Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[C:14](=[O:20])[NH:13][C:12](=[O:21])[N:11]([CH3:22])[C:10]1=2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][I:34])(=[O:27])[CH3:26].O>CS(C)=O>[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][I:34])(=[O:27])[CH3:26].[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][N:13]1[C:14](=[O:20])[C:15]2[N:16]([CH3:19])[C:17](=[O:18])[N:9]([CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:10]=2[N:11]([CH3:22])[C:12]1=[O:21])(=[O:27])[CH3:26]
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c2c1c(=O)[nH]c(=O)n2C
Agent: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(n(C)c1=O)n(COC(=O)C(C)(C)C)c(=O)n2C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a stirring solution of 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.14 g, 0.45 mmol) in dimethylsulfoxide (10 ml) was added sodium hydride (12 mg, 0.47 mmol) in one portion. The solution was stirred for 15 minutes. (R)-5-Acetoxy-1-iodohexane (0.13 g, 0.47 mmol) in dimethylsulfoxide (1 ml) was added. The solution of (R)-5-acetoxy-1-iodohexane was prepared according to methods described in U.S. patent application Ser. No. 09/002,345, which is incorporated herein by reference. After stirring at room temperature for 24 hours, water (25 ml) was added and the aqueous solution was extracted with ethyl acetate (3×15 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (15 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-9-pivaloyloxymethyl-3,7-dimethyluric acid (0.10 g, 50% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([OH:7])[C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:25][C:19]([O:7][C:4]1[C:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[NH:6][N:5]=1)([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1[nH]nc(O)c1-c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1n[nH]c(C)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-ol (200 mg, 0.89 mmol), ethyl bromoisobutyrate (0.14 mL, 0.89 mmol) and potassium carbonate (136 mg, 0.98 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded compound ethyl 2-methyl-2-(5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-yloxy)propanoate as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[C:5]=2[C:4](=[O:30])[CH2:3]1.[OH-:32].[Na+].OO>C(O)C.CS(C)=O.O>[CH3:1][C:2]1([CH3:31])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:32])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([C:26]([F:28])([F:29])[F:27])[C:5]=2[C:4](=[O:30])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C(N)=O)c(NC4CCOCC4)c3)c2C1
Yield: 98 %

Procedure:
To a solution/suspension of 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (772 mg, 1.79 mmol, 1.0 eq) in 10 mL of 4:1 ethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes the reaction mixture was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (788 mg, 98%) as a tan solid: LC/MS (m/z): [M+H]+ 451.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](OC)[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH2:25]([N:27](CC)CC)C.Cl[C:33]1N=C(Cl)N=C(N(C)C)N=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:10]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[CH3:33])[N:5]=[C:6]([NH:27][CH3:25])[N:7]=1
Reactant: CCN(CC)CC
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Solvent: CO
Product: CNc1nc(Cl)nc(N(C)c2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
(4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (800 mg, 3.94 mmol) was dissolved in 10 ml of methanol and cooled in an ice-bath. Triethylamine (0.6 ml, 4.33 mmol) was added, followed by (4,6-dichloro-[1,3,5]triazin-2-yl)-dimethyl-amine (760 mg, 3.94 mmol; Chem. Pharm. Bull. 45, 291 (1997)). The resulting slurry was stirred for 1 hour at 0° C. and filtered, to give the title compound as a slightly brownish solid in 57% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:19][C:20](=[O:22])[CH3:21])[CH:5]=[N:6][CH:7]=1
Reactant: Sc1cncc(Br)c1
Reactant: CC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CSc1cncc(Br)c1

Procedure:
5-Bromo-pyridine-3-thiol (0.880 g, 4.63 mmol) in THF (100 mL) was cooled to 0° C. and Hünig's base (2.4 mL, 13.89 mmol) was added. Chloroacetone (0.371 mL, 4.63 mmol) was added and the ice bath was removed. After 15 minutes the reaction mixture was concentrated, diluted with EtOAc, and washed with H2O/brine. After drying over MgSO4 the mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[OH:23][C:24]1[C:31]([O:32][CH3:33])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:34][CH3:35].[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:26]=[C:25]([O:34][CH3:35])[C:24]([OH:23])=[C:31]([O:32][CH3:33])[CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1O

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 4-hydroxy-3,5-dimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(4-hydroxy-3,5-dimethoxy-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; HPLC: TRet (Grad5-40)=17.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.Cl[CH:22]([CH3:26])[C:23](Cl)=[O:24].C(Cl)[Cl:28]>O>[Cl:28][CH2:26][CH2:22][C:23]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:24]
Reactant: ClCCl
Reactant: CC(Cl)C(=O)Cl
Reactant: N#Cc1ccc2c(c1)CCN2
Solvent: O
Solvent: CN(C)c1ccccc1
Product: N#Cc1ccc2c(c1)CCN2C(=O)CCCl
Reaction time: 3 h

