Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:29]#[C:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1
Yield: 18.9 %

Procedure:
40 mg 2-[(1-Bromo-naphthalene-2-carbonyl)amino]-2-methyl-propionic acid methyl ester and 2 mg Bis(triphenylphosphine)palladium(II)chloride were suspended in 2 ml of DMF and deoxygenated with Argon. 0.26 ml of TMEDA were added, the mixture was again bubbled with Argon, and then 14 mg (0.137 mmol) phenylacetylene were added. After 14 h at 80° the reaction was filtered, purified by RP-HPLC and freeze-dried to give 8 mg of 2-{[1-(Phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester (19%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c(N)c1
Yield: 81.5 %

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>O1CCOCC1.O>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:10])[CH:6]=[C:7]([N:12]([CH3:13])[CH3:11])[N:8]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CNC
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 97.9 %

Procedure:
To a solution of 46 g 2-methylthio-4,6-dichloropyrimidine in 250 ml dioxane, were added at room temperature and over a period of 10 minutes, 65.6 ml of 40% dimethylammonia-solution in water and the mixture was stirred for one hour. The solvent was evaporated and the residue purified on silica gel with toluene as eluent to give 57.0 g (97.9%) of 2-methylthio-4-chloro-6-(N,N-dimethylamino)-pyrimidine of m.p. 102° C.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)N1CCC(C(=O)O)CC1
Yield: 73 %

Procedure:
1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester (0.8 g, 26.7 mmol) from step 4, was dissolved in ethyl acetate (100 ml) and methanol (10 ml), Pd/C 10% (80 mg) was added and the resulting mixture was hydrogenated at 1 bar. The catalyst was filtered over celite, the solvent was removed under reduced pressure to give a white solid. Yield 73%, 0.4 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32]([NH:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[C:7]3[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:18]=1)(=[O:34])=[O:33]
Reactant: Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine (82 mg, 0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat 2,4-difluorobenzenesulfonyl chloride in one portion. The reaction was stirred at room temperature for 30 minutes then was purified directly by prep-HPLC. The combined, desired fractions were evaporated under reduced pressure to remove organic solvents then diluted with small portions of brine and saturated aqueous sodium bicarbonate. The basic solution was extracted with ethyl acetate then the extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting colorless film was crystallized from methylene chloride and diethyl ether. The solids were collected by filtration, rinsed with diethyl ether then vacuum dried to afford the title compound (219 mg, 48%) as a white solid. MS (ES)+ m/e 475 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([Cl:23])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To an ice cooled methylene chloride solution of 1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (512 mg, 1.95 mmol) under nitrogen was added oxalyl chloride (0.185 mL, 1.95 mmol) and a few drops N,N-dimethylformamide. The reaction flask was warmed slowly to room temperature and after 2 hours the solvent was removed in vacuo. Toluene was added and removed in vacuo (2×) to give the title compound.
Reaction SMILES: Cl[C:2]([SiH3:5])(Cl)Cl.[Si:6]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Mg]>O1CCCC1>[Si:6]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][C:2]([SiH3:5])([CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[O:13][Si:6]([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:8])[CH3:7])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: [SiH3]C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CC([SiH3])(Cc1ccccc1O[Si](C)(C)C(C)(C)C)Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reaction time: 72 h

