Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:17])=[CH:10][C:11]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1Cl
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CN(C(=O)OC(C)(C)C)c1ccc(CBr)c(Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
N-(tert-Butoxycarbonyl)-3-chloro-N,4-dimethylaniline (62.6 g) was dissolved in carbon tetrachloride (310 ml), and N-bromosuccinimide (52.3 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (3.77 g) were added. The mixture was stirred at 55° C. for 2 hr and 75° C. for 1 hr, and hexane (500 ml) was added. The mixture was stirred under ice-cooling for 1 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (310 ml) and washed successively with saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated brine (500 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromomethyl-N-(tert-butoxycarbonyl)-N-methyl-3-chloroaniline as a brown oil (75.6 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)c1ccccc1
Yield: 84 %

Procedure:
18 g of cyclohexylamine was dissolved in 150 ml of benzene. To the resulting solution was very slowly added 20 g of benzoyl chloride with stirring at temperatures below 40° C. White crystals separated from the mixture, generating white smoke. The mixture was stirred for one hour and was then made alkaline by addition of pyridine thereto. The product was filtered with suction. Crude crystals melting at 142° C. to 144° C. were recrystallized from a mixture of methanol and ethanol (1:1 in volume), from which white needles melting at 144° C. to 145° C. separated. The yield was 84%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][N:3]=1.[NH2:16][NH2:17]>>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][N:3]=1)[NH2:17]
Reactant: COc1cccc(-c2ccc(Cl)nc2)c1
Reactant: NN
Product: COc1cccc(-c2ccc(NN)nc2)c1

Procedure:
In the manner described in Example 31, a mixture of 2-chloro-5-(3-methoxyphenyl)pyridine and hydrazine yields the product of the Example.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30]([CH:27]5[CH2:29][CH2:28]5)=[O:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CC1

Procedure:
The title compound, off-white solid (72 mg, 73%), MS (ISP) m/z=397.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and cyclopropanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
To a solution of [9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (82 mg, 0.21 mmol) and tributyl phosphine (0.10 mL, 0.41 mmol) in tetrahydrofuran (0.84 mL) was added 1,1′-(azodicarbonyl) dipiperidine (104 mg, 0.41 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2,2,2-trifluoroethanol (0.15 mL, 2.06 mmol), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled at room temperature and concentrated in vacuo. The residue was diluted with diethyl ether. The residual solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40% ethyl acetate/n-hexane mixture. The desired fractions were concentrated in vacuo. The residual oil was crystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (35.8 mg, 0.075 mmol, 36%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][O:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)(=O)C.O>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][OH:35])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCC#CCCOC(c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCC#CCCO)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A suspension of 6-(5-cholesten-3β-yloxy)-1-(triphenylmethyloxy)hex-3-yne (21 g) in p-dioxan (40 ml) is heated on a steam cone until dissolution. This is followed by the addition of 90% acetic acid (30 ml) until turbidity, and the reaction mixture is heated overnight at 100°. Water (15 ml) is added and the mixture is concentrated to a small volume. Ether and petroleum ether are added and crystals (triphenylmethanol) are filtered and discarded. The filtrate is concentrated to dryness and put on a silica gel column and eluted with 20% ether in petroleum ether. The desired compound, 6-(5-cholesten-3β-yloxy)hex-3-yne-1-ol, is isolated as an oil (7.0 g).
Reaction SMILES: C(OC([C:6]1[C:7](=[O:23])[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:11]=1[OH:12])=O)C.Cl>O1CCOCC1.ClCCl>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][N:8]1[C:7](=[O:23])[CH2:6][C:11](=[O:12])[C:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:9]1
Reactant: CCOC(=O)c1c(O)c(-c2cccs2)nn(CCC(C)C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCN1N=C(c2cccs2)C(=O)CC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
5-Hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester (0.3 g, 0.892 mmol, prepared as described in WO06066079A2) was dissolved in 1,4-dioxane (10 mL) and a 1.0 M aqueous hydrochloric acid solution (10 mL) was added. The mixture stirred in a sealed tube at 100° C. for 4 h. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. The oil was dissolved in dichloromethane (15 mL) and passed through a plug of silica gel (Merck silica gel 60, 40-63 μm), eluting with ethyl acetate. Upon concentrating, the desired product, 2-(3-methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.215 g, 0.814 mmol) was obtained as a thick oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.91 (6H, d, J=6.2 Hz), 1.49-1.61 (3H, m), 4.03 (2H, t, J=7.1 Hz), 6.09 (1H, s), 7.10 (1H, dd, J1=8.6 Hz, J2=0.0 Hz), 7.58 (1H, d, J=5.4 Hz), 7.77 (1H, dd, J1=4.0 Hz, J2=1.6 Hz), 12.02 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=C(O)C1CC1
Reactant: CC(=O)c1ccc(F)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol), cyclopropyl carboxylic acid (0.62 ml, 7.84 mmol), HATu (2.5 g (6.57 mmol), and DIEA (2.3 ml, 13.08 mmol) in DMF (15 ml). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained was then purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 5-15% EtOAc in DCM to give 458 mg of the title compound (32% isolated yield). 1H NMR: 10.16 (s, 1H) 8.53 (dd, J=7.91, 2.26 Hz, 1H) 7.67-7.82 (m, 1H) 7.40 (dd, J=10.55, 8.67 Hz, 1H) 2.54 (s, 3H) 1.95-2.09 (m, 1H) 0.78-0.88 (m, 4H).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:13]=[CH:12][O:11][CH:10]=1.[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].CN(C=O)C>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.O>[O:11]1[CH:12]=[CH:13][C:9]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[O:15])=[CH:10]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(-c2ccoc2)c1
Yield: 9.7 %

