Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.CN.[CH:13]([N:16](C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNc1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
2,4,6-Trichloropyrimidine (I, 30 g) is added to a suspension of methylamine hydrochloride (II, 10 g) in THF (250 ml). The mixture is cooled to -6° and diisopropylethylamine (55 ml) is added slowly. The mixture is stirred for 3 days at 20°-25° and then is concentrated under reduced pressure. The residue is absorbed on silica gel (75 g) with ethyl acetate/methylene chloride (1/1) and applied to a silica gel (1 kg) column packed in ethyl acetate/hexane (1/1). Elution is performed with ethyl acetate/hexane (1/1) collecting 500 ml fractions. The appropriate fractions (8-14) are pooled and concentrated to give the title compound, NMR (CDCl3) 6.29, 6.2 and 2.9δ.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11].C([Li])CCC.FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O>C(OCC)C>[CH3:24][Si:23]([CH3:25])([C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11]
Reactant: Fc1cc(F)c(F)c(Br)c1F
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)cc(F)c1F
Temperature: -78 °C

Procedure:
The compound, 1-bromo-2,3,5,6-tetrafluorobenzene, C6HBrF4, (14.8 g, 64.6 mmol) was dissolved in diethyl ether (200 ml) in a 500 ml flask and was cooled down to -78° C. Butyllithium (40 ml, 1.6M in hexanes) was then added to the flask dropwise while the solution was being stirred vigorously. After it had been stirred for one hour, t-butyldimethylsilyl trifluoromethane sulfonate (17.0 g, 64.6 mmol) was injected via a syringe. The reaction mixture was allowed to slowly warm up to room temperature over a period of eight hours, and the resulting suspension was filtered. After the solvent was removed from the filtrate at 25° C. under reduced pressure, the nonvolatile residue was distilled and a colorless liquid product was collected (45°C./0.8 mm Hg). Yield, 80%, 1H NMR(CCl2D2): δ0.40 (t, 6H), 0.93 (s, 9H), 7.10 (m, 1H); 13C NMR(CCl2D2): δ -3.7(t), 18.1(s) , 26.5(s) , 108.0(t), 144.8(m), 148.1(t), 151.4(t).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reaction time: 4 h
Yield: 70.9 %

Procedure:
1.60 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butyl ester (compound C1) are dissolved in 70 ml of dichloromethane at ambient temperature. Then 7 ml of trifluoroacetic acid (TFA) are added and stirred for 4 hours. The solvent is evaporated to dryness and to the residue are added 30 ml of water. The water phase is extracted exhaustively with ethyl acetate. Then the organic phase is dried over sodium sulfate. The filtrate is evaporated and dried under vacuo to give 0.951 g of the title compound as a pale grey solid.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCCC2)C1
Yield: 85.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of cyclohexen-1-ylboronic acid (115 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 85.4%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].O.NN>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:13])[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 87.7 %

Procedure:
To a solution of 196 (2.0 g, 5.7 mmol) and THF:MeOH (1:1, 20 mL) at RT was added hydrazine monohydrate (2.9 g, 57 mmol) and the reaction was heated to 50° C. for 18 h. The reaction was cooled to RT, filtered, and the filtrate was poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:30) to afford 1.1 g (88%) of (S)-1-(3,4-dichlorophenyl)-2-methoxyethanamine as a off-white solid (198).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][C@@H:16]([CH2:23][O:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C>>[ClH:1].[CH3:25][O:24][CH2:23][C@H:16]([NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 ml of 4N-HCl/dioxane solution was added to 4.02 g (16.0 mmols) of N-t-butoxycarbonyl-(R)-α-methoxymethylbenzylamine, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. 30 ml of ether were added to the residue, and this was further concentrated to obtain (R)-α-methoxymethylbenzylamine hydrochloride in quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=O)[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=[N:18][OH:19])[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)CC(C)N1Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CC(=NO)CC(C)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
10 g of 1-benzyl-2,6-dimethyl-4-piperidone (prepared from benzylamine and ethyl crotonate in analogy to Bull. Chem. Soc. Japan 31 (1958) 418) are dissolved in 60 ml of methanol and this solution is added dropwise to a solution of 3.8 g of hydroxylamine hydrochloride and 4.5 g of sodium acetate in 150 ml of water. The mixture is stirred at 60° C. for 2 h and cooled to 0° C., and the oxime which has separated out is filtered off with suction. Drying results in 5.2 g of the title compound.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.[OH-].[Na+].O.CN(C=O)C>C(O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[N:3]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1c(S)nc2c(c1=O)CCCC2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2c(c1=O)CCCC2
Yield: 60.5 %

