Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[C:26]([CH3:33])=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[C:26]([CH3:33])=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Reactant: Cc1c(Br)cccc1C#N
Product: CC1=CC(C)(C)Nc2ccc(-c3cccc(C#N)c3C)cc21
Yield: 20.2 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (56.5 mg, 0.18 mmol) and 3-bromo-2-methylbenzonitrile (34.8 mg, 0.18 mmol). The crude material was purified by flash column chromatography (50 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 20% acetone/hexane) to afford 10.5 mg (20%) of Compound 278. Data for Compound 278: 1H NMR (400 MHz, acetone-d6) 7.59 (dd, J=7.7, 0.9, 1 H), 7.48 (dd, J=7.8, 0.8, 1 H), 7.36 (t, J=15.3, 7.7, 1 H), 6.99 (d, J=1.8, 1H), 6.91 (dd, J=8.1, 1.9, 1 H), 6.58 (d, J=8.1, 1 H), 5.37 (s, 1 H), 5.30 (s, 1 H), 2.48 (s, 3 H), 1.97 (s, 3 H), 1.30 (s, 6 H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[CH:34]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:34][C:26]2[O:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NCc2cc3ccccc3o2)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 97 mg (0.661 mmol) of benzofuran-2-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml of toluene and subsequently reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound ##STR93## is obtained (150 mg, 55%) as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.18, FD-MS: M+ =492, 494. IR: 1630 cm-1.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:27]2[O:28][C@@H:26]2[C@@:25]2([CH3:29])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1.[CH2:31]([OH:35])[CH2:32][CH2:33][OH:34].CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>O>[OH:34][CH2:33][CH2:32][CH2:31][O:35][C@H:27]1[C@H:26]([OH:28])[C@@:25]2([CH3:29])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3][C@H:2]1[OH:1]
Reactant: OCCCO
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H](OCCCO)[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 110 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A mixture of 21 mg (5.1×10-5 mol) of 3β,25-dihydroxy-1α,2α-epoxy-5,7-cholestadiene, 294 μl (4.1×10-3 mol) of 1,3-propanediol, 19 mg (1.5×10-4 mol) of potassium t-butoxide and 4.8 mg (1.3×10-5 mol) of dibenzo-18-Crown-6 was stirred in an argon atmosphere at 110° C. (bath temperature) for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted twice with ethyl acetate and washed once with a saturated aqueous sodium chloride solution. After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by fractional thin layer chromatography (silica gel:dichloromethane:ethanol=100:15) to obtain 18 mg (72% yield) of the titled compound as a white powder.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([NH2:28])[N:4]=1>[Pd].CO>[ClH:1].[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:25]=[CH:26][CH:27]=[C:10]([NH:9][C:7]3[CH:6]=[C:5]([NH2:28])[N:4]=[C:3]([NH2:2])[N:8]=3)[CH:11]=2)=[CH:17][CH:18]=1
Reactant: Nc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(NC(=O)c2cccc(Nc3cc(N)nc(N)n3)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
To a suspension of compound B5 (567 mg, 1.41 mmol) in (MeOH) (30 mL) was added 10% Pd/C (20 mg) and hydrogenated under 40 Hg mm for 6 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The residue was dissolved in a small volume of MeOH then 1 ml of 1.25M HCl in MeOH was added, stirred 10 min and evaporated to dryness. The residue was recrystallized from MeOH/EtOAc to give B6 (398 mg, 76%); mp (MeOH/EtOAc)>300° C., 1H NMR [(CD3)2SO] δ10.37 (s, 1 H, NH), 9.93 (s, 1 H, NH), 7.92-7.80 (m, 4 H, ArH & NH2), 7.68 (d, J=7.7 Hz, 1 H, ArH), 7.61 (br s, 2 H, NH2), 7.49-7.45 (m, 3 H, ArH), 7.24 (br d, J=8.7 Hz, 2 H, ArH), 5.45 (s, 1 H, ArH), mass APCI+ 336.
Reaction SMILES: [C:1]([C@@:3]1([CH2:25][CH3:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:24])#[N:2].Cl.[NH2:28][C:29]1([C:32]#[N:33])[CH2:31][CH2:30]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:32]([C:29]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][C:10]3[N:9]=[C:8]([N:5]4[CH2:6][CH2:7][C@@:3]([C:1]#[N:2])([CH2:25][CH3:26])[C:4]4=[O:24])[CH:13]=[CH:12][N:11]=3)=[CH:16][CH:17]=2)[CH2:31][CH2:30]1)#[N:33]
Reactant: N#CC1(N)CC1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)O)cc3)n2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)NC4(C#N)CC4)cc3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 4-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg) obtained in Example 231 in N,N-dimethylformamide (2.0 mL) were added 1-aminocyclopropanecarbonitrile hydrochloride (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 1-hydroxybenzotriazole (40 mg) and triethylamine (56 μL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (38 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[OH:21])[CH:16]=[O:17].O>CN(C=O)C.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[C:20]2[O:21][CH2:8][CH2:9][CH2:10][O:12][C:13]=2[CH:14]=[C:15]([CH:16]=[O:17])[CH:18]=1
Reactant: BrCCCBr
Reactant: COc1cc(C=O)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc2c1OCCCO2
Yield: 53 %

