Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([F:17])[C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([F:18])[CH:3]=1.[C:19](=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CB1OB(C)OB(C)O1>[F:17][C:15]1[CH:16]=[C:2]([CH3:19])[CH:3]=[C:4]([F:18])[C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1c(F)cc(C)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
Ethyl 2-(4-bromo-2,6-difluorophenoxy)-2-methylpropanoate (200 mg), tetrakis-triphenylphosphine palladium (36 mg) and sodium carbonate (200 mg) were dissolved in a mixed solvent of dioxane (4.0 ml) and water (1.0 ml), trimethylboroxine (0.26 ml) was added thereto, followed by stirring under an argon atmosphere at 100° C. overnight. After cooling to room temperature, an insoluble substance was removed by celite filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain, as a colorless oily product, ethyl 2-(2,6-difluoro-4-methylphenoxy)-2-methylpropanoate (115 mg).
Reaction SMILES: [N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][C:34]1[C:39]([CH:40]=[O:41])=[CH:38][CH:37]=[C:36]([CH3:42])[N:35]=1>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:40]([C:39]4[C:34]([CH3:33])=[N:35][C:36]([CH3:42])=[CH:37][CH:38]=4)[OH:41])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(Cc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)c(C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.09 g, 2.40 mmol, Intermediate 16) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 2,6-dimethyl-pyridine-3-carbaldehyde (0.36 g, 2.6 mmol) in THF (20 mL) was added via cannula and stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-100% DCM/(10% of a 2 M NH3 MeOH in DCM)) to afford the title compound. MS (ESI): mass calcd. for C28H25ClF3N3O, 511.2; m/z found, 512.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.44 (dd, J=8.7, 2.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 6.09 (s, 1H), 4.34 (s, 2H), 4.12 (t, J=7.6 Hz, 4H), 2.74 (s, 1H), 2.51 (s, 3H), 2.46 (s, 3H), 2.29-2.18 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([OH:27])[CH2:10][C@H:11]([C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH2:21][CH2:22]2)[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([OH:27])[CH2:10][C@H:11]([C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH2:21][CH2:22]2)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Agent: [Pd]
Solvent: CO
Product: CC(C)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2

Procedure:
[(1S,2S,4R)-1-Benzyl-4-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-hydroxy-7-methyl-oct-6-enyl]carbamic acid tert-butyl ester (D31) (1.61 g, 3.33 mmol) in methanol (30 ml) was hydrogenated over 10% Pd/C (300 mg) for 3.75 h. The catalyst was filtered and the filtrate evaporated to afford D32 1.51 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13]([O:17][C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.Cl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:24])[CH:19]([NH:20][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:21]([CH3:22])[CH3:23])([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (20 g, 0.070 mol) and (L)-valine-tert-butyl ester, hydrochloride (16.4 g, 0.078 mol) in aqueous tetrahydrofuran (400 mL, 1:1) was added dropwise triethylamine (15.6 g, 0.15 mol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with aqueous HCl (1M, 300 mL) and ethyl acetate (300 mL). The layers were separated and the organic portion was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo leaving a white solid. The crude product was recrystallized from hexane/ethyl acetate to give the title compound as white crystalline needles. Yield: 19.7 g (67%); mp 108°-110°;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-].[Si]([C:16]#[N:17])(C)(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:16]#[N:17])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1cc([N+](=O)[O-])cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-chloro-4-nitropyridine 1-oxide (1.8 g, 10.31 mmol) was slowly added to a solution of TMS-CN (4.98 ml, 37.1 mmol) in 1,2-dichloroethane (25 ml) at RT under N2 and dimethylcarbamic chloride (3.41 ml, 37.1 mmol) was then slowly added. The mixture was stirred for at RT overnight then heated to 85° C. for 5 days. The reaction was cooled RT and sat. NaHCO3 was added and then extracted with CH2Cl2. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 0-10% EtOAC in hexane to give the product as a white solid (0.79 g, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (1H, d) 7.59 (1H, d).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1N
