Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](=[O:37])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([CH:29]1[C:28](=[O:37])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=3)=[N:9][C:8]=2[CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)nc2C(c2ccccc2)C1Cc1ccccc1
Yield: 57 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(3,5-bis(trifluoromethyl)phenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 21 as an off-white solid (88 mg, 57%). Analytical data for 21: 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1H), 8.15 (s, 2H), 7.80 (s, 1H), 7.40-7.26 (m, 6H), 7.15-7.06 (m, 2H), 7.00-6.96 (m, 2H), 4.11 (d, J=6.9 Hz, 1H), 3.63 (ddd, J=10.1, 6.8, 4.6 Hz, 1H), 3.37 (dd, J=14.8, 4.7 Hz, 1H), 2.44 (dd, J=14.8, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.8, 149.4, 139.0, 137.7, 136.8, 132.4 (q, JCF=33.6 Hz), 131.2, 129.2, 129.0, 128.6, 128.4, 127.9, 126.8, 124.6 (d, JCF=4.0 Hz), 122.9 (d, JCF=273.0 Hz), 122.0, 112.1, 47.1, 38.5, 32.7; IR (film) cm−1 1780, 1641, 1618, 1528, 1401, 1361, 1279, 1186, 1133, 896, 730, 697, 682; LRMS (ESI): Mass calcd for [M+H]+ C27H19F6N2O2: 517.1. found 517.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 3% IPA/1% MeOH/hexanes 1.0 mL/min, 210 nm), Rt1 (minor)=17.2, Rt2 (major)=20.9 min; er=99:1.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccccc2Br)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccccc2Br)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
Triethylsilane (2.25 mL, 14.1 mmol) was added to a stirring, room temperature solution of 63 (1.5291 g, 4.55 mmol) in trifluoroacetic acid (TFA) (10.8 mL, 0.42 M) under N2. After stirring at room temperature for 3 hours, the reaction was heated to 35° C. for 35 min, then the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O:CH3CN; 14-15 min, 35:65 to 0: 100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/ injection. 0.8402 g (57.3%) of 64 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.281 min by HPLC.) 1H (CDCl3, 400 MHz): δ 9.07 (1H, broad s), 7.55 (1H, dd, J=8.0, 1.3 Hz), 7.21 (1H, td, J=7.3, 1.3 Hz), 7.17 (1H, dd, J=7.6, 2.4 Hz), 7.06 (1H, ddd, J=7.9, 7.0, 2.3 Hz), 6.82 (1H, s), 6.72 (1H, s), 4.32 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=8.0 Hz), 2.78 (2H, t, J=7.9Hz), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.21, 141.03, 132.75, 130.41, 127.63, 127.32, 125.31, 124.43, 122.66, 120.68, 114.83, 60.22, 37.78, 27.03, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 60.22, 37.78, 27.03; CH carbons: 132.75, 130.41, 127.63, 127.32, 120.68, 114.83 ppm. HPLC: 11.355 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:8][C:7]2=O)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:25])=O.O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[Cl:25])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1c(O)c(C(C)=O)cc2c1N=C(C(=O)OC)CC2=O
Solvent: O
Solvent: c1ccccc1
Product: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12

Procedure:
The product of step (b) (3 g, 0.0099 mole) was dissolved in dry benzene (50 mls), treated with phosphoryl chloride (2.5 mls) and refluxed for 1 hour. The reaction mixture was cooled, poured into water and extracted with ether, which was then washed with water and dried over magnesium sulphate. The solvent was evaporated to leave 2.8 g of yellow-brown solid. Recrystallisation from cyclohexane gave yellow needles mp 163°-164°.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH2:34][CH3:35])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:28][CH2:27][CH2:26][C@@H:25]2[C:29]2[N:33]([CH2:34][CH3:35])[N:32]=[CH:31][CH:30]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Yield: 69.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (125 mg, 0.213 mmol) prepared in Example 12b, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (70.0 mg, 68%) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[C:3]=1[CH3:24].[Br-].[CH3:26][C:27]1[N:32]=[C:31]([Zn+])[CH:30]=[CH:29][CH:28]=1.C1COCC1>CCOC(C)=O.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]>[CH3:23][C:4]1[C:3]([CH3:24])=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(C)c3C)c(C)nc12
Reactant: Cc1cccc([Zn+])n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)c(C)c3C)c(C)nc12
Temperature: 65 °C
Yield: 29 %