Procedure:
A mixture of trichloromethylsilane (0.12 ml, 1.0 mmol) and Grignard reagent, which was prepared from 2-((tert-butyldimethylsilyl)oxy)benzyl bromide (IIa) (1.54 g, 5.0 mmol) and magnesium (1.2 g, 50 mmol) in tetrahydrofuran (12 mL), was stirred for 3 days. The reaction was quenched with satd. ammonium chloride (50 mL). The mixture was extracted with hexanes (3×50 mL). Purification by flash column chromatography (hexane/ethyl acetate=50:1, v/v) provided compound Ma (0.51 g, 72%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([OH:16])[C:8]([OH:17])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].Br[CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[O:17][CH2:25][CH2:26][CH2:27][O:16][C:9]2=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Temperature: 105 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 500-mL round-bottom flask containing a stir bar and an argon atmosphere was added diethyl 1-(2-ethoxy-2-oxoethyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (48.00 g, 146 mmol), 1,3-dibromopropane (29.48 g, 146 mmol), anhydrous potassium carbonate (50.36 g, 364 mmol), and anhydrous dimethylformamide (DMF) (250 mL). The reaction was heated to 105° C. and became lime green after about 30 minutes. The reaction was stirred for 12 hours, during which, it became yellow, and was cooled to room temperature. The mixture was poured into DI water (500 mL), the solids were collected via vacuum filtration, and washed with several portions of DI water. The solids were recrystallized from hot methanol to yield 44.90 g (80%) of a yellow solid. mp 139.7-139.9° C.; 1H NMR (300 MHz, CDCl3): δ 5.43 (s, 2H), 4.30 (q, 4H, J=7.7 Hz), 4.22 (q, 2H, J=8.0 Hz), 4.20 (t, 6H, J=63 Hz), 2.25 (p, 2H, J=6.3 Hz), 1.34 (t, 6H, J=7.7 Hz), 1.28 (t, 3H, J=8.0 Hz); 13C NMR (75 MHz, CDCl3): δ 169.6, 161.0, 142.7, 114.1, 71.7, 61.5, 60.9, 48.0, 33.4, 14.5, 14.4; HRMS (EI): Calcd for C17H23NO8 ([M]+), 369.1424, found m/z, 369.1417; Anal. Calcd for C17H23NO8: C, 55.28; H3, 6.28; N, 3.79%, found: C, 55.29; H, 6.37; N, 3.80
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](SC)[N:11]=2)=[CH:8][C:7]([C:18]([NH2:20])=[O:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.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:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)=[CH:8][C:7]([C:18]([NH2:20])=[O:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CSc1nccc(-c2cc(C(N)=O)nn2C(C)(C)C)n1
Agent: [Cu+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(-c2ccccc2)n1
Temperature: 130 °C
Yield: 23 %

Procedure:
50 mg (0.172 mmol) of 1-tert-butyl-5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide, 42 mg (0.343 mmol) of phenyl boronic acid, 98 mg (0.515 mmol) of copper thiophencarboxylate and 20 mg (0.017 mmol) of palladium tetrakis were suspended in 1.5 mL of dry THF under argon atmosphere. The resulting suspension was heated a 130° C. for 1 h by microwave irradiation. The reaction mixture was then filtered on a silica plug, diluted with AcOEt and washed with aqueous NH4OH. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC/MS to provide the title compound (23%).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.CN(C)C=O>BrN1C(=O)CCC1=O.O>[Br:20][C:9]1[C:8](=[O:19])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
1-Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone (186 g), N-bromosuccinimide (141.7 g) and N,N-dimethylformamide (900 ml) were stirred at room temperature. After 2.5 hr, 6.45 g of N-bromosuccinimide was added thereto. After depletion of the reactant was confirmed, the reaction solution was poured into water (4.5 L) under ice-cooling, followed by stirring in a cold-room (approximately 4° C.) overnight. The resulting crystals were collected by filtration under reduced pressure, followed by dissolving in isopropanol (3.25 L) and water (650 ml) under heating. After the complete dissolution was confirmed, the solution was left to cool gradually, and then ice-cooled. Then, the mixture was stirred in a cold-room overnight. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60° C., to give 191 g (81%) of the title compound.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.Cl>C(O)C.O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:36])=[O:5])=[CH:17][CH:16]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2N KOH(aq) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH=2.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (40% ethyl acetate in Hexanes+0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC/MSD m/e: 444.0 (M+H); 1H NMR (400 MHz) (acetone) δ 8.21 (2H, m), 7.89 (2H, d, J=8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][CH3:13])[CH2:8][C:7]2=[O:14].[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:25])[C:20]([NH:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[C:7](=[O:14])[CH2:8][CH:9]2[CH2:11][CH2:12][CH3:13])=[O:21])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCC1CC(=O)c2c(N)ccc(C)c21
Product: CCCC1CC(=O)c2c(NC(=O)C(=O)OCC)ccc(C)c21
Temperature: 25 °C