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8, 7.0 g) in dichloromethane (100 ml) was added trifluoroacetic acid (36.3 ml) and stirring was continued at 22° C. for 4 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaHCO3 and dichloromethane, the organic layer was dried and evaporated and the residue triturated with n-pentane to give the intermediate (S)-2-amino-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (5.4 g) as a white solid. To a solution of the intermediate (0.88 g) in dichloromethane (13 ml) was added 4,4′-dimethoxytrityl chloride (0.96 g) and triethylamine (0.52 g) and stirring was continued at 22° C. for 2 h. The solution was washed with water, the organic layer was dried, evaporated and the residue was purified by chromatography over silica using AcOEt/n-heptane, gradient from 0 to 20% AcOEt) to give (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one as (1.61 g) as a pale blue solid. MS (ESI): m/z=642.3 and 644.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1)=[O:9].B.[Na].O>CO>[OH:9][CH:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH2:20][CH2:21][O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:26][C:24]=3[CH:25]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Agent: B
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)C4CCCCN4C)cc2)CCO3)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
In methanol (40ml) was dissolved N-(4-(1-methyl-piperidin-2-ylcarbonyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1g) under ice-cooling, and to the mixture was added sodium boron hydride (10mg). The mixture was stirred for 15 minutes, and to the mixture was added water. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4-(hydroxy(1-methylpiperidin-2-yl)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 158) (0.07g) as colorless crystals.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:38])/[CH:23]=[C:24](\[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:49]>CO>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1/[C:24](/[C:30]1[CH:31]=[C:32]([C:36]([NH2:37])=[NH:49])[CH:33]=[CH:34][CH:35]=1)=[CH:23]/[C:22](=[O:38])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)/C=C(\c2cccc(C#N)c2)c2ccco2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N=C(N)c1cccc(/C(=C\C(=O)Nc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-3-(2-furyl)prop-2-enamide (176 mg, 0.336 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(2-furyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (60 mg, (37%) as a fluffy off-white powder after lyophilization. ES-MS (MA+H+): 487.15
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([NH2:14])=[O:13])=[CH:9][CH2:8][CH2:7]2>CO>[F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[C@H:10]([C:12]([NH2:14])=[O:13])[CH2:9][CH2:8][CH2:7]2
Reactant: NC(=O)C1=CCCc2cc(Sc3ccccc3)cc(F)c21
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21

Procedure:
A suspension of 8-fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carboxylic acid amide (1.46 kg) in methanol (23.2 kg) and [Ru(OAc)2((S)-MeOBIPHEP)] (1.83 g) in methanol (1.5 liters) were combined and subjected to hydrogenation at 40° C. and 150 psig (10.3 bar). Completion of the reaction to form (R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide (not isolated) was monitored by HPLC. The resulting reaction solution was distilled and the solvent exchanged from methanol to THF (7.6 kg). Analysis of an aliquot of the THF solution provided the following data: MP=167.4-168.2° C.; MS (M+1)=302; H1 NMR (300 MHz): δ (DMSO): 1.56-1.84 (2H, m), 1.91 (2H, m), 2.66 (2H, m), 3.67 (1H, t, J=5.65 Hz), 6.80 (1H, dd, J=1.88, 10.17 Hz), 6.88 (1H, bs, NH), 6.92 (1H, m), 7.32-7.44 (6H, m, Phenyl, NH): [α]D=30.5° (MeOH). Chiral Assay (Area Norm): Column: ChiralCel OD-H (250×4.6 mm), mobile phase 85/15 hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.32/(S)-isomer 0.68.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH3:47])[N:18]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH3:47])[N:18]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:41][CH:42]=2)[C:19](=[O:36])[C:20]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[NH:3][C:4](=[O:7])[O:5][N:35]=2)=[CH:26][CH:27]=1)[CH3:14]
Reactant: CCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.86 g), sodium hydrogen carbonate (1.23 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.62 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[CH2:17][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:15]([CH3:24])[N:14]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:13]1=[O:30]>CC(OC)(C)C.ClC1C=C(Cl)C=C(C=O)C=1O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[CH3:24][C@H:15]1[N:14]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:13](=[O:30])[C@@H:12]([NH3+:11])[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)CC(N)C(=O)N1CC(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: COC(C)(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H]([NH3+])C(=O)N1CC(F)(F)F