Procedure:
To a flask containing 3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.25 mmol) and PdCl2(dppf) (9 mg, 0.012 mmol) is added a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (0.98 mL, 0.49 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.029 g, 0.069 mmol, 29%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.72-1.92 (m, 4H), 2.04 (s, 3H), 2.45 (s, 3H), 2.47 (s, 3H), 2.50 (s, 3H), 2.59 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.0, 7.8 Hz, 1H). LC/MS (m/z): calcd. for C25H30N4S (M+H)+: 419.6; found: 419.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.03 g) in ethanol (10 mL) were added pyridine-2-carbaldehyde (329 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (85.5 mg) and triethylamine (173 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.13 g, yield 84%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][CH:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(=O)Oc1ccc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To an ice-cooled solution of product obtained in Step 4 of Example 8 (5.3 g) in dimethylformamide (18 ml) was added (2-aminothiazol-4-yl)glyoxylic acid (2.03 g), and the mixture was stirred overnight at room temperature. The resulting solution was poured into ice water (100 ml), and the mixture was acidified (pH 2) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 6.30 g of the objective compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[CH2:28][O:27][C@@H:26]([CH2:29][OH:30])[CH2:25][O:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[CH2:28][O:27][C@@H:26]([CH:29]=[O:30])[CH2:25][O:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@H](CO)CO2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@H](C=O)CO2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A solution of oxalyl chloride (14.2 mL, 165.5 mmol, Spectrochem) in DCM (30 mL) was cooled to −78° C. and was added DMSO (21.1 mL, 298 mmol, Spectrochem) drop wise. The reaction mixture was stirred for 20 minutes at the same temperature and a solution of rac ((2S*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (20 g, 66.2 mmol, Preparation #11: Step c) in DCM (60 mL) was added slowly. The reaction mixture was stirred at the same temperature for another 1 h and quenched with TEA (26.7 mL, 364.2 mmol). The reaction mixture was warmed to RT, diluted with DCM (50 mL) and washed successively with 1N HCl (2×150 mL), saturated sodium bicarbonate (2×100 mL) and brine (2×100 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure to afford racemnic ((2S*,5R*)-5-formyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 20 g (crude, 100%); 1H NMR (400 MHz, CDCl3): δ 9.55 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 4.01-3.92 (m, 5H), 3.76 (m, 1H), 3.53-3.42 (m, 2H), 2.45 (s, 3H); MS m/z: 301.3 (m+H)+
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:9][C:8]2=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:30].C(OO)(C)(C)C>CO>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:9][C:8]2=[NH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COc1ccc(C2(c3ccc(OC)cc3)NC(=S)N(C3CCCCC3)C2=O)cc1
Agent: CC(C)(C)OO
Solvent: CO
Product: COc1ccc(C2(c3ccc(OC)cc3)NC(=N)N(C3CCCCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 3-cyclohexyl-5,5-bis(4-methoxyphenyl)-2-thioxoimidazolidin-4-one (3.0 g, 7.3 mmol) in methanol was added aqueous ammonium (25%, 40 mL) and tert-butyl hydroperoxide (70%, 10 mL) separately, and the resulting solution was stirred at room temperature overnight. The mixture was extracted with dichloromethane and the organic layer was concentrated in vacuo. The residue was purified over a silica column to give the title compound as a white solid (1.7 g, 59% two steps). 1H NMR (400 MHz, d6-DMSO) δ 7.25 (d, J=8.0 Hz, 4H), 6.84 (d, J=7.6 Hz, 4H), 6.47 (s, 1H), 3.71 (s, 6H), 3.70 (s, 1H), 2.09 (m, 2H), 1.74 (m, 2H), 1.52-1.60 (m, 3H), 1.26 (m, 2H), 1.13 (m, 1H). LC-MS m/z 394.2 (M+H).
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:24](=[O:26])=[O:25]>O1CCCC1>[C:19]([O:18][C:17]([NH:16][C:10]1[C:9]([C:24]([OH:26])=[O:25])=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1OC
Reactant: O=C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
N-butyllithium (232 mL, 464 mmol) was added slowly to a solution of tert-butyl (3,4-dimethoxyphenyl)carbamate (50 g, 193 mmol) in Tetrahydrofuran (THF) (500 mL) under N2 at −20° C. After being stirred for 2 h at −10° C. to −20° C., the mixture was cooled to −78° C. and diluted with Tetrahydrofuran (THF) (500 mL), followed by addition of solid carbon dioxide. The mixture was allowed to warm up to r.t. and was then partitioned between water and Et2O. The aqueous layer was acidified with 6N HCl to pH 1-2 and extracted with Et2O. The organic layer was separated, dried over Na2SO4 and evaporated. The crude product was purified by recrystallization from i-Pr2O to afford 6-((tert-butoxycarbonyl)amino)-2,3-dimethoxybenzoic acid (27.9 g, 94 mmol, 48.5% yield) as a white solid. LCMS: (M+H)+: 319.9.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:20][C@@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[Cl:19][C:18]1[C:13]([N:25]2[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: C[Si](C)(C)c1cccc(N)c1
Product: CC1CN(c2ncccc2Cl)CCN1
Yield: 93.2 %

Procedure:
Compound A-02 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively —Cl, -Me and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (6 g), compound 2 is (R)-2-methylpiperazine, the synthesized compound 3 is 1-(3-chloro-2-pyridyl)-3-methyl-piperazine (38 g, yield about 93.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:24])[CH2:10][CH2:9][C:8](=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N2C(=O)CCNc3ccc(Cl)cc32)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)CCN(C)c3ccc(Cl)cc32)cc1

