Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]=[CH:12][C:13](=[CH2:15])[CH3:14].[BH4-].[Na+]>O>[CH2:3]([O:10][CH2:14][CH:13]([CH3:15])[CH2:12][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: C=C(C)C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CO)COCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.59 g. of sodium hydroxide and 1.6 ml. of water in 402 ml. (420 g; 3.89 moles) of benzyl alcohol was stirred and cooled to -10° C. while 100 ml. (83.7 g.; 1.19 moles) of freshly distilled methacrolein were added dropwise keeping the temperature between -10° C. and -5° C. After the reaction mixture had stirred for 0.5 hr. at -10° C., a solution of 44.9 g. (1.19 moles) of sodium borohydride in 180 ml. of water was added dropwise over 1.75 hr. keeping the temperature below 5° C. Stirring was continued for an additional hour during which time the reaction mixture was allowed to warmto room temperature. The resulting mixture was poured into ice-water and the organic materials were extracted several times with ether. The ether extracts were worked up by first combining the extracts washing with saturated brine and drying over anhydrous magnesium sulfate. After filtration and removal of the solvents in vacuo, the residue was carefullyfractionated, giving, after removal of low boiling materials, 39.6 g. of rac. 3-benzyloxy-2-methyl-1-propanol as a colorless liquid, b.p. 91°-98° C. (0.5 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Br:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:64][CH2:63]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.074 g, 0.00027 mol) in DMF (5 mL) was added DIPEA (0.088 g, 0.0006827 mol), HOBt (0.036 g, 0.00027 mol) and EDCI.HCl (0.065 g, 0.00034 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.066 g, 0.00023 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.036 g (31%) of N-{2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LCMS: 507.13 (M+1)+, 96.75%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.4 (dd, 1H), 7.3 (t, 2H), 7.2 (m, 3H), 7.1 (d, 2H), 6.9 (t, 1H), 6.8 (d, 1H), 6.6 (t, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 3H), 2.8 (m, 2H), 2.0 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][CH3:48])[C:45]#[CH:46].C(NCC)C>CN(C=O)C.[Cu](I)I>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:46]#[C:45][CH2:44][O:47][CH3:48])=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CCOC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a mixture of 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (450 mg), 52 mg bistriphenylphosphinpalladium dichloride, 14 mg copperiodide, 146 mg triphenylphosphine and methyl propargyl ether (0.12 mL) in 10 mL DMF is added diethylamine (1.9 μL). The mixture is heated in the microwave oven for 40 min at 120° C. The reaction mixture was cooled to room temperature and partitioned between 1 N hydrochloric acid and ethyl acetate. The organic phase was purified by gradient chromatography on silica gel with heptane:ethyl acetate to yield 0.13 g of the title compound as a light yellow solid, MS (ISP) 399.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Br[CH2:25][CH2:26][CH2:27][Cl:28]>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:25][CH2:26][CH2:27][Cl:28])[CH:5]([CH3:7])[CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: ClCCCBr
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Yield: 75 %

Procedure:
According to the procedure of Example 5, 1.00 g (2.95 mmol) 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.88 mL (8.849 mmol) of 1-bromo-3-chloropropane provided 0.92 g of methyl2-[{[4-(2-butynyloxy)penyl]sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate as a white solid. Electrospray Mass Spec 416.2 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=O)=[CH:19]2.N1CCCCC1>C(O)C>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:19]2
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of oxindole (28 mg, 0.216 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 59 mg (79%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1([CH3:13])[CH2:5][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([OH:8])=O)[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([CH3:29])[NH2:28])=[CH:23][CH:22]=1.O>S(Cl)(Cl)=O.O1CCOCC1.O>[Cl:1][C:2]1([CH3:13])[CH2:3][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([NH:28][C@@H:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH3:29])=[O:8])[CH2:5]1
