Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 12608 %

Procedure:
To a solution of chinaldine (14.3 g, 0.1 mmol) and N-bromosuccinimide (17.8g, 0.1 mmol)in CCl4 (150 mL) was added benzoylperoxide (2.6 g, 0.025 mol) and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuum. The residue was treated with 5% HBr solution, the precipitate was filtered offand the filtrate was treated with celite and then basified with NaHCO3solution. The product was extracted with ether and crystallized from petrolether to yield 2-(bromomethyl)-quinoline (2.8 g, 12.6%) as light tancrystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[C:4]#[N:5].[S:18](Cl)(=[O:21])(=[O:20])[NH2:19]>>[S:18](=[O:21])(=[O:20])([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:18](=[O:21])(=[O:20])[NH2:19])[C:3]=1[C:4]#[N:5])[NH2:19]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1c(N)cccc1OCCCCCCO
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCCCOS(N)(=O)=O
Yield: 20 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(6-hydroxy-hexyloxy)benzonitrile (Example 240b) and sulfamoyl chloride in 20% yield. MS 393 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:19][C:20](=[O:22])[CH3:21].[BH4-].[K+].Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(=O)CCC1(C(C)C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CC(O)CCC1(C(C)C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of [1-oxo-2-isopropyl-2-(3-oxobutyl)-6,7-dichloro-5-indanyloxy]acetic acid (2.0 g., 0.0052 mole) in water (50 ml.) is cooled to 5° C. and treated over a 1/2 hour period with a solution of potassium borohydride (0.6 g., 0.11 mole). The reaction is stirred at 10°-15° C. for 1/2 hour then acidified with dilute aqueous hydrochloric acid affording [1-oxo-2-(3-hydroxybutyl)-2-isopropyl-6,7-dichloro-5-indanyloxy]acetic acid as a white solid which is filtered, rinsed with water and dried.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:32])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:18][C:17]=2[CH:31]=1.CI>O1CCCC1>[F:28][C:22]([F:27])([C:23]([F:24])([F:25])[F:26])[C:21]([F:30])([F:29])[C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:12]([CH3:1])[C:11]([O:10][CH3:9])=[O:32])=[CH:31][C:17]=2[N:18]=1
Reactant: COC(=O)Cc1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethyl benzene/heptane, 15.32 ml, 0.0306 mol) was added dropwise to a solution of methyl(2-heptafluoropropylbenzoxazol-5-yl)acetate (11.0 g, 0.0306 mol) in tetrahydrofuran (175 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (39.1 g, 0.275 mol) in tetrahydrofuran (25 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 3 hours. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g) as a reddish oil, which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([CH3:20])[CH:19]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[N:11]=[CH:10][C:9]([C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(I)cnc1Cl
Reactant: Cc1cc(C)cc(B(O)O)c1
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: C1COCCO1
Product: Cc1cc(C)cc(-c2cnc(Cl)c(C(=O)O)c2)c1
Temperature: 90 °C

Procedure:
To a deoxygenated solution of methyl 2-chloro-5-iodonicotinate (1-1, 2.01 g, 6.72 mmol, 1 equiv) and 3,5-dimethylphenylboronic acid (1.01 g, 6.72 mmol. 1.00 equiv) in dioxane (250 mL) was added tetrakis(triphenylphosphine)palladium(0) (155 mg, 0.134 mmol) and 2 N aqueous sodium bicarbonate solution (16.8 mL, 33.6 mmol, 5.00 equiv) and the reaction mixture was heated at 90° C. for 48 hours. The reaction mixture was allowed to cool to 23° C., then partitioned between ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL). The aqueous layer was filtered and acidified to pH 2 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration washed with water (2×100 mL) and air dried to afford 2-chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2) as an off white solid. LRMS m/z (M+H) 262.3 found, 262.1 required.
Reaction SMILES: O.N.Cl.C[N:5](C)CCCN=C=NCC.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2>CN(C)C1C=CN=CC=1.ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40]([NH2:5])=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.8 %