Procedure:
23 g 8-chloro-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one is stirred in 150 ml dimethylformamide for about 2 hours on a boiling water bath to which has been added 15 g methyl iodide and 11 g anhydrous potassium carbonate. The reaction mixture is poured into 1 liter water whereby the product is thoroughly crystallized with stirring. The reaction mixture is filtered by suction, washed thoroughly with water, and crystallized from isopropyl alcohol. The yield is 19 g having an m.p.=144°-145° C. (79% of the theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:35][C:36]3[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the suspension of 0.5 g (1.24 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 22, int. c) in 3 ml dichloromethane 0.01 ml (0.12 mmol) N,N-dimethylformamide, 0.13 ml (1.54 mmol) oxalylchloride were added dropwise under gas evolution. The resulting clear, light yellow solution was stirred for 1 h at room temperature, then evaporated to dryness, treated twice with 5 ml of dichloromethane and again evaporated to dryness. The light yellow solid was dissolved in 8 ml of dichloromethane and added dropwise to a stirred mixture of 0.13 g (1.24 mmol) 4-aminobenzonitrile and 0.46 ml (3.31 mmol) triethylamine in dichloromethane. After stirring for 3.75 h the clear yellow solution was poured on water and extracted twice with dichloromethane. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered and after addition of silica gel evaporated to dryness. Purification by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane to heptan/ethyl acetate (1:0 to 1:1 v/v) yielded 0.45 g (81%) of the title compound as a light brown solid. MS (ES−): M−H: 571.2.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:12]>C(O)C>[NH2:12][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)cc(F)c1F
Reactant: N
Solvent: CCO
Product: N#Cc1cc(F)cc(F)c1N
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 2,3,5-trifluorobenzonitrile (25.0 g, 159 mmol) and ethanol (300 ml) pre-saturated with ammonia gas was heated at 120° C. in an autoclave for 8 h. The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was partitioned between water (1 l) and ethyl acetate (1 l). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2) to afford 3.7 g (15%) of the title compound as a cream solid: 1H NMR (360 MHz, CDCl3) δ 4.08 (2H, s), 6.60-6.64 (1H, m), 6.67-6.72 (1H, m).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[C-:25]#[N:26].[Na+].Cl>CN(C)C=O>[CH3:23][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([C:25]#[N:26])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:6]=1[OH:24])([CH3:21])[CH3:22]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nnc(C#N)s2)cc(C(C)(C)C)c1O
Temperature: 85 °C
Yield: 45 %

Procedure:
A solution of 0.52 g (1.41 mmol) of methyl sulfone (Example 36) and 0.15 g (3.06 mmol, 2.17 equiv.) of NaCN in 4 ml dimethylformamide is warmed at 65° C. for 25 hours. An additional portion of NaCN is added and the reaction is warmed at 75° C. for 16 hours and 85° C. for one hour. The reaction is poured onto 3N aqueous HCl and extracted with ethyl acetate (three times). The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography (SiO2, 230-400 mesh, 15×4.5 cm, 15% ethyl acetate-hexane) gives 0.20 g of the nitrile. Recrystallization from cyclohexane gives 0.14 g (0.44 g theor., 31%) of the pure nitrile, mp 140°-140.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.COC(=O)CC1C2C(=CC=C(Cl)C=2)N[C:29]=1[C:38]([C:40]1[NH:41][CH:42]=[CH:43][N:44]=1)=[O:39]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:38]([C:40]1[NH:41][CH:42]=[CH:43][N:44]=1)=[O:39]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2ccc(Cl)cc12
Product: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (Step 1 of Example 8, Method A) and 2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (Preparation is described in step 1 of Example 245).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH:29]=O)[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:28][CH2:27][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([CH2:11][CH2:12][CH3:13])[CH2:19][CH2:18]3)[CH2:21][CH2:22]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3cc(F)cc(F)c3)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under a nitrogen gas stream, 3.32 g (136 mmol) of magnesium was added to 50 ml of THF, and 300 ml of a THF solution containing 23.9 g (124 mmol) of 3,5-difluorobromobenzene was added dropwise, while a reaction temperature was maintained at about 50° C. After stirring at room temperature for 1 hour, 300 ml of a solution containing 28.7 g (103 mmol) of 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the reaction in the fifth step was added dropwise. After stirring at 50 to 60° C. for 2 hours, 200 ml of an aqueous saturated ammonium chloride solution was added, thereby terminating the reaction. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure, followed by extraction with 500 ml of toluene. The resulting organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. After drying, 1.50 g of p-toluenesulfonic acid monohydrate was added, and heating was done under reflux for 4 hours. The organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (a developing solvent: heptane) to obtain 18.7 g of crude 1,3-difluoro-5-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butenyl)benzene.