Reactant: CC1(Cl)CC(C(=O)O)(C(F)(F)F)C1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C1(C(F)(F)F)CC(C)(Cl)C1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 0.240 g (1.11 mmol) of 3-chloro-3-methyl-1-(trifluoromethyl)cyclobutane carboxylic acid (prepared according to the method described by H. K. Hall, Jr., E. P. Blanchard Jr. and E. L Martin in Macromolecules 4(2) 142-146 (1971)) in 5 mL thionyl chloride was heated at reflux for 1 h. Solvent was removed in vacuo. The residue was added to a solution of 0.176 g (1.66 mmol) sodium carbonate and 0.172 g (1.11 mmol) (R)-4-chloro-α-methylbenzenemethanamine in 6 mL of 1:1 dioxane-water, pre-cooled to 0° C. After stirring at room temperature overnight, the mixture was poured into 50 mL water and extracted two times with 50 mL ethyl acetate (EtOAc). Drying (magnesium sulfate) and removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 25% hexane-dichloromethane, to afford 43 mg of the cis isomer of the title compound: mp 129-130° C., 1H NMR (CDCl3) δ1.49 (d, 3H), 1.69 (s, 3H), 2.86-2.95 (m, 2H), 2.98-3.05 (m, 2H), 5.05-5.12 (q, 1H), 5.86 (s, 1H), 7.20 (d, 2H), 7.32 (d, 2H), and 77 mg of the trans isomer of the title compound: mp 145-146 C, 1H NMR (CDCl3) 1.54 (d, 3H), 1.74 (s, 3H), 1.74 (s, 3H), 2.79-2.86 (m, 2H), 3.13 (d, 2H), 5.14 (q, 1H), 5.85 (s, 1H), 7.23 (d, 2H), 7.31 (d, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-BOC-glycine (150 mmol) in DMF (250 mL) at 0° C., is added proline methyl ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts are washed as follows: KHSO4 (0.25M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo to give title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: COc1ccc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from (4-methoxyphenyl)acetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2Nc2ccccc2-c2ccccc2)cc1
Temperature: 110 °C
Yield: 70.9 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), 2-bromobiphenyl (3.50 g, 15 mmol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After the flask including the reactant mixture was cooled to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10), and were then recrystallized in normal hexane to produce 3.42 g of dibiphenyl-2-yl amine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([NH:11]N=C2CCCNC2=O)[CH:3]=1.[CH:20]([OH:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:2]3[CH2:3][CH2:4][NH:11][C:20](=[O:22])[C:10]=3[NH:11]2)=[C:6]2[CH2:7][CH2:8][O:9][C:10]=12
Reactant: O=CO
Reactant: O=C1NCCCC1=NNc1cc(Cl)c2c(c1)CCO2
Product: O=C1NCCc2c1[nH]c1cc(Cl)c3c(c21)CCO3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[(7-chloro-2,3-dihydro-1-benzofuran-5-yl)hydrazinylidene]piperidin-2-one (a mixture of E and Z isomers) (3.66 g) and formic acid (65.4 mL) was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain an orange solid. This solid was washed with ethyl acetate to obtain a mixture (1.74 g) of 4-chloro-1,2,6,8,9,10-hexahydro-7H-furo[3,2-e]pyrido[3,4-b]indol-7-one and 10-chloro-2,3,5,7,8,9-hexahydro-6H-furo[2,3-f]pyrido[3,4-b]indol-6-one as an orange solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:15])=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[F:29][C:30]([F:39])([F:38])/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CS(C)=O>[CH3:14][C:12]1[CH:13]=[C:3]2[C:4](=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=1)[O:15][CH:31]([C:30]([F:29])([F:39])[F:38])[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:1]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CCOC(=O)c1cc(C)cc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C(=O)OCC)c2OC1C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h
Yield: 42.3 %

Procedure:
A mixture of ethyl 3-formyl-2-hydroxy-5-methylbenzoate (6.18 g, 29.69 mmole), K2CO3 (8.19 g, 59.38 mmole), triethylamine (1.99 g, 118.75 mmole), and ethyl 4,4,4-trifluorocrotonate (19.95 g, 118.75 mmole) in anhydrous DMSO (40.0 mL) was heated to 90° C. under a dry N2 atmosphere for 5 hrs. The mixture was then cooled and allowed to stir at room temperature for 15 hours. The reaction was poured into 1.2 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark red oil which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give a light orange solid (4.5 g, 42%): 1H NMR (acetone-d6/400 MHz) 7.84 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 5.86 (q, 1H, J=7.0 Hz), 4.30 (m, 4H), 2.31 (s, 3H), 1.33 (m, 6H).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[CH:23][CH:22]=3)[CH3:20])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(O)cc3)cc2)C1
Reactant: BrCC1CC1
