Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:54]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:54])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1

Procedure:
2-(Ethoxymethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline (4.4 g, 11 mmol) was treated with mCPBA (5.54 g, 32.1 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.74 g, 14.4 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part D of Example 8 and then dried for two days at 60° C. to provide 1.061 g of 2-(ethoxymethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinolin-4-amine as a beige powder, mp 160-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Cl:27]N1C(=O)CCC1=O.Cl>O1CCCC1.O>[Cl:27][C:6]([CH2:5][C:4]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:3]=1[O:2][CH3:1])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cl)(Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
In 70 ml of anhydrous tetrahydrofuran is dissolved 6.5 g of diethyl 2,4,5-trimethoxybenzylmalonate and, then, 760 mg of 60% oily sodium hydride is added. The mixture is stirred at room temperature for 15 minutes, after which time 2.54 g of N-chlorosuccinimide is added. The mixture is further stirred at room temperature for 30 minutes. The reaction mixture is poured into a mixture of 300 ml water and 10 ml 6N-HCl and, then, extracted with ether. The ethereal layer is washed with water, dried (over MgSO4) and distilled to remove the ether, whereupon 6.5 g (91.5%) of diethyl α-chloro-α-(2,4,5-trimethoxybenzyl)malonate is obtained as crystals melting at 84°-85° C.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([CH3:17])([NH:15][CH3:16])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]1[O:35][C:34]2[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][C:26]=2[O:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([N:15]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:34]3[O:35][CH2:24][O:25][C:26]=3[CH:27]=2)[CH3:16])([CH3:17])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc2c(c1)OCO2)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methyl-5-methylaminohexanamide (0.5 g-see Preparation 13), 3,4-methylenedioxyphenethyl bromide (0.38 g), anhydrous potassium carbonate (0.8 g) and acetonitrile (10 ml) was heated under reflux for 5.5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give an oil which solidified on standing. The solid was recrystallised from ethanol to give the title compound as colourless needles, yield 0.09 g, m.p. 165° (softens at 45°).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:27]([CH3:26])[C:31]=2[CH3:32])=[O:34])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CC(C)(CO)Oc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC(C)(C)CO)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Yield: 76.2 %