Procedure:
A solution of 2-mercapto-3-methyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone (980 mg), 4-(4-chlorobenzoyl) benzyl bromide (1.53 g), and 1N-sodium hydroxide/water (5.5 ml) in ethanol (10 ml)-DMF (5 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from methanol-ethyl acetate to provide the title compound as colorless solid (1.27 g).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][NH:31][CH3:32]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:4]3[O:3][C:2]([N:31]([CH3:32])[CH3:30])=[N:6][C:5]=3[CH3:7])=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CNC
Reactant: CCC(CC)c1cc(C)nn2c(-c3oc(Br)nc3C)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3oc(N(C)C)nc3C)c(C)nc12
Temperature: 110 °C
Yield: 89 %

Procedure:
32 mg of 3-(2-Bromo-4-methyl-oxazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.08 mmol) and 78 mg of cesium carbonate (0.24 mmol) are placed into vial with 3 ml of dimethylamine 2.0 M in THF. The vial is capped with a Teflon cap and heated at 110° C. for 3 days. The reaction mixture is cooled to room temperature, concentrated, and applied onto a silica-gel chromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give 24 mg of the title product. Yield 89%. mass spectrum (m/e): 342 (M+1). 1H-NMR (CDCl3): 6.71 (s, 1H), 3.34 (m, 1H), 3.13 (s, 6H), 2.56 (s, 3H), 2.49 (s, 3H), 2.14 (s, 3H), 1.84 (m, 4H), 0.89 (t, J=7.5 Hz, 6H).
Reaction SMILES: [H-].[Na+].I[CH3:4].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:16]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH3:6].[NH4+].[Cl-]>C1COCC1>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:16]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[CH2:17][CH2:18][O:19][CH3:4])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH3:6]
Reactant: CCOc1cc(C(CCO)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1cc(C(CCOC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.8 %

Procedure:
To a stirred mixture of sodium hydride (110 mg, 60%, 2.75 mmol) in THF (8 mL) at room temperature, was added iodomethane (0.54 grams, 3.78 mmol) followed by 3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimido-1-propanol (850 mg, 2.39 mmol). The mixture was stirred at room temperature for 15 h. To the mixture was added NH4Cl (20 mL, sat). The organic layer was separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel 200 grams, 1:12 EtOAc:CH2Cl2) gave 3-(3'-ethoxy-4'-methoxyphenyl)-1-methoxy-3-phthalimidopropane as an oil (360 mg, 41% yield). The resulting oil solidified after standing at room temperature over weekend: mp, 67.5°-70.0° C.; 1H NMR (CDCl3)δ1.45 (t, J=7 Hz, 3H, CH3), 2.50-2.60 (m, 1H, CHH), 2.71-2.85 (m, 1H, CHH), 3.26 (s, 3H, CH3), 3.39 (t, J=6 Hz, 2H, CH2), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.47 (dd, J=7, 9.3 Hz, 1H, NCH), 6.81 (d, J=Hz, 1H, Ar), 7.09-7.16 (m, 2H, Ar), 7.66-7.69 (m, 2H, Ar), 7.76-7.82 (m, 2H, Ar). 13C NMR (CDCl3)δ(APT) 14.67 (CH3), 31.23 (CH2), 51.89 (CH3), 58.63 (CH), 64.25 (CH2), 69.62 (CH2), 111.13 (CH), 112.98 (CH), 120.58 (CH), 123.06 (CH), 131.87 (C), 131.92 (C), 133.78 (CH), 148.09 (C), 148.84 (C), 168.33 (C); Anal Calcd for C21H23NO5 0.05H2O: C, 67.66; H, 6.23; N, 3.75. Found: C, 67.91; H, 6.00; N, 3.71.
Reaction SMILES: [O-:1]O.[C:3]1([CH:9](C)C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(C)=O>[C:3]1([OH:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:4][C:3]([CH3:9])=[O:1]
Reactant: [O-]O
Reactant: CC(C)c1ccccc1
Solvent: CC(C)=O
Product: Oc1ccccc1
Temperature: 57 °C