Procedure:
To a solution of 2,3-dihydro-1H-indole-5-carbonitrile (8 g, 0.0556 mol; see step (iv) above) in DCM (50 mL) at 0° C. was added N,N-dimethylaniline (13.5 g, 0.1112 mol) followed by 2-chloropropionyl chloride (8.46 g, 0.0667 mol). The reaction mixture was stirred for 3 h before being diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel to yield the sub-title compound as a pale yellow solid. Yield: 10.5 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH2:18][C:19]#[N:20])#[CH:10]>C(#N)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH2:18][C:19]#[N:20])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)cc1CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CCc1cc(F)ccc1C#Cc1ccnc(Cl)n1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
2,4-Dichloropyrimidine (764 mg, 5.13 mmol) is dissolved in degassed acetonitrile (19.700 ml) and triethylamine (19.70 ml). Copper(I) iodide (75 mg, 0.395 mmol) is added, the mixture is degassed again for 10 min., and 2-(2-ethynyl-5-fluorophenyl)acetonitrile (628 mg, 3.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (138 mg, 0.197 mmol) are then added successively to the greenish solution. The reaction phase is warmed at 80° C. for 30 min. The mixture is subsequently worked up, as described above, and the crude mass obtained is purified by chromatography on silica gel (petroleum ether/ethyl acetate=80/20 to 75/25), giving 700 mg of 2-(2-((2-chloropyrimidin-4-yl)ethynyl)-5-fluorophenyl)acetonitrile (2.58 mmol, 65.3% yield) as orange solid;
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Methanesulfonyl chloride (364 mg) was added to a solution of 1-t-butoxycarbonyl-4-(2-aminophenyl)piperidine (880 mg) and pyridine (252 mg) in dichloromethane. The mixture was heated under reflux for 30 min., cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between aqueous citric acid (10%) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (1.15 g), δH (CDCl3) 1.48 (9H, s), 1.60 (2H, m), 1.73 (2H, m), 2.83 (2H, m), 3.04 (3H, s), 3.09 (1H, m), 4.26 (2H, m), 6.21 (1H, br s), 7.21-7.37 (2H, m). m/e (ES+) 355 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[C@@H](C1C=CC=CC=1)O>>[C:1]1([CH2:7][C@@H:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cc1ccccc1)NCc1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Product: C[C@@H](Cc1ccccc1)NCc1ccccc1
Yield: 43 %

Procedure:
A sample of 5.0 g (22.2 mmol) of racemic 1-phenyl-2-benzylaminopropane (38) was reacted with 3.4 g (22.2 mmol) of (R)-(−)-mandelic acid to give 2.15 g (86% based on enantiomeric abundance) of the free amine after workup. 1H NMR (CDCl3) δ 1.11 (d, 3H, J=6.0 Hz), 2.62-2.84 (m, 2H), 2.92-2.99 (m, 1H), 3.81 (dd, 2H, J=13.2, 34.5 Hz), 7.14-7.29 (m, 5H); MS (APCI+) m/z (rel): 226 (100); [α]D=+18.2° (c=0.85 MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH:16]([OH:28])[CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][N:18]1[CH2:17][CH:16]([OH:28])[CH2:15][NH:14][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: COc1ccc(OCC(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.5 %

Procedure:
A mixture of compound 2-(4-methoxyphenoxy)acetic acid (100 mg, 0.55 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113.7 mg, 0.55 mmol), BOP-Cl (177.2 mg, 0.696 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at room temperature for 4 h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the title compound (13.3 mg, yield 6.5%). 1H NMR (500 MHz, MeOD): δ 7.11-7.06 (m, 3H), 7.02-7.00 (m, 1H), 6.90-6.60 (m, 4H), 4.45 (s, 2H), 4.01-3.98 (m, 1H), 3.73 (s, 3H), 3.66 (s, 1H), 3.41-3.39 (m, 2H), 2.90-2.87 (m, 2H), 2.81-2.76 (m, 2H), 2.55 (d, J=6.0 Hz, 2H) ppm; ESI-MS (m/z): 371.2 [M+1]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (78 mg, 69.1%), MS (ISP) m/z=416.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (100 mg, 0.272 mmol) and 1-hydroxycyclopropanecarboxylic acid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C[O:18][C:19]([C@@H:21]1[C@@H:26]2[CH2:27][C@@H:23]([CH2:24][CH2:25]2)[N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:31]([O:30][C:28]([N:22]1[C@H:21]([CH2:19][OH:18])[C@@H:26]2[CH2:27][C@H:23]1[CH2:24][CH2:25]2)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CO
Reaction time: 1.33 h

