-bromoindole in 200 ml of ethanol was added 1 g of palladium-carbon and then 15 ml of a 20% aqueous sodiium hydroxide solution. This mixture was subjected to catalytic reduction at room temperature and at atmospheric pressure. The reaction was stopped when a theoretical amount (about 1.7 l) of hydrogen was absorbed, and the catalyst was removed by filtration followed by concentration. The residue was purified through silica gel column chromatography (Wako gel C-200; eluent:chloroform:n-hexane=5:1) to give 11.8 g of 2-methyl-4-morpholino-5-fluoroindole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:33][NH2:34]>C(O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][NH:34][CH3:33])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Reactant: CN
Solvent: CCO
Product: CNCC(=O)N1CCC[C@H]1COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Yield: 47 %

Procedure:
Using a procedure similar to that described for the synthesis Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloracetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g; prepared as described in Example 43, preparation of starting materials) was reacted with 33% methylamine in ethanol (5 ml) to give the title product as a foam (0.131 g, 47%); 1H NMR Spectrum: (CDCl3) 1.91-2.22 (m, 4H), 2.22 (s, 3H), 2.70-2.90 (m, 1H), 3.28-3.40 (m, 2H), 3.44-3.54 (m, 2H), 3.97-4.09 (m, 4H), 4.47-4.51 (d, 1H), 4.60-4.66 (t, 1H), 7.06-7.20 (m, 2H), 7.24 (s, 1H), 8.07-8.13 (m, 1H), 8.57-8.70 (m, 3H); Mass Spectrum: (M−H)− 472.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[CH:37][CH:36]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cccnc5c4)cc3F)CC2)OCC1=O

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (214 mg, 0.5 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (127 mg, 0.5 mmol) and 2M aq K2CO3 (0.55 mL, 1.1 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (20.4 mg, 0.025 mmol). The reaction mixture was purged with nitrogen and the vessel was sealed and irradiated in the microwave at 110° C. for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HCl. The organic phase was then washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (5-65% acetonitrile:water with 0.1% NH4OH) afforded the title product as a racemate, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to yield the title product in >98% ee (31 mg, 13%). αD=+21 deg (c=0.06, methanol); MS(ES)+ m/e 477 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.65-1.74 (m, 1 H) 1.75-1.80 (m, 1 H) 1.89-2.01 (m, 2 H) 2.31-2.41 (m, 1 H) 2.58-2.70 (m, 2 H) 2.78 (br. s., 1 H) 3.19 (s, 2 H) 3.41 (q, J=7.33 Hz, 2 H) 3.97-4.08 (m, 2 H) 4.54 (s, 1 H) 5.65 (br. s., 1 H) 7.27 (br. s., 1 H) 7.43-7.48 (m, 2 H) 7.55 (d, J=1.77 Hz, 1 H) 7.64 (dd, J=7.96, 1.89 Hz, 1 H) 7.87 (dd, J=8.59, 2.02 Hz, 1 H) 7.98 (d, J=8.59 Hz, 1 H) 8.25 (dd, J=8.34, 1.01 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 8.97 (dd, J=4.04, 1.77 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C(=O)C)[C:18]2=[O:28])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-].[NH4+]>C(#N)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[C:18]2=[O:28])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(=O)OCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)c1cc(C=C2SCN(CCO)C2=O)cc(C(C)(C)C)c1O
Reaction time: 90 h
Yield: 46.7 %