Procedure:
To a solution of 2-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-1-ol (2.84 g, 8.3 mmol) in DCM (30 mL) was added 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.97 g, 8.4 mmol), EDCI (1.92 g, 10.0 mmol) and HOAT (0.23 g, 1.7 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated in vacuo. The residue was stirred in 95% EtOH (50 mL)/water (30 mL), and then filtered to give the title compound as a light yellow solid (3.52 g, 76.2%).
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:24]#[N:25])=[C:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:13]=3[C:12]3[CH:26]=[C:27](Br)[CH:28]=[N:29][C:11]2=3)(=O)=O)C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>[F-].[K+].C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:18]1[C:13]2[C:12]3[CH:26]=[C:27]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:28]=[N:29][C:11]=3[NH:10][C:14]=2[CH:15]=[N:16][C:17]=1[C:24]#[N:25]
Reactant: COCCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: CC#N
Product: COCCOc1c(C#N)ncc2[nH]c3ncc(-c4cnn(C)c4)cc3c12
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-(2-methoxyethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (35 mg, 0.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (20 mg, 0.096 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (7 mg) in 1N aqueous potassium fluoride solution (0.30 mL) and acetonitrile (0.30 mL) was degassed and heated under microwave irradiation at 130° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and ethyl acetate (5 mL) added. The solid was collected by filtration, washed with water (5 mL) and acetonitrile (5 mL) and left to air dry. The resultant solid was purified by flash chromatography (silica, 500 mg column, Si-SPE, 10% MeOH in DCM) and trituration with acetonitrile (2×0.25 mL) to afford the title compound as a grey solid (12 mg, 50%). 1H NMR (DMSO-D6, 400 MHz): 12.91 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 4.66-4.62 (m, 2H), 3.92 (s, 3H), 3.87-3.83 (m, 2H), 3.36 (s, 3H). LCMS (Method A): RT=7.66 min, M+H+=349.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)=[CH:2]1.[N:17]#[N:18].C([O-])(O)=O.[Na+].BrN1C(=O)CCC1=O>CC(C)=O.C1COCC1.O>[N:17]1[CH:5]=[CH:4][C:3]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)=[CH:2][N:18]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccoc2)CC1
Reactant: N#N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccnnc2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(furan-3-yl)cyclopropylcarbamate (2.15 g, 9.64 mmol, 1.0 eq), in acetone (86 ml) and water (86 ml) at r.t. was purged with N2 and cooled to −20° C. NaHCO3 (1.62 g, 19.28 mmol, 2.0 eq) and N-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to the mixture at −20° C. and the stirring was continued at the same temperature for 2 hr. To the reaction mixture at −20° C. was added THF (4.3 ml) and the temperature raised to 0° C. over 30 min. Acetone was removed from the reaction mixture with a stream of N2, and to the residue at 0° C. was added isopropanol (86 ml) followed by hydrazine hydrate (12.9 ml). The reaction mixture was stirred at r.t. overnight. Product formation was confirmed by LCMS. The solvent was evaporated under reduced pressure, and the residue diluted with water and then extracted with EtOAC. The organic was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as an eluent. Yield: 1.3 g (57.5%). 1H NMR (400 MHz, CDCl3): δ9.04 (d, J=5.6, 1H), 8.95 (d, J=2.8, 1H), 7.19 (s, 1H), 5.25 (bs, 1H), 1.42 (s, 9H), 1.25 (bs, 4H). LCMS: (ES+) m/z=236.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9]1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(NCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of aniline (1.89 g, 19.6 mmol) and 3-furaldehyde (2.50 g, 26.8 mmol) in 1,2-dichloroethane (100 mL) under argon at 5° was treated with sodium triacetoxyborohydride (5.65 g, 26.8 mmol) and acetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was diluted with ethyl acetate. The combined extracts were washed with satuirated sodium bicarbonate, dried over MgSO4 and concentrated. The product was purified by flash chromatography on silical gel (Hexane/EtOAc (20:1) to yield the title compound (3.31 g, 98%). Analysis calculated for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.58; H, 6.46; N, 8.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].I[CH2:35][CH3:36]>CN(C)C=O>[CH2:35]([N:13]([C:12]1[C:3]([O:2][CH3:1])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:36]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc2ccccc2nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
1-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(106 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and was sodium hydride(6.0 mg, 0.25 mmol) was added and the solution was stirred at room temperature for 15 min. Iodoethane(35 mg, 0.25 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4].B1([O-])O[O:22]1.O.O.O.O.[Na+]>CC(O)=O>[Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:22])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4]
Reactant: [O-]B1OO1
Reactant: CSc1ccc(C(=O)c2cc(C(=O)CCl)cn2C)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(S(C)=O)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A mixture of 2.5 g (0.008 mole) of 2-chloro-1-[1-methyl-5-(4-(methylthio)benzoyl]-1H-pyrrol-3-yl]-ethanone, 1.2 g of sodium perborate tetrahydrate and 50 mL of HOAc was stirred for 3 h. The solvent was evaporated in vacuo and the residue partitioned between CH2Cl2 and NaHCO3. The organics were separated off and washed again with NaHCO3, water, brine and dried (Na2SO4). The solvent was evaporated in vacuo. The residue was passed through a Biotage flash 40 L column (silica gel 9:1 CH2Cl2: MeOH) to give 2.2 g (85%) of 2-chloro-1-[1-methyl-5-(4-(methylsulfinyl)benzoyl]-1H-pyrrol-3-yl]-ethanone. CIMS m/z=324 (MH+). HNMR (CDCl3) δ8.0 (d, 2H); 7.75 (d, 2H); 7.6 (s, 1H); 7.15 (s, 1H); 4.4 (s, 2H); 4.1 (2, 3H); 2.8 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.ClCCl.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: OB(O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Temperature: 87.5 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (0.18 g, 0.74 mmol) in N,N-dimethylformamide (10 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 60 mg, 0.07 mmol), 1-naphthylboronic acid (0.32 g, 1.89 mmol), and triethylamine (0.15g, 1.52 mmol). The solution was degassed with nitrogen for 3-5 min. The reaction was then heated to 85-90° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (300 mL). The crude solution was passed through a pad of silica gel under vacuum. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford impure product. Column purification on silica (8:2 hexanes/ethyl acetate) afforded methyl 3-amino-6-naphthalen-1-ylpyrazine-2-carboxylate (80 mg, 39% yield) as yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.52 (br s, 1H), 8.12 (br s, 1H), 7.92 (m, 2H), 7.52 (m, 5H), 4.02 (s, 3H); MS (EI) for C16H13N3O2: 280 (MHz).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([NH2:35])=[N:32][O:33][CH:34]=2)=[CH:26][CH:25]=1.[BH4-].[Na+].[OH-].[Na+]>[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:35][C:31]2[C:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)=[CH:34][O:33][N:32]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Nc1nocc1-c1ccc(Cl)cc1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(N[C@H]1CC[C@H](CNc2nocc2-c2ccc(Cl)cc2)CC1)c1cc(C(F)(F)F)ccc1Cl
Reaction time: 3 h