Procedure:
At −78° C. a solution of DIBAL in toluene (1.7M, 137 mmol) is added dropwise to a solution of (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (61.0 mmol) in THF (180 mL). After 80 min the solution is allowed to reach rt, stirred for additional 2 h and poured into a mixture of aq. NaOH solution (1.0M, 200 mL) and ice. EtOAc (150 mL) is added, the layers are separated and the aq. layer is extracted three times with EtOAc (150 mL each). The combined organic layers are washed with aq. NaOH solution (1.0M) and brine, dried over Na2SO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.78 min; [M+H]+=228.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]([CH3:14])[CH3:13])[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>>[CH3:13][N:12]([CH3:14])[C:4]1[N:3]=[C:2]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CN(C)c1cc(C(C)(C)O)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(N(C)C)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1

Procedure:
Using in analogous manner the procedure described in example 1e), 2-(2-chloro-6-dimethylamino-pyrimidin-4-yl)-propan-2-ol (65 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound was obtained as light yellow foam (24 mg, 21%). MS ISP (m/e): 383.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.75 (d, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 7.15 (d, 1H), 6.99 (dd, 1H), 6.87 (s, 1H), 6.01 (s, 1H), 4.38 (br s, 1H), 3.86 (s, 3H), 3.16 (s, 6H), 2.30 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[C:32]([CH3:34])[C:31](O)=[C:30]([CH3:36])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:29]=[C:30]([CH3:36])[C:31]([O:15][CH2:14][CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][C:11]=23)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:32]([CH3:34])[CH:33]=1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethanol (100 mg, 290 umol) in THF (2 ml) was added 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (57 mg, 319 umol; CAS Reg. No. 34137-14-9) and tri-phenylphosphine (91 mg, 348 umol) at ambient temperature under an argon atmosphere. The mixture was cooled to 0° C., di-tert-butyl azodicarboxylate (80 mg, 348 umol) was added and the suspension was stirred for 48 h at ambient temperature. The solvent was removed under reduced pressure to give a solid which was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to obtain the title compound (19 mg, 37 umol; 13%) as yellow solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH2:12]1[O:13][C:14]2([CH2:19][CH2:18][C:17]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)([OH:20])[CH2:16][CH2:15]2)[O:21][CH2:11]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2cc(F)cc(F)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
In an argon atmosphere, 20.3 g of magnesium was suspended in THF (40 mL), and a solution of 3,5-difluorobromobenzene (149 g) in THF (450 mL) was added dropwise to the resultant suspension at an inside temperature of 40 to 65° C. After stirring at room temperature for 1 hour, a solution of 1,4-cyclohexanedione monoethylene ketal (100 g) in THF (300 mL) was added dropwise at an inside temperature of 40 to 60° C., followed by stirring at room temperature for 1 hour. Then, water (250 mL), 10% hydrochloric acid (200 mL), and 750 mL of toluene were added in that order, and the mixture was stirred at room temperature for 30 minutes to separate an organic layer. The organic layer was washed with saturated brine two times, and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield 178 g of 4-(3,5-difluorophenyl)-4-hydroxycyclohexanone ethylene ketal as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:18]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[ClH:1].[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(Oc5ccccc5)cc4)c3c2)o1
Product: Cl

Procedure:
4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)quinazoline was treated with 4-phenoxyaniline according to Procedure A to give the title compound as a yellow solid; δH [2H6]DMSO 11.78 (1H, bs), 9.45(1H, s), 8.95 (1H, s), 8.60(1H, dd), 8.10 (1H, d), 7.75 (2H, d) 7.45(2H, d), 7.10(5H, m), 2.68(3H, s); m/z (M+1+) 396.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:43][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and cyclopentylamine (10 mmol) according to conditions described in general procedure C. Compound is produced (25 mg) as a light yellow solid; Mp: 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 1.23-1.38 (m, 4H), 1.53-1.88 (m, 4H), 3.22-3.25 (m, 4H), 3.84-3.86 (m, 4H), 4.08-4.15 (m, 1H), 5.06 (bs, 1H), 6.07 (bs, 1H), 6.76 (d, J=11.7 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.25-7.31 (m, 2H), 7.48-7.58 (m, 2H), 7.85-7.98 (m, 3H), 8.14 (s, 1H), 8.25 (s, 1H); MS: 528 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.C(O[C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([CH3:31])[C:25]=1[F:32])(=O)C.C(N(CC)CC)C.O1CCCC1.[C:45]([O:48][CH2:49]C)(=[O:47])C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:49][O:48][C:45](=[O:47])[CH2:31][C:26]1[CH:27]=[CH:28][C:29]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:24][C:25]=1[F:32]
Reactant: CCOC(C)=O
Reactant: CC(=O)Oc1ccc(I)c(C)c1F
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 44, 0.125 g, 0.5 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.14 g, 0.5 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) followed by preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.096 g, 46%).