Procedure:
A solution of 85.2 g of 5-[[3,5-bis(1,1-dimethylethyl) -4-hydroxyphenyl]methylene]-3-[2-(acetyloxy)ethyl]-4-thiazolidinone from Example 26 in 1.5 l of acetonitrile was treated with 1 liter of concentrated ammonium hydroxide. The reaction mixture was allowed to stand for approximately 90 hours at room temperature. The solution was concentrated in vacuo and 500 ml of ethyl acetate were added, with the pH adjusted to 3.0 with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with 250 ml of ethyl acetate. The combined organic layers were washed with 250 ml of a saturated sodium chloride solution and concentrated in vacuo. The residue was crystallized from 95 ml of hexane and 70 ml of ethyl acetate to provide 35.68 g of the desired subtitled intermediate, m.p. 131°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:6][CH:7]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-amino-phenyl)-cyclopentyl]-amide (73 mg, 0.26 mmol, prepared in example 23) was dissolved in 10 mL of methylene chloride and cooled to 0° C. under nitrogen. Triethylamine was added (40 uL, 0.28 mmol) followed by methanesulfonyl chloride (22 uL, 0.28 mmol) and after stirring 15 min the ice bath was removed and stirring continued. After 4 hours an additional 10 uL of methanesulfonyl chloride was added and stirring continued overnight. The reaction was concentrated in vacuo and purified by radial chromatography eluting with 99:1 methylene chloride:methanol and slowly increasing the percentage of methanol. The appropriate fractions were dried to 25 mg (27%) of the title compound as an off-white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][N+:3]=1[O-:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[CH:4][N+:3]=1[O-:12]
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-fluoro-4-nitropyridine 1-oxide (3000 mg, 12.66 mmol) in THF (10 mL) was added cyclopropylamine (868 mg, 15.1 mmol). Solution was stirred at room temperature for 1 h. Mixture was partitioned between EtOAc and saturated aqueous NaHCO3. Organic layer was washed with brine and dried over MgSO4 to provide 2-bromo-5-(cyclopropylamino)-4-nitropyridine 1-oxide 2.67. Residue was used for next step without further purification. LC/MS found for C8H8BrN3O3 as (M+H)+ 275.9.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg]I>CCOCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH3:16])[C@:10]([CH3:24])([OH:15])[C:11]([F:14])([F:12])[F:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Mg]I
Reactant: C[C@H](C(=O)C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCOCC
Product: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)[C@](C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(R)-3-(Dibenzylamino)-1,1,1-trifluorobutan-2-one (Example 52A) (3.41 g, 10.61 mmol) was dissolved in Et2O (80 mL) and then cooled to ca. 0° C. (ice external temp) prior to the addition of MeMgI (7.07 mL, 3 M). Addition of the Grignard reagent caused the reaction to become heterogeneous. After stirring for 10 min, TLC indicated good conversion to a slightly less polar than sm product (a trace of what appeared to be sm remained), the mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic portions were dried over Na2SO4 and concentrated. The resulting bright yellow residue was purified by flash chromatography (ISCO, 80 g silica, 0% to 40% over 27 min. ca. 10 min ret time; hex/EtOAc) to afford the desired product as a bright yellow oil. TLC, LCMS, and NMR showed ca.15-20% of the bis CF3 alcohol contaminating the desired product. A trace of the other diastereomer also existed. The material was concentrated and rechromatographed (straight CH2Cl2, 80 g SiO2, 254/230 nm) to afford separation of the bis-CF3 alcohol and desired product (1.94 g, 54%). This material was used in its entirety for the debenzylation step: 1H NMR (400 MHz, DMSO-d6) δ 7.62-7.48 (m, 10H), 6.11 (s, 1H), 4.16 (d, J=13.6 Hz, 2H), 3.61 (d, J=13.7 Hz, 2H), 3.15 (q, J=6.8 Hz, 1H), 1.42-1.40 (m, 6H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:43]=[CH:44][N:45]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:63])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:43]=[CH:44][N:45]=5)=[O:63])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:54]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)OCC)cc2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)OCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of ethyl 4-(2-(((4-(((8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-yl)carbonyl)amino)phenyl)sulfanyl)methyl)-imidazol-1-yl)butanoate (400 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloroperbenzoic acid (144 mg) in dichloromethane (10 ml) at −78° C. As such, the mixture was stirred for 1 hour. Then, dry ice-acetone bath was removed and an aqueous sodium thiosulfate solution was added with vigorous stirring. After stirring the mixture at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate), and recrystallized from hexane-ethyl acetate to give ethyl 4-(2-(((4-(((8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-yl)carbonyl)amino)phenyl)sulfinyl)methyl)imidazol-1-yl)butanoate (317 mg) as yellow crystals (Compound 54).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:28]([CH3:39])[C:27]=1[CH3:40]>>[F:24][C:18]1[CH:17]=[C:16]([C:8]2[C:7]([CH2:6][O:5][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([CH3:39])[C:27]=3[CH3:40])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-fluoro-4-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, DMSO) δ 12.12 (s, 1H), 7.48-7.58 (m, 2H), 7.31 (t, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 3.89 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.5 Hz, 2H), 2.14 (s, 3H), 1.97 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H21F4NO4S, 482.1 (M−H). found 482.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1.Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:19]2[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(C)(C)CO)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(OCC(C)(C)OCc2ccc(OC)cc2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 2-[(4-methoxybenzyl)oxy]-2-methylpropan-1-ol (0.30 g) in N-methylpyrrolidone (4.5 mL) was added sodium hydride (63 mg) under ice-cooling, followed by stirring at 60° C. for 30 minutes. To the reaction mixture was added methyl 5-chloropyrazine-2-carboxylate (246 mg), followed by stirring at 120° C. overnight. To the reaction mixture was added 1 M hydrochloric acid for neutralization in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to obtain methyl 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylate (0.20 g) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O1CCCC1.O.[OH-].[Li+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 80 °C
Yield: 96.5 %