Product: Cc1ccc(C(=O)[O-])cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a suspension of 4-methylbenzoic acid (6.8 g, 49.9 mmol) and 3,5-dichlorosalicylaldehyde (93 mg, 0.49 mmol) in MTBE (40 mL) was added a solution of 12 (13.9 g, 48.5 mmol) in MTBE (about 150 mL) over 1 h at 50° C. The resulting suspension was agitated for about 3 h at 50° C. The solids were collected by filtration after cooling to −5° C. over 1 h. The cake was washed with MTBE (50 mL). The solids were dried in a vacuum oven to give 13 (17.6 g, 86%) as crystals with 99.5% LC purity and 99.6% de. 1H NMR (DMSO-d6, 400 MHz): δ 7.85 (d, J=8.1 Hz, 2H), 7.40 (m, 2H), 7.25 (m, 5H), 6.0 (br, 3H), 4.65 (m, 1H), 3.65-3.80 (m, 2H), 3.45-3.65 (m, 2H), 2.35 (s, 3H), 2.30 (m, 1H), 2.15 (m, 1H), 0.88 (d, J=6.5 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 172.4, 168.5, 142.1, 141.1, 130.9, 129.7, 129.2, 129.0, 128.0, 125.5 (q, J=279 Hz), 59.1, 51.6, 45.1 (q, J=32 Hz), 41.6, 28.0, 21.5, 13.9.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[K+].[C:15]([C:17]1[N:18]=[C:19]([C:30]([O-])=[O:31])[N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=1)#[N:16].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:30]([C:19]2[N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=[C:17]([C:15]#[N:16])[N:18]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccccc1N1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a mixture of 2-piperidin-1-yl-phenylamine (63.5 mg, 0.360 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 100 mg, 0.327 mmol) and PyBroP (152 mg, 0.327 mmol) in 4 mL of 1,2-dichloroethane was added DIEA (171 μL, 0.981 mmol). After stirring at RT for 16 h under Ar, the mixture was treated with 50 mL of EtOAc, washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 118 mg (85%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C22H31N5O2Si, 426.2 (M+H), found 426.1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=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].[C:29]([Cu])#[N:30].CN(C=O)C.CCCCCC>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[C:29]#[N:30])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: N#C[Cu]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3C#N)c(C)nc12
Temperature: 150 °C
Yield: 27.2 %

Procedure:
50 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.11 mmol), and 30 mg of CuCN (0.33 mmol) are put into 4 ml vial with 2 ml of DMF and the vial is capped with a Teflon cap. The vial is heated at 150° C. overnight. The reaction mixture is applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 12.3 mg of the title compound. Yield 28%. Mass spectrum (m/e): 411 (M+1). 6.77 (s, 1H), 3.89 (t, J=4.8 Hz, 4H), 3.61 (t, J=5.0 Hz, 4H), 3.32 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Cl-].[Al+3].[Cl-].[Cl-].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:4]=1)(=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To a well stirred solution of 4-chloro-3-sulfamoyl-benzoyl chloride (0.5 g, 1.97 mmol) in 5 mL methylene chloride is added aluminum chloride (0.485 g, 1.85 mmol). After 30 min, benzene (1 mL, 5.72 mmol) is added and the reaction is stirred for 2 h at room temperature. The reaction mixture is then poured over ice, acidified with 6 N HCl and extracted three times with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography to yield 40 mg (69%) of the title compound as a tan solid. MS (m/z): 294 (M−1). Analytics calculated for C13H10ClNO3S: C, 52.8; H, 3.41; N, 4.74. Found: C, 52.62; H, 3.21; N, 4.72.
Reaction SMILES: [CH:1]1([CH:7]([N+:23]([O-])=O)[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[NH2:23][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:20])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)C(NC(C(C1CCCCC1)[N+](=O)[O-])C(F)(F)F)C(C)(C)C
Agent: [Ni]
Solvent: CCO
Product: COC(=O)C(NC(C(N)C1CCCCC1)C(F)(F)F)C(C)(C)C

Procedure:
Methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate (isomer 5B1, 0.3 gm) in ethanol (30 mL) was hydrogenated over Raney Ni catalyst at 50 psi for 20 hours. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure, to provide crude methyl 2-(3-amino-3-cyclohexyl-1,1,1-trifluoropropan-2-ylamino)-3,3-dimethylbutanoate (6) which was used in the next reaction with no further purification.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[OH-].[Na+].C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C\CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
In 125 ml of anhydrous tetrahydrofuran was suspended 18 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C in a stream of nitrogen. The resulting mixture was stirred at -20° C in a for 1 hour and to this was further added 8.4 g of (Z)-1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 3) in 25 ml of anhydrous tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours and, after addition of ice-water, extracted with n-hexane, and from the extract was obtained an oil. The oil was treated with a sodium hydroxide solution and acetic acid and reduced with 150 mg of sodium borohydride in the same manner as in Example 13, yielding 3.0 g of a mixture of the (E,Z,Z) and (E,E,Z) isomers.