Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:43])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:30][CH2:29][C:28]=2[CH:42]=1.Cl>O1CCOCC1.COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:43][C:25]2[C:24]([O:23][CH3:22])=[CH:42][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CCN1CCOCC1)CC2

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (100 mg, 0.289 mmol) and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine (92.6 mg, 0.303 mmol) and 100 μL of 4M HCl in Dioxane (9:1, 1,4-Dioxane:Hydrogen Chloride) in 4 mL of 2-methoxyethanol were heated in a sealed tube at 120° C. over night. The reaction was extracted with DCM and washed with bicarb followed by water. Dried organic layer over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-15% MeOH:DCM). The desired fractions were concentrated and the product was collected as a foam from a small amount of DCM (65 mg, 37%). MS (ESI+): 615 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.53 (s, 1H), 8.58 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.75 (d, J=8 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.50 (s, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.74 (t, J=4 Hz, 4H), 3.27 (m, 1H), 2.88 (br s, 2H), 2.73-2.69 (m, 8H), 2.58 (m, 2H), 2.52 (br s, 4H), 1.70 (br s, 1H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[O:14]=[CH:15][CH2:16][C@H:17]1[O:22][C:21]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:20][C@@H:19]([CH2:28][C:29]#[N:30])[CH2:18]1.C(OCC)C>CC(C)=O>[C:29]([CH2:28][C@H:19]1[O:20][C:21]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:22][C@@H:17]([CH2:16][C:15]([OH:3])=[O:14])[CH2:18]1)#[N:30]
Reactant: CC(C)=O
Reactant: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reaction time: 0.25 h

Procedure:
Jones reagent (chromium trioxide-sulfuric acid-water), 4.4 mL (8.85 mmol), is added dropwise to a 0° C. solution of (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile, 3.62 g (12.6 mmol), dissolved in 30 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 3.65 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid as a yellow solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH2:8])[CH2:2]1.C(N(CC)CC)C.S=[C:18]1[CH2:22][S:21][C:20](=[O:23])[NH:19]1>C(O)C>[O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:9])[CH2:7][NH:8][C:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]=2)[CH2:2]1
Reactant: NCC(=O)NC1COC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CNC1=NC(=O)SC1)NC1COC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (5.7 g) containing N-oxetan-3-ylglycinamide obtained in B) and triethylamine (13.3 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.8 g), and the mixture was stirred at room temperature is for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol/dichloromethane) to give the title compound (2.03 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][N:23]1[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=[C:18]1[N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1
Reactant: O=C(Nc1ccccc1)C1CCCNC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCC(C(=O)Nc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 91.6 %

Procedure:
A solution of 3-piperidinecarboxanilide hydrochloride (96.0 mg, 0.40 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (66.0 mg, 0.30 mmol) and triethylamine (0.33 ml, 2.50 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The whole reaction mixture was evaporated in vacuo and the precipitate was washed with water and diethyl ether to give the title compound (107 mg, 92%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1)N1CCCC1
Yield: 57 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and pyrrolidine following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1): tR=2.27 min; Mass spectrum (ESI+): m/z=429 [m+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].CC[O:16]C(C)=O>CO>[CH2:12]1[CH:10]([NH:9][C:7]([C:6]2[CH:5]=[N+:4]([O-:16])[CH:3]=[C:2]([Br:1])[CH:13]=2)=[O:8])[CH2:11]1
Reactant: O=C(NC1CC1)c1cncc(Br)c1
Reactant: CCOC(C)=O
Solvent: CO
Product: O=C(NC1CC1)c1cc(Br)c[n+]([O-])c1

Procedure:
Prepared according to the procedure described in EXAMPLE 9 (Step 4) but using 5-bromo-N-cyclopropyl-nicotinamide from Step 1 as starting material. Flash chromatography (EtOAc:MeOH; 9:1) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 47 %

Procedure:
1,1,1,4,4,4-Hexafluoro-2-chloro-2-butene in 300 ml ethanol was hydrogenated in the presence of potassium hydroxide (12 g) and Raney nickel (25 g) at a temperature of 20° to 100° C. and under a pressure of 20 to 40 bar. The solid constituents were filtered off and the filtrate was extracted with water. The organic phase was separated and purified by distillation, giving 15.5 g (47% of theory) of 1,1,1,4,4,4-hexafluorobutane, boiling point 24°-27° C. at 1013 bar.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 0.31 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (80 mg, 0.34 mmol) and DIPEA (104 μL, 0.61 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (128 mg, 78%). LCMS (Method C): RT 3.57 min [M+H]+ 536.3/538.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:19])([F:18])[F:17])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:19])([F:18])[F:17])(=[O:30])=[O:29]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.17 mmol, 1.00 equiv), triethylamine (53 mg, 0.52 mmol, 3.01 equiv), dichloromethane (2.0 mL), MsCl (40 mg, 0.35 mmol, 2.02 equiv). The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 75 mg of [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C14H14F3NO3S2, 366.0 (M+H). found 366.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](C(N)=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(N)=O)CC1