Procedure:
Ammonia water (28%, 0.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(0.36 g, 1.9 mmol) and 4-dimethylaminopyridine (DMAP) (0.05 g, 0.4 mmol) were added to a dichloromethane solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-cyclohexanecarboxylic acid (0.5 g, 1.2 mmol) and the mixture was stirred at room temperature for 19 hours. To the reaction solution, dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-cyclohexanecarboxylic acid amide (0.1 g, 22% yield), as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:20][CH:21]([CH3:26])[CH:22]([OH:25])[C:23]#[CH:24]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH:22]([OH:25])[CH:21]([CH3:26])[CH3:20])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#CC(O)C(C)C
Product: CC(C)C(O)C#Cc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of 39 with 4-methyl-pent-1-yn-3-ol yielded tert-butyl 3-hydroxy-3-(3-(3-hydroxy-4-methylpent-1-ynyl)phenyl)propylcarbamate as dark brown oil. Yield (1.73 g, 81%): 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.28-7.34 (m, 3H), 4.86 (bs, 1H), 4.72 (bs, 1H), 4.39 (t, J=6.0 Hz, 1H), 3.46-3.51 (m, 2H), 3.11-3.19 (m, 1H), 1.78-2.04 (m, 4H), 1.45 (s, 9H), 1.02 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(Cl)cc(Cl)c1
Reaction time: 12 h
Yield: 81 %

Procedure:
1.03 ml (0.02 mol) of bromine are added, at room temperature, to 3.77 g (0.019 mol) of (3,5-dichlorophenyl)ethanone in solution in 50 ml of acetic acid. After stirring for 12 hours, evaporation of the acetic acid leads to the production of a yellow precipitate: 2-bromo-1-(3,5-dichlorophenyl)-1-ethanone (yield 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([N+:26]([O-])=O)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:41])[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c([N+](=O)[O-])cccc32)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To 3 mL of a methanol solution containing 150 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 15 mg of 10% palladium on carbon was added under nitrogen atmosphere, then stirred under hydrogen atmosphere at room temperature for 2 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 140 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][O:7][CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=COC[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H]1CCOC[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (3R,4S)-3,4-dihydro-2H-pyran-3,4-diyl diacetate (8 g, 40 mmol) and Pd/C (10%, 5.0 g) in MeOH was stirred at RT for 12 h under H2 atmosphere (50 psi). After filtration, the residue was concentrated to give the title compound, which was used without further purification (7.5 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.06 (s, 6H), 3.95-4.03 (m, 2H), 4.84 (t, J=4.0 Hz, 1H), 5.15-5.20 (m, 1H), 5.43 (t, J=4.0 Hz, 1H), 6.49 (d, J=4.0 Hz, 1H).
Reaction SMILES: C[O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH3:17])[C:10]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:9]=3[C:8]=2[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.C(=O)=O>[CH3:28][N:26]1[CH2:25][CH2:24][C:10]2[N:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH3:17])[C:12]3[CH:13]=[CH:14][C:6]([NH:5][CH2:4][CH2:3][OH:2])=[CH:7][C:8]=3[C:9]=2[CH2:27]1
Reactant: COCCNc1ccc2c(c1)c1c(n2C=C(C)c2ccncc2)CCN(C)C1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Product: CC(=Cn1c2c(c3cc(NCCO)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
(2-Methoxy-ethyl)-[2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]-amine (350 mg, 0.9 mmol) was dissolved in DCM and the reaction mixture was cooled in dry ice (−78° C.). Boron tribromide (699 mg, 2.7 mmol), diluted with DCM (3 mL) was added to the solution dropwise at −78° C. After completion of this addition, the reaction mixture was allowed to come to RT gradually, and was stirred at RT for 1 h. After completion of reaction (reaction monitored by TLC & LCMS), the reaction mixture was concentrated under vacuum and the crude compound was basified with 1N NaOH solution. The compound was extracted with EtOAc (3×60 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum under vacuum to obtain the crude compound which was recrystallized in diethyl ether (20 mL) to yield 170 mg of 2-[2-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-ylamino]-ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.90 (d, 2H), 8.40 (d, 2H), 7.84 (s, 1H), 7.78 (s, 1H), 7.52 (d, 1H), 7.42 (d, 1H), 4.84 (m, 1H), 4.50 (m, 1H), 3.90 (m, 1H), 3.80 (t, 2H), 3.68 (m, 1H), 3.58 (t, 2H), 3.40-3.30 (m, 2H), 3.18 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:10]N)[CH:5]=[C:6]([I:9])[C:7]=1[I:8].[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15]>C(O)(=O)C>[I:1][C:2]1[C:7]([I:8])=[C:6]([I:9])[CH:5]=[C:4]2[C:3]=1[C:13]([CH3:17])([CH3:12])[C:14]([CH3:15])=[N:10]2
Reactant: NNc1cc(I)c(I)c(I)c1
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Product: CC1=Nc2cc(I)c(I)c(I)c2C1(C)C
Yield: 27.1 %