Procedure:
To a 250-ml round bottom flask fitted with a condenser, heater, stirrer and feed control, is charged a mixture of 60.0 g of acetone and 0.1 g of Engelhard Clay-24. The mixture is heated to reflux (57° C.) with stirring, and 40.0 g of "80%" cumene hydroperoxide solution added dropwise such that the pot temperature does not exceed 66° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:8][CH:4]=[CH2:5])[CH:10]=1)[C:5]([O:7][CH2:3][CH:2]=[CH2:10])=[O:6])[CH:19]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(OCC=C)cc(OCC=C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 173.1 %

Procedure:
3,5-Dihydroxybenzoic acid (15.0 g, 97.3 mmol) and potassium carbonate (44.0 g, mol) were mixed in N,N-dimethylformamide (60 ml) and heated to 80° C. Allyl bromide (42.0 g, 0.35 mol) was added dropwise during 1 h and efficient stirring was continued for 24 h. The reaction mixture was then evaporated to a semisolid residue, which was treated with chloroform (500 ml) and filtered. The filtrate was washed with water (3×150 ml), dried (Na2SO4) and filtered through a short column of alumina. Evaporation of the solvent gave 23.1 g (87%) of the product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][NH:14][C:15]([NH:24][CH3:25])=[C:16]([C:22]#[N:23])[C:17]([O:19]CC)=O)[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][N:31]=[C:32]=[S:33].O>CN(C=O)C>[C:22]([C:16]1[C:17](=[O:19])[N:31]([CH3:30])[C:32](=[S:33])[N:24]([CH3:25])[C:15]=1[NH:14][CH2:13][CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)[CH2:8]1)#[N:23]
Reactant: CCOC(=O)C(C#N)=C(NC)NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(NCC2CN(Cc3ccc(F)cc3)CCO2)c(C#N)c(=O)n(C)c1=S
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl 3-[4-(p-fluorobenzyl)-2-morpholinylmethylamino]-3-methylamino-2-cyanoacrylate (1.00 g, 2.66 mmol) in DMF (10 ml) was added under ice-cooling sodium hydride (0.11 g, 2.66 mmol) and the mixture was stirred for one hour. To the reaction mixture was added dropwise a solution of methyl isothiocyanate (0.19 g, 2.66 mmol) in DMF (1 ml) and the mixture was stirred under ice-cooling for 8.5 hours. Then, the reaction mixture was poured into water (30 ml) and extracted with chloroform (50 ml×4). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound from the fraction from ethyl acetate. Yield=90%.
Reaction SMILES: Br[C:2]1[N:3]([CH3:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[CH2:20]([Li])CCC.IC>C1COCC1.CCCCCC>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([CH3:20])[N:3]([CH3:19])[N:4]=[C:5]12
Reactant: [Li]CCCC
Reactant: Cn1nc2c(c1Br)CCCN2c1ccc(Cl)cc1Cl
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of 3-bromo-7-(2,4-dichloro-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-2; 0.100 g, 0.277 mmol) in 2 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under an argon atmosphere and treated with 0.21 mL of 1.6 M n-butyllithium in hexane. After 10 m the mixture was treated with iodomethane (0.21 mL, 0.047 g, 0.33 mmol) and stirred at −78° C. for 1 h and allowed to come to room temperature overnight. The reaction mixture was quenched with 40 mL of saturated ammonium chloride and extracted twice with 25 mL portions of ethyl acetate. The combined the extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness to yield 79 mg of crude product. Purification by preparative TLC using ethyl acetate/toluene (1:9) afforded 19 mg of 7-(2,4-dichloro-phenyl)-2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (2-17; 23% theory) as a pink solid: mp 66.6-76.6° C.