Procedure:
A solution of 7.2 g of 7-methyl-3-oxo-1-propyl-4-indanylamine in 34 ml oxalic acid diethyl ester is boiled under reflux for 2 hours and then cooled to room temperature. The reaction mixture is then heated at 90°-100° at 11 mm Hg to remove the excess oxalic acid diethyl ester. The residue is chromatographed on 200 g silica gel to afford the pure title compound which is recrystallised from ether. M.pt. 84°-86°.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.55 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (135 mg, 0.56 mmol) in THF (1.0 mL) at 0° C. After 1 h at 0° C., [(Z)-4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (150 mg, 0.56 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 16.5 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% →60% EtOAc/CH2Cl2, gradient) afforded 91 mg (42%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1.[NH:33](C)[CH3:34].Cl.[BH3-]C#N.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH2:23][NH:33][CH3:34])=[CH:25][CH:26]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1
Reactant: COc1ccc(CN2Cc3c(-c4ccc(C=O)cc4)nc4cccc(n34)C2=O)c(OC)c1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CNCc1ccc(-c2nc3cccc4n3c2CN(Cc2ccc(OC)cc2OC)C4=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (B3) in DCE (0.1 M) was added Me2NH.HCl (8 eq.) and Ti(iPrO)4 (2.0 eq.) and the mixture stirred at RT for 12 h. To this solution, NaBH3CN (1.1 eq.) was added and stirring was continued for 12 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3, then, the aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue of 4-(2,4-dimethoxybenzyl)-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydro-5H-1,4,8b-triazaacenaphthylen-5-one which was used in the next step without further purification. MS (ES+) C26H26N4O3 requires: 442, found: 443 (M+H)+.
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:10][O:11][CH:20]([C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(CO)CO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCC1COC(c2ccc(C#N)cc2)OC1
Yield: 72.9 %

Procedure:
In a 500-ml egg-plant type flask were put 32.3 g of 2-octyl-1,3-propanediol, 22.5 g of p-cyanobenzaldehyde, 0.11 g of p-toluenesulfonic acid monohydrate and 300 ml of benzene, and the mixture was heated. The generated water was removed by azeotropy with benzene. Then, benzene was distilled away, and the residue was neutralized with aqueous saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the extract was washed with water and then dried over anhydrous sodium sulfate. Dichloromethane was distilled away to give a solid which was then recrystallized from isooctane to give 37.7 g of colorless crystals.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:32][C:30]2[S:31][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:34]=[CH:33][C:28]=3[N:29]=2)=[O:19])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCCc5ccccc54)c3)sc2c1

Procedure:
3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (18) (100 mg, 0.32 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as an off-white solid. Yield: 32 mg (25%). 1H-NMR: 8.48 (s, 1H), 8.40-8.35 (m, 1H), 7.77-7.59 (m, 5H), 7.24-7.18 (m, 1H) 7.11-7.05 (m, 3H), 3.87-3.81 (m, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.68-1.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25](O)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:65][C:66]([F:70])([F:69])[CH2:67][NH2:68]>CN(C=O)C>[F:65][C:66]([F:70])([F:69])[CH2:67][NH:68][C:25]([CH:23]1[CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:16][CH:17]=2)[CH2:24]1)=[O:26]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added DIPEA (0.052 g, 0.406 mmol), HOBt (0.027 g, 0.203 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.027 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), dried over sodium sulphate and evaporated in vacuo to get 0.170 mg crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford pale yellow solid, which was re-purified by DCM in pentane (1:9) to afford pale yellow solid (0.082 g, 71%). 1H-NMR (400 MHz, CDCl3) δ: 3.43-3.48 (m, 1H), 3.62 (d, 1H, J=17.04), 3.93-4.00 (m, 2H), 4.04 (d, 1H, J=17.0), 4.09-4.14 (m, 4H), 5.94 (t, 1H, J=6.06 Hz), 6.43 (d, 2H, J=8.72 Hz), 7.47-7.50 (m, 2H), 7.63 (s, 2H); LC-MS (m/z): [M−H] 571.70.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.17 g, 0.85 mmol), acetonitrile (4 mL), sodium carbonate (0.11 g, 2.12 mmol) and iodoethane (0.13 g, 0.85 mmol) was stirred at ambient temperature for 72 h. Water (30 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.11 g). [α]D=−21.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 111-112° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).