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(OCC4CC4)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclopropane by method H. This resulted in the product with the molecular weight of 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH2:14]2)[N:7]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: O=C([C@H]1CNCCO1)N1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
2-Chloro-5-nitropyrimidin-4-amine (106 mg, 0.612 mmol) was added to a solution of (R)-morpholin-2-yl(pyrrolidin-1-yl)methanone hydrochloride (0.15 g, 0.68 mmol) and triethylamine (0.28 mL, 2.04 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was heated at 80° C. for 1 h, then was cooled to room temperature and stirred for 12 h. The solvent was removed under reduced pressure and the resulting crude material was triturated with diethyl ether to afford (R)-(4-(4-amino-5-nitropyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (0.11 g). MS (ES+APCI) (M+H) 323.1; LCMS retention time: 3.518 min (Method S1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC1OCCO1

Procedure:
2,6-Dimethylaniline (75 grams), 2-chloromethyl-1,3-dioxolane (25 grams), potassium carbonate (34 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of about 18 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2,6-dimethylaniline.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]#[N:12])([CH3:3])[CH3:2].[OH:13]O.[OH-].[Na+]>CS(C)=O.O>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]([NH2:12])=[O:13])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.105 g (0.634 mmol) of (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile in 4.9 mL of dimethyl sulfoxide was placed in a 10 mL flask with a magnetic stir bar. After adding 0.60 mL of 35% hydrogen peroxide and 0.097 g (1.2 mmol) of 50% sodium hydroxide solutions the flask was capped and stirred at room temperature for 20 h. The reaction mixture was diluted with 10 mL of water, extracted twice with 10 mL of methylene chloride. The combined methylene chloride layers were back extracted with 3×20 mL of water, dried over magnesium sulfate, and concentrated in vacuo to provide an off-white solid that was further purified by column chromatography (silica gel, 75:25 hexane:ethyl acetate) to provide (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14](F)[CH:13]=1.[CH2:27]([OH:29])[CH3:28].ClCCl>C1COCC1>[NH2:11][C:12]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([O:29][CH2:27][CH3:28])[CH:13]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
KHMDS (1.92 g, 9.64 mmol) was added to a mixture of ethyl 4-amino-2-fluoro-5-nitro-benzoate (2.00 g, 8.77 mmol) and ethanol (0.56 mL, 9.64 mmol) in 70 mL THF at 0° C. The mixture was stirred at 60° C. for 16 h. Then KHMDS (1.92 g, 9.64 mmol) and ethanol (1.2 mL, 20.7 mmol) were added at ambient temperature and the mixture was stirred at 60° C. for 2 h. 100 mL dichloromethane were added and the mixture extracted with sat. NH4Cl (aq). The organic layer was evaporated, the residue mixed with ethyl acetate, washed with sat. NaCl (aq), dried over Na2SO4, filtered and evaporated. The residue was purified twice by chromatography (silica gel; eluens: petrol ether/ethyl acetate=1:1 and 2:1).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH2:20][CH3:21])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH2:19][CH2:20][CH3:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CCC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 11 (123 mg, 0.44 mmol) and 1-bromopentadecane (318 mg, 1.09 mmol), alcohol 65 was obtained as a colorless oil (161 mg, 75% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[N:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1>C(O)C>[Br-:1].[OH:4][CH2:3][CH2:2][N+:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: OCCBr
Reactant: Cc1ccncc1
Solvent: CCO
Product: Cc1cc[n+](CCO)cc1
Product: [Br-]
Temperature: 50 °C
Yield: 34 %

Procedure:
In a 3-neck, round-bottomed flask flushed with nitrogen, 2-bromo-1-ethanol (40.01 mmol), 4-picoline (43.57 mmol) and absolute ethanol (16 mL) were combined and heated for 3.5 hours at 50° C. under nitrogen with stirring. The reaction was stopped and the contents of the flask were transferred to a one-neck round-bottomed flask. The solvent was removed under vacuum and the residue was washed with diethyl ether (4×100 ml) and any remaining solvent was removed under vacuum. The product was obtained as a viscous orange liquid in a 34% yield. 1H NMR (200 MHz, CDCl3) 8.9 (2H, protons on pyridine ring), 8.0 (2H, protons on pyridine ring), 2.6 (3H, CH3), 4.6 (2H, —CH2O), 3.8 (2H, —NCH2—), 5.2 (1H, —OH); IR (neat, cm−1) 3303 (OH), 1640 (aromatic C═N), 1474 (aromatic C—C).