Procedure:
To a toluene (10 mL) solution of 3-bromofuran (0.54 mL, 6.0 mmol) was added 3-formylphenylboronic acid (1.00 g, 6.7 mmol) and DMF (4 mL). To the resulting solution was added K2C03 (1.85 g, 13.4 mmol) and Pd(PPh3)4 (0.40 g, 0.35 mmol). The slurry was heated to reflux under argon for 2 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.10 g (10%) of the desired 3-(3-furanyl)benzaldehyde product as a yellow oil. MS: m/z=173.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: COc1cccc(CN2C(=O)CC[C@@H]2C(=O)O)c1
Agent: [N-]=O
Agent: [NH-]O
Product: COc1cccc(CN2C(=O)CC[C@@H]2C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)c1

Procedure:
Coupling of (R)-1-(3-methoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:12](O)(=[O:15])[CH2:13][CH3:14].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: NC1CCc2c(Br)cncc21
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCc2c(Br)cncc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a stirred black solution of (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-4 [C]) (213 mg, 1 mmol) and propionic acid (82.1 μL, 1.1 mmol) in CH2Cl2 (5.0 mL) at 0° C. was added EDCI (230 mg, 1.2 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to RT. The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered, evaporated and purified by flash chromatography (75 g SiO2, Telos-cartridge, CH2Cl2/MeOH (2%)) to afford the title compound (105 mg, 39%) as a dark grey solid. MS: 269.0 (M+H+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH:35](NC(C)C)([CH3:37])[CH3:36].C(OCC)(=[O:44])C>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:36]#[C:35][CH2:37][OH:44])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Reactant: CCOC(C)=O
Reactant: CC(C)NC(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3c(Cl)cc(C#CCO)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.35 g, 0.59 mmol) propargyl alcohol (0.075 ml, 1.3 mmol) and diisopropylamine (0.18 ml, 1.3 mmol) in ethyl acetate (10 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.034 g, 0.12 mmol) and bis(triphenylphospine)palladium (II) chloride (0.082 g, 0.17 mmol). The reaction was allowed to warm to ambient temperature and then stirred overnight. The reaction was filtered through Celite and the filtrate was then evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-10% methanol in dichloromethane to give the product as a solid (0.16 g, 51%). NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.5 (s(broad), 4H), 2.61 (t, 2H), 3.61 (t, 4H), 3.92 (s, 3H), 4.21 (t, 2H), 4.37 (s, 2H), 5.02 (s(broad), 1H), 6.06 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.83 (s, 1H), 8.25 (s(broad), 1H), 9.18 (s(broad), 1H). Mass Spectrum: M+H+ 527 and M+H− 525.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)[CH3:12])=[CH:7][C:6]=1[O:29][CH3:30])(=[O:3])C.Cl>[OH-].[Na+].C(O)C.C(OCC)(=O)C>[OH2:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)[CH3:12])=[CH:7][C:6]=1[O:29][CH3:30].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)[CH3:12])=[CH:7][C:6]=1[O:29][CH3:30]
Reactant: COc1cc(C(C)N2CCN(c3ccc4ccccc4n3)CC2)ccc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(C)N2CCN(c3ccc4ccccc4n3)CC2)ccc1O
Product: O
Yield: 41.7 %