Procedure:
A mixture of trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Example 1 Step 3) (100 mg, 0.30 mmol) and 4-(4-chlorophenyl)isoxazol-3-amine (this compound can be prepared according to method described in ‘Chemistry of Heterocyclic Compounds’ (New York, N.Y., United States) (2007), 43(1), 118-119) (58 mg, 0.300 mmol) is stirred in titanium(IV) isopropoxide (1 ml, 3.4 mmol) for 3 h. A thick slurry results. After 3 h, methanol (5 ml) is added followed by slow addition of sodium borohydride (18 mg, 0.5 mmol). after 5 minutes, sodium hydroxide solution 91 ml, 0.1 M) is added to the reaction followed by dilution with ethyl acetate and brine. The organic extract is washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification by chromatography on silica, eluting with chloroform-ethanol (10:1) affords a sample of product containing minor amounts of starting materials. Trituation with methanol yields a pure sample or the title compound. MS m/z 512.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.25 8H, m), 1.75 (1H, m), 1.95 (2H, m), 2.22 (2H, m), 3.20 (2H, d), 4.00 (1H, m), 5.97 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.55 (1H, d), 7.62 (1H, d), 7.90 (1H, s), 8.15 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)=[NH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: N#CNc1ccccc1-c1cccc(F)c1
Solvent: COCCOC
Product: N=C(Nc1ccccc1-c1cccc(F)c1)N1CCC(O)CC1

Procedure:
A mixture of 3'-fluoro-2-biphenylylcyanamide (4.1 g) and 4-hydroxypiperidine (1.95 g) in 1,2-dimethoxyethane (30 ml) was heated at 90°-95° C. for 4 hours to give N-(3'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine as a colourless solid (m.p. 147°-148° C.) which was recrystallised from ethylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]=[CH2:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[OH-].[K+].I[CH3:16]>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH3:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][CH3:16]
Reactant: CI
Reactant: C=CCc1cc(C)c(O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC=Cc1cc(C)c(OC)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(3,5-Dimethyl-4-hydroxyphenyl)-1-propene (5.0 g) is added to a mixture of powdered potassium hydroxide (7.98 g) in dimethylsulfoxide (50 ml) at 15°. Iodomethane (8.8 ) is then added and stirred below 20° for 0.5 hr. The reaction mixture is poured into ice/water and the product is extracted with ether (2×). The ether extracts are washed with water (3×), saline, dried over sodium sulfate and concentrated under reduced pressure to give 3-(3,5-dimethyl-4-methoxyphenyl-1-propene. The "propene" is transformed to the corresponding "propanol" with borane-dimethylsulfide by the general procedure of PREPARATION NA-19 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:11]([S:10][C:9]1[C:4]2[N:5]([CH:16]=[C:2]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:13]([NH2:15])=[O:14])[CH3:12]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCSc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (1.2 g, 4.00 mmol), (6-methoxypyridin-3-yl)boronic acid (0.881 g, 6.00 mmol), palladium (II) acetate (0.090 g, 0.400 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (XPhos) (0.381 g, 0.800 mmol) was pumped under vacuum and backfilled with nitrogen three times. Next, potassium phosphate, tribasic, 2M (7.60 mL, 15.19 mmol) and dioxane (Volume: 30 mL) were quickly added. The resulting orange suspension was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 4 h. LCMS and HPLC showed that the desired product was formed, but the reaction was incomplete. The mixture was cooled to room temperature and 4-cyanophenylboronic acid (0.366 g, 3.00 mmol), palladium (II) acetate (0.045 g, 0.200 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.191 g, 0.400 mmol) were added. The resulting mixture was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 1.5 h. The reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). The two phases were separated. The aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (100 mL), dried (MgSO4) and concentrated to give a yellow solid. The solid residue was treated with Et2O (50 mL), stirred for 30 min, filtered, and washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give a yellow solid (889 mg). 1H NMR, HPLC and LCMS showed that the main component was the desired product, but the material was impure. The filtrate was found to contain a minor amount of the desired product. The impure material was treated with Et2O (50 mL), stirred for 30 min, filtered, washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give the title compound as yellow solid (787 mg). 1H NMR showed some improvement, but the material was still impure. The mixture was taken to the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:20]>CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:16]([OH:17])[CH2:18][NH2:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
To a solution of ((S)-(S)-1-oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (25 g, 95.1 mmol, 1 equiv)) in MeOH (350 ml) was added aqueous ammonia (32% w/w, 180 ml, 3.2 mol, 3.3 equiv). The resulting mixture was stirred at room temperature for 16 h then concentrated in vacuo to give ((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid tert-butyl ester (D102) (25.2 g, 95%) as a white solid.
Reaction SMILES: [CH2:1]([CH:8]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1)[CH2:9][NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([CH:8]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1)[CH2:9][N:10]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC(CNC2Cc3ccccc3C2)C2CCCCN2)cc1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CC(CN(c2nccs2)C2Cc3ccccc3C2)C2CCCCN2)cc1

Procedure:
To a stirred solution of compound 51 (2 g, 5.98 mmol) in dry toluene (35 mL) were added 2-bromo-thiazole (0.53 mL, 5.98 mmol) and NaOtBu (0.805 g, 8.38 mmol) and the solution was degassed with argon for 30 minutes. Pd2 dba3 (0.274 g, 0.30 mmol) and Verkade's super base (0.42 mL, 1.19 mmol) were then added and the resulting mixture was refluxed for 16 hours. The reaction mixture was filtered through a Celite® pad and was washed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 20-22% ethyl acetate-hexane to provide compound 52.