Procedure:
2 g of 3,4,5-triiodophenylhydrazine, and 0.86 g (10 mmol) of 3-methyl-2-butanone were refluxed in 15 mL of acetic acid for 16 hours. The acetic acid was evaporated, the residue was dissolved in chloroform, washed with aqueous solutions of NaHCO3, followed by Na2S2O3 and water. The organic layer was dried and chloroform was removed under reduced pressure by a rotary evaporator. The residue was column purified (Silica gel 60, 0-2% methanol-chloroform) to give 0.6 g of 4,5,6-triiodo-2,3,3-trimethyl-3H-indole. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 8.04 (1H, s, arom.), 2.19 (3H, s, 2-CH3), 1.30 (6H, s, C(CH3)2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([OH:43])([CH3:42])[CH3:44])[N:25]=2)[CH2:21][CH2:22]1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Reactant: N#Cc1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 4-aminobenzonitrile (16.34 mg, 0.138 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 hour. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (16 mg, 28%).
Reaction SMILES: [CH:1]1([CH:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][CH2:21]3)=[C:16]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:15]=2)=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[O:7][N:6]=2)[CH2:3][CH2:2]1.[CH3:31]I.[H-].[Na+]>>[CH:1]1([CH:4]([N:11]([CH3:31])[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][CH2:21]3)=[C:16]([O:23][CH2:24][CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:15]=2)=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[O:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1nc(C(NC(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)C2CC2)no1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(C(C2CC2)N(C)C(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)no1

Procedure:
In analogy to the procure described in Example 16 b), 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide was reacted with methyl iodide (CAN 74-88-4) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=427.2 [MH]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH2:31][O:32][CH3:33])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and 2-bromoethylmethyl ether (44 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 43 as a colorless oil (19 mg).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)/[CH:43]=[CH:44]/C(O)=O>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6](=[O:7])/[CH:44]=[CH:43]/[C:42]2[CH:48]=[CH:49][CH:50]=[C:40]([O:39][CH3:38])[CH:41]=2)[CH2:9]1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)c1
Yield: 73.7 %

Procedure:
Deprotection of 13 (250 mg, 0.69 mmol) as in Example C above, and reaction of the product with EDCI.HCl (331 mg, 1.73 mmol), (E)-3-methoxycinnamic acid (129 mg, 0.72 mmol) and DMA (3 mL) at 20° C. for 3 h, followed by addition of dilute KHCO3, gave a solid. This was recrystallised from CH2Cl2 /i-Pr2O followed by EtOAc to give 14l (215 mg, 74%), mp 200° C. 1H NMR [(CD3)2SO] δ 9.22 (s, 1 H, H-4), 8.33 (dd, J=7.9, 1.8 Hz, 1 H, H-6), 8.19 (dd, J=7.5, 1.7 Hz, 1 H, H-9), 7.78-7.68 (m, 2 H, H-7,8), 7.72 (d, J=15.4 Hz, 1 H, PhCH=CH), 7.45-7.34 (m, 2 H, H-5',6'), 7.39 (s, 1 H, H-2'), 7.26 (d, J=15.4 Hz, 1 H, PhCH=CH), 7.02 (dt, J=7.2, 2.2 Hz), 1 H, H-4'), 4.71-4.56 (m, 3 H, H-1,2), 4.11-4.05 (m, 2 H, CH2Cl), 3.84 (s, 3 H, CH3). Anal. Calculated for C23H19ClN2O4 : C, 65.3; H, 4.5; N, 6.6; Cl, 8.4. Found: C, 65.0; H, 4.6; N, 6.6; Cl, 8.5%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.442 g, 1.2 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example H.4) (0.381 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 22%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:5][N:4]=[C:3]1[CH3:15].Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][OH:18])=[CH:5][N:4]=[C:3]1[CH3:15]
Reactant: Cc1ncc(C(=O)c2ccccc2)n1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncc(C(=NO)c2ccccc2)n1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A solution of (1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methanone (8.41 g, 42 mmol) and hydroxylamine hydrochloride (7.30 g, 105 mmol) in pyridine (60 mL) was stirred for 5 h at room temperature, and for 3 h at 50° C. Hydroxylamine hydrochloride (3.00 g, 43 mmol) was added again and the reaction mixture was stirred for 9.5 h at 50° C. After removal of the solvent in vacuo and addition of water (600 mL), the pH of the aqueous solution was adjusted to pH>7 by addition of aq. NaOH (1 M). After extraction with ethyl acetate (4×150 mL), the combined organic layers were washed with water (150 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 1-(1,2-dimethyl-1H-imidazol-5-yl)-N-hydroxy-1-phenylmethanimine [2.31 g, yield 24%; HPLC/MS: m/z=216 (M+H); log P(HCOOH)=0.43].