Procedure:
trans-4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide (40 mg, 0.10 mmol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (33 mg, 0.12 mmol), and sodium carbonate (33 mg, 0.31 mmol) were added to DME:Water (5:1) (2 mL) and the mixture degassed with Argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.007 mmol) was then added and the reaction mixture microwaved at 110° C. for 1 h, The mixture was concentrated in vacuo, taken up in DMSO, and purified by mass-directed preparative HPLC to afford desired product. 1H NMR (d6-DMSO, 400 MHz): 11.50 (br s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.46 (dd, J=7.6, 0.4 Hz, 1H), 7.25 (br s, 1H), 7.13 (m, 1H), 7.08-7.00 (m, 2H), 6.70 (br s, 1H), 6.69 (br s, 1H), 3.16 (m, 1H), 2.20 (m, 1H), 2.10-1.80 (m, 4H) and 1.65 (m, 4H). MS (ES+): m/z 375.17 [MH+].
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[CH:6][C:5]=1[OH:12].[F:13][C:14](F)([F:22])S(OC(F)F)(=O)=O>C(#N)C.O>[F:13][CH:14]([F:22])[O:12][C:5]1[C:4]([I:3])=[CH:9][C:8]([O:10][CH3:11])=[N:7][CH:6]=1
Reactant: COc1cc(I)c(O)cn1
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(I)c(OC(F)F)cn1
Reaction time: 0.03 h

Procedure:
4.8 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 600 mg (purity 93%, 2.22 mmol) of 4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile, the mixture was cooled in an ice bath and 863 μl (purity 75%, 3.56 mmol, 1.6 eq.) of difluoromethyl trifluoromethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added with vigorous stirring. The reaction mixture was stirred for 2 min and diluted with 33 ml of water. The aqueous phase was extracted twice with in each case 40 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (IR-50SI, petroleum ether/ethyl acetate 12-20%). Yield: 407 mg (purity 90%, 55% of theory)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=[S:42])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(NC(=O)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cnc(NC(=S)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 60.7 %

Procedure:
To a suspension of N-[5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-2-(4-methanesulfonyl-phenyl)-acetamide (Int. 10, 305 mg, 0.579 mmol) in toluene (15 mL) was added Lawesson's reagent (234 mg, 0.579 mmol) and the reaction mixture was heated at 110° C. for 24 hrs. A further amount of Lawesson's reagent (351 mg) was added and heating was continued for 2.5 hrs before a final addition of Lawesson's reagent (234 mg) was made. The reaction mixture was heated for 19 hrs then cooled, concentrated in vacuo and the resultant residue purified by flash chromatography eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give the title compound as an orange glass (191 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH:32]([CH3:34])[CH3:33]>>[CH3:31][CH:32]([CH3:34])[CH2:33][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: CC(C)C
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)COCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-methylpropane chloride are treated as described in Example 5.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)#[N:1]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN)cc1
Yield: 93.5 %

Procedure:
10% Pd-on-C (Aldrich, 800 mg) catalyst was added to a solution of α-azido-4-cyanotoluene (compound 33, 8 g, 51 mmol) in EtOAc (150 mL). The reaction mixture was hydrogenated (H2, 45 psi) in a Parr apparatus for 11 hours. Catalyst was removed by filtering and the solvent was removed under vacuum to give the title compound (6.3 g, 93%). 1HNMR (CDCl3) δ3.85 (s, 2H), 7.45 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1 Hz), 7.78 (s, 2H, NH2).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C>[C:15]([O:18][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])(=[O:17])[CH3:16]
Reactant: O=Cc1ccccc1OC/C=C/CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC/C=C/COc1ccccc1C=O