Procedure:
Ethyl (1R,2R)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylate (2.0 g, 7.84 mmol., 1.0 eq.), water (60 mL) and tetrahydrofuran (50 mL) were charged into a 250 mL round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (0.523 g, 12.94 mmol., 1.65 eq.) was added portion wise and the reaction mixture heated at 80° C. for 15 hours. TLC analysis of the reaction mixture (heptanes:ethyl acetate, 1:1) showed full consumption of the starting material. The reaction mixture was left to cool down to ambient temperature and diluted with ethyl acetate (50 mL). The organic phase was discarded, and the aqueous phase washed further with ethyl acetate (50 mL). The aqueous phase was acidified to pH 3 by slow addition of 1M hydrochloric acid then extracted with ethyl acetate (2×80 mL). The organic extracts were pooled, washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated to dryness to give 1.72 g (96%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.67-5.86 (m, 1 H), 5.31 (d, J=17.10 Hz, 1 H), 5.18-5.28 (m, 1 H), 5.15 (d, J=10.32 Hz, 1 H), 2.20 (q, J=8.86 Hz, 1 H), 1.70-1.92 (m, 1 H), 1.50-1.65 (m, 1 H), 1.46 (s, 9 H). LC-MS: purity 100% (ELS), tR 1.56 min, m/z [M−H]-226.10.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:47]1[CH:46]=[C:45]([CH:50]=[C:49]([F:51])[CH:48]=1)[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:54][CH:53]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)cc(F)c4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cc(F)cc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 47.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3,5-difluorobenzyl)-1-piperidinecarboxamide (0.165 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.095 mmol)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH2:14][CH2:15][O:16][CH3:17]>C([O-])([O-])=O.[Na+].[Na+].CCOCC>[CH3:8][C:3]1[CH:4]=[CH:14][C:15]2[O:16][C:17]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])=[CH:10][C:11]=2[CH:2]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1cc2cc(C)ccc2o1
Temperature: 25 °C

Procedure:
A solution of methyl 2-bromobenzoate (11.70 g), Intermediate 1 (12.75 g) and tetrakistriphenylphosphine palladium (0) (0.5 g) in DME (300 ml) and 2N aqueous Na2CO3 (60 ml) was heated at reflux with vigorous stirring under nitrogen. After 1.5 h a further 500 mg of catalyst was added and stirring at reflux under nitrogen continued. After about 5 h the reaction was cooled to room temperature and diluted with ether (300 ml). The organic layer was separated and washed with water (3×100 ml) and dried. Filtration and evaporation gave a yellow oily suspension (19.27 g) which was purified by chromatography eluting with System A (1:9) to give a yellow oil (11.06 g). This was further purified by Kugelrohr distillation to give the title compound (4.31 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[OH-].[K+]>CS(C)=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:2][CH2:3][CH2:4][Cl:5])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1
Reactant: ClCCCBr
Reactant: Clc1ccc(CN2CCCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
15.7 g of 1-bromo-3-chloropropane were added to a cooled solution of 15.0 g of 1-(4-chlorobenzyl)homopiperazine and 12.0 g of potassium hydroxide in 50 ml of dimethyl sulfoxide. The mixture was stirred at 5°-10° C. for one hour, and then an additional 30 minutes at room temperature. After the addition of ice water, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated in vacuo. Final purification was effected on a silica gel column (methylene chloride:methanol, 9:1), and the solvent was removed in vacuo to give 8.4 g (42% of theory) of 1-(4-chlorobenzyl)-4-(3-chloropropyl)homopiperazine as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH:12]([CH3:14])[CH3:13])[N:6]=1)=O.[Li+].[BH4-].O>C1COCC1>[CH:12]([S:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(SC(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Sc1cccc(CO)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
6-Isopropylsulfanyl-pyridine-2-carboxylic acid methyl ester (0.13 g, 0.61 mmol) obtained in Step A was dissolved in anhydrous THF (3 mL). 2.0M LiBH4 solution (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at 40° C. for 1 hour. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.08 g, 70%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20](C(OCC3C=CC=CC=3)=O)[CH3:21])[CH:16]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OCC)(=O)C>CO.[Pd]>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1

Procedure:
A solution of 475 mg of the above 1-(SR)-(3,5-bis(trifluoromethyl)-phenyl)methoxy-2-(SR)-phenyl-3-(RS)-(N-(benzyloxycarbonyl)-N-methylamino) cyclopentane in 5 mL of 1:1 methanol: ethyl acetate was hydrogenated over 100 mg of 10% Pd/C for 2 hours. The reaction was filtered and concentrated to afford the title compound as an oil. Mass spec (NH3/CI): 418 (M+1).