Reaction SMILES: [CH2:1]([N:3]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:4]1[C:5]([CH3:26])=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][C:68]1[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=1[CH3:74]>CN(C=O)C>[CH2:1]([N:3]([CH:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:4]1[C:5]([CH3:26])=[C:6]([C:7]([NH:66][CH2:67][C:68]2[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=2[CH3:74])=[O:9])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:12]=1)[CH3:2]
Reactant: Cc1[nH]c(=O)c(CN)c(C)c1F
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
A stirred solution of 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzoic acid (100 mg, 0.22 mmol) in anhydrous DMF (4.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (99 mg, 0.26 mmol) and DIPEA (75 μl, 0.43 mmol) dropwise. The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-5-fluoro-4,6-dimethyl-1,2-dihydropyridin-2-one (50%, 81 mg, 0.24 mmol). The resulting suspension was stirred at 0° C. for 30 minutes and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between water (20 ml) and CH2Cl2 (15 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (2×25 ml), brine (20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-6% MeOH/CH2Cl2) and then dissolved in a mixture of EtOAc (40 ml) and CH2Cl2 (10 ml), and washed with water (6×30 ml), brine (2×30 ml), dried (MgSO4), filtered and concentrated in-vacuo. The solid was thoroughly dried in-vacuo at 40° C. for 40 hours to give 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (93 mg, 73%) as a powdery white solid. LC-MS 100%, 2.76 min (7 minute LC-MS method), m/z=591.2; 1H NMR (500 MHz, Chloroform-d) δ 11.79 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.4 Hz, 3H), 7.08 (t, J=6.0 Hz, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.76-3.66 (m, 4H), 3.51 (s, 2H), 3.31 (td, J=11.3, 2.7 Hz, 2H), 3.10 (q, J=7.0 Hz, 2H), 3.00 (tt, J=9.6, 4.6 Hz, 1H), 2.45 (s, 4H), 2.43 (d, J=1.8 Hz, 3H), 2.34 (s, 3H), 2.13 (d, J=2.7 Hz, 3H), 1.74-1.62 (m, 4H), 0.89 (t, J=7.0 Hz, 3H). One proton assumed to be coincident with a solvent peak.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Oc1ccc2cc(C3(O)CCNCC3)ccc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1ccc2cc(C3(O)CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A mixture of 0.172 gm (0.82 mMol) 1-(4-indolyloxy)-3-chloropropane, 0.200 gm (0.82 mMol) 4-hydroxy-4-(6-hydroxynaphth-2-yl)piperidine, and 0.17 gm (1.2 mMol) potassium carbonate in 6 mL acetonitrile were stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to radial chromatography (silica, 2 mm plate), eluting with 2% methanol in dichloromethane containing a trace of ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.085 gm (25%) 1-(4-indolyloxy)-3-[4-hydroxy-4-(6-hydroxynaphth-2-yl)piperidine-1-yl]propane as a foam. The oxalate salt was prepared to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:5]=2[CH2:6][C:7]2[NH:8][CH2:9][CH2:10][N:11]=2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(#N)C.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:5]=2[CH2:6][C:7]2[NH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(C2CC2)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(C2CC2)c1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
This compound was prepared using methodology described in Synlett 2004, 2803-2805. To a solution of 400 mg (1.87 mmol)) 2-(2-cyclopropyl-6-methyl-benzyl)-4,5-dihydro-1H-imidazole in 5 ml acetonitrile at −17° C. were added sequentially 0.50 ml (3.36 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a solution of 217 mg (0.93 mmol) trichloroisocyanuric acid (TCCA) in 2 ml acetonitrile. The reaction mixture was then stirred for 2 hours at room temperature, before being diluted with ethyl acetate and washed sequentially with water and with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 62 mg (16%) of the title compound as a white crystalline solid. MS (ISP): 213.4 ([M+H]+, 100%).