Procedure:
The mixture of 50 g of 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde, 50 g of sodium acetate and 200 ml of acetic acid is refluxed for 2 hours and concentrated. The concentrate is diluted with water, extracted with diethyl ether, the extract washed with water and 5% aqueous sodium bicarbonate, dried and evaporated, to yield the 2-(4-acetoxy-trans-2-butenyloxy)-benzaldehyde.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27]O>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1
Reactant: OCCc1ccccc1F
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccccc2F)cc1
Yield: 73.4 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (231 mg, 0.919 mmol) prepared in Example 1 (1a) and 2-(2-fluorophenyl)ethanol (137 μL, 1.02 mmol) to give 214 mg of the title compound (white powder, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:17].[CH2:18]1[CH2:22]OC[CH2:19]1>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C@H:9]([NH:10][S@@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH:18]([CH3:22])[CH3:19])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Reactant: C1CCOC1
Product: Cc1cc([C@H](N[S@](=O)C(C)(C)C)C(C)C)cc(C)c1Cl
Temperature: 25 °C

Procedure:
In a separate flask a solution of imine INT 36 (5 g, 18.4 mmol) in THF (140 mL) was cooled in a dry ice bath under argon to −78° C. At this temperature the organozincate solution from above was added dropwise over a period of about 30 minutes. Stirring was continued for another hour before the resulting mixture was first quenched carefully with 10% ammonium chloride solution (40 mL), then water (50 mL). The reaction mixture was allowed to warm up to room temperature and was then extracted with Et2O (3×). The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH3:31])=[CH:26][C:27]([O:29]C)=O)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]>>[OH:29][C:27]1[C:20]2[C:21](=[CH:22][CH:23]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:19]=2)[N:24]=[C:25]([CH3:31])[CH:26]=1
Reactant: COC(=O)C=C(C)Nc1ccc(NC(C)=O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Temperature: 252.5 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Phenyl ether (1 L) was heated to 255° C. Butenoate 3 (334 g, 1.35 mol) was carefully added portionwise while maintaining temperature 245-260° C. After the addition was complete, the yellow-orange suspension was held at 255° C. for an additional 15 min. The mixture was slowly cooled to 40° C., the solids were collected by filtration and washed with EtOAc (3×500 mL) followed by MeOH (3×500 mL) to give hydroxy quinoline 4 as yellow-orange solid (256 g, 88% yield); 1H NMR (DMSO) δ 11.52 (br, s, 1H), 10.07 (s, 1H), 8.24 (s, 1H), 7.82 (d, 1H), 7.42 (d, 1H), 5.84 (s, 1H), 2.31 (s, 3H), 2.05 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1>>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:14][CH:13]1[C:12](=[CH2:17])[CH3:18])(=[O:4])[CH3:5]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C1CC1(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl acetoacetate (125.8 g) in 400 ml of toluene was added dropwise to a suspension of sodium hydride (68.3 g of a 60% oil dispersion washed with pentane) in 1 L of toluene under an N2 blanket at -6° C. to 2° C. After 20 minutes, 1,4-dibromo-2-methyl-2-butene (220.6 g) in 300 ml of toluene was added dropwise at -2° C. to 0° C. The reaction mixture was allowed to warm to ambient temperature and after 22 hours, was diluted with water and extracted with ethyl acetate (thrice). The combined organic extracts were washed with water, brine, dried and concentrated in vacuuo. GLC of the crude material indicated 77% of the two desired isomers. The isomers were separated by flash chromatography using 7.5% ethyl acetate in hexane, giving ca 90% pure isomers.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=C(N)[N:5]=1.[H-].[Na+].[CH3:14][N:15]([CH:17]=O)[CH3:16]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:17]([N:15]([CH3:16])[CH3:14])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
MeI (0.46 ml, 1.04 g, 7.32 mmol, 2.4 eq) was added to a stirred solution of 4,6-dichloropyrimidin-2-amine (Aldrich, 0.5 g, 3.05 mmol, 1 eq) in 10 ml anhydrous DMF under Ar. After cooling to 0° C., NaH (0.27 g, 6.71 mmol, 2.2 eq) was added. The reaction was stirred at 0° C. to room temperature overnight. The reaction was quenched with water and extracted with Et2O (×1). The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.4947 g (2.58 mmol, 84% yield) of 4,6-dichloro-N,N-dimethylpyrimidin-2-amine.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5])(=[O:29])=[O:28]
Reactant: CCCCCCCCCCCCC[C@@H](O)CC(N)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-hydroxyhexadecanamide (100 mg) and pyridine (210 μl) in dichloromethane (10 ml) was added methanesulfonyl chloride (144 μl). This mixture was stirred at room temperature overnight, and the resulting precipitate was filtered off. The filtrate was concentrated, and dissolved in ethyl acetate (20 ml). This solution was washed with 1N-hydrochloric acid (20 ml×3), saturated sodium carbonate (20 ml×2), and brine (20 ml). After drying over MgSO4 and concentration, the residue was chromatographed on a silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give (R)-3-methanesulfonyloxyhexadecanamide (40 mg).