Procedure:
A solution of 1-[1-(4-acetoxy-3-methoxyphenyl)ethyl]-4-(2-quinolinyl)piperazine(4.7 g) in 50% sodium hydroxide solution (8 ml) and 50% aqueous ethanol (50 ml) was heated at 50° C. for 24 hrs, under nitrogen. The reaction mixture was diluted with ethyl acetate (150 ml), neutralized with 10% hydrochloric acid and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 1% acetone/1% methanol/dichloromethane. The appropriate fractions were collected and concentrated to afford 1.8 g (43%) of product, mp 53-54° C.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(NC(C)C)(C)C.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30]>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.[Cu]I.O>[CH:31]1([C:29]#[C:30][C:2]2[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=2)[O:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:33][CH2:32]1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#CC1CC1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (873 g, 2 mmol), bis(triphenylphosphine)palladium dichloride (140 mg, 0.2 mmol), and CuI (19 mg, 0.1 mmol) were added to 15 mL of degassed diisopropylamine under nitrogen in a screw cap flask. Ethynylcyclopropane (0.25 mL, 3 mmol) was added, and the flask was sealed and heated to 70° C. for 18 hours. The reaction mixture was cooled, poured into water, and extracted into dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 100 g of flash silica (2%-3% MeOH/CH2Cl2) to give 605 mg of 5-(5-cyclopropylethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. MP 225.5-226.8° C.; MS (M+H)=339.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2].[CH:18]1([CH:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:40])O)CCCC1.[CH2:41](P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:23]([CH3:18])([C:25]2[S:29][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)=[N:27][C:26]=2[CH3:40])[CH3:41])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(CC)Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-(4-hydroxy-2-methyl-benzyl)-butyric acid ethyl ester (example 125 c]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-2-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-2-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzyl)-butyric acid ethyl ester as colorless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=1>C(#N)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][C:38]([NH:39][C:40]3[N:41]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=3)=[O:37])=[CH:12][C:13]=2[CH3:33])[CH2:22][CH2:21]1)=[O:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1
Temperature: 80 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Add DIEA (2 equiv.) to a solution of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (400 mg, 1.205 mmol) and [5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (1 equiv) in acetonitrile (12 mL). Stir the mixture at 80° C. in a sealed tube. After 4 days, remove solvent. Dilute crude with DCM, extract with water, and dry over Na2SO4. Filter and remove solvent under reduced pressure. Subject solid to silica gel chromatography, eluting with hexane/acetone 3:1 to obtain 352 mg of 1-{6-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-5-methyl-pyridin-3-yl}-3-[5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid (48% yield). ES+(m/z): 606 [M+1]
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.Cl[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[C:12]([C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Cl
Reactant: c1csc(-c2cccs2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,2′-bithiophene (10 g, 60.1 mmol) was dissolved in DCM (300 mL) and 2-chloro-2-methylpropane (7.95 g, 72.2 mmol) was added. Aluminum chloride (8.82 g, 66.2 mmol) was added in one portion, and the colourless solution turned a green/brown colour immediately. The reaction mixture was stirred at room temperature for 30 minutes, then was poured into water (500 mL), mixed well and separated. The aqueous portion was extracted with DCM (200 mL) and the combined organics were washed with brine (2×400 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation to afford a clear, green oil (13.3 g, 99%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=5.1, 1.1 Hz, 1H), 7.10 (dd, J=3.6, 1.1 Hz, 1H), (dd, J=5.1, 3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.73 (d, J=3.7 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:15]([F:34])=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([CH:20]=[C:21]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]#[N:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[NH4+].[Cl-].CO>[Zn].C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][C:15]=2[F:34])[N:31]=[C:22]([NH2:23])[C:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:20]3)[CH:10]=[CH:11][CH:12]=1
Reactant: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-])CC1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2cc(F)c(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1

Procedure:
In three μwave tubes 3-[5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-4-fluoro-2-nitro-phenyl]-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (0.25 g, 0.52 mmol, each tube), Zn (3 g, 0.046 mol, each tube), NH4Cl (0.98 g, 0.018 mol, each tube), CH3OH (3 mL, in each tube), and THF (1 mL, in each tube) were reacted via μwave @ 300W, 130° C. for 12 min. The resulting mixtures were combined, filtered through Celite®, and the solvent removed to yield a residue, which was purified by silica column chromatography (50% EtOAc/heptanes) to yield a solid.