Procedure:
After adding 1.5 g of potassium carbonate and 1.2 g of 1,3-dibromopropane to a solution of 920 mg of 3,4-dihydroxy-5-methoxybenzaldehyde [CAS No. 859785-71-0] in 10 ml of DMF, the mixture was stirred at 60° C. for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (604 mg) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:13](C#N)[C:14]#[N:15].[Na].BrBr.[Br-].[Na+]>C(=O)(O)[O-].[Na+].CO>[C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: N#CSC#N
Agent: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.0 g (6.1 mmol) of 5-tert-butyl-2-methyl-phenylamine prepared in Example CCCC, sodium thiocyanide (1.62 g, 20.0 mmol) and MeOH (4.0 mL) was cooled to 0° C. and treated via addition funnel with a solution of bromine (0.35 mL, 6.7 mmol), sodium bromide (0.63 g, 6.13 mmol), and MeOH (5.0 mL). The mixture was stirred for 30 minutes and then carefully diluted with saturated sodium bicarbonate. The mixture was extracted with CH2Cl2 and the organic layers combined, dried (Na2SO4), and the solvent evaporated. The residue was then submitted to column chromatography (4:1 CH2Cl2 :hexanes to 19:1 CH2 C12 :hexanes+1% MeOH) to provide the title compound. 1H NMR (CDCl3) δ 1.42 (s, 9 H), 2.09 (s, 3 H), 3.80 (bs, 2 H), 6.69 (s, 1 H), 7.35 (s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=1.Cl>C(O)C>[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:19])([F:20])[F:21])[CH:12]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cccc(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 82.5 %

Procedure:
Add potassium carbonate (257 mg, 1.86 mmol) to a solution of trimethyl-(3-trifluoromethoxyphenylethynyl)-silane (960 mg, 3.72 mmol) in ethanol (15 mL) and stir for 16 h. Add a 10% aqueous solution of hydrochloric acid to neutralize the reaction mixture and then partition between water and hexanes. Separate the organic layer and concentrate with cooling to give the title compound (571.4 mg, 83%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-n3ccnc3)c(F)c21
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 48.1 %

Procedure:
To 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (13.6 g) and imidazole (10.2 g) is added dimethylformamide (80 ml), and the mixture is stirred at 100° C. for 1.25 hour. The reaction mixture is cooled to room temperature, and the precipitated crystals are separated by filtration and washed with ethanol. The crude crystals thus obtained are recrystallized from dimethylformaide to give the title compound (7.7 g) as colorless needles. Melting point: 283°-288° C. (decomp. with foam), being gradually colored from about 245° C. IR (KBr, νC=O): near 1720 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24].[NH2-].[Na+]>C1C=CC=CC=1>[OH:9][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][C:23]#[N:25]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC#N
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(O)(c1ccc(Cl)cc1)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
4'-Chloro-4-biphenylyl 4-chlorophenyl ketone (16.4 g.) and acetonitrile (2.25 g.) were reacted in benzene in the presence of sodamide (2.5 g.) by the method of Lettre and Wick (Annalen, 1957, 603, 194) to give 3-hydroxy-3-(4'-chloro-4-biphenylyl)-3-p-chlorophenylpropionitrile, m.p. 123°C after recrystallisation from benzene; λ max (ethanol) = 260 nm.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[CH3:32][C:31]1[N:33]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 44A and 74 mg (0.75 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 119 mg (52% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:15][N:16]([CH2:31][CH3:32])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To 4-[1-(2-Fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (408) (1.43 g, 3.56 mmol) in THF (30 mL) was added NaH (60% in oil) (0.16 g, 3.92 mmol) and the solution was allowed to stir for 1 h at room temperature. Iodoethane (0.31 mL, 3.92 mmol) was then added and the reaction was allowed to stir for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (100 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 10% MeOH in CHCl3) yielding 0.54 g (36%) pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:38]2[CH:46]=[C:45]3[C:41]([C:42]([CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:43][CH2:44]3)=[CH:40][CH:39]=2)O1>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([C:38]2[CH:46]=[C:45]3[C:41]([C:42]([CH2:47][NH:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:43][CH2:44]3)=[CH:40][CH:39]=2)[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:16][C:17]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[N:18][CH:19]=2)[CH:5]=1)([CH3:12])([CH3:11])[CH3:13]
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Reactant: CC1(C)OB(c2ccc3c(c2)CC=C3CNS(C)(=O)=O)OC1(C)C
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
The product from Example 2 Part A (55.9 mg, 0.12 mmol) and N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide (41.9 mg, 0.120 mmol) were reacted in the same manner as Example 2 Part B. The crude product was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (5% to 25%) to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:27][CH3:28])[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[CH:17]=3)=[CH:10][CH:9]=1)=[O:6].[OH-].[K+]>CO>[CH2:27]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[CH:17]=2)[C:22]([C:23]#[N:24])=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1)[CH3:28]
Reactant: CCn1c(-c2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(-c2ccc(N3CCNC3=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 49 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) is added aqueous 1M KOH (504 uL) and then stirred at 49° C. for 24 h. The solvents are removed under reduced pressure. The residue is diluted with ethyl acetate and then washed with water. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 62%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1OC)C1C=CC=CC=1.[C:31](O)(C(F)(F)F)=[O:32]>>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[C:16]([O:32][CH3:31])[N:15]=1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: COc1nc(Nc2ccc(C)cc2F)c2ccc(O)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline hydrochloride (2 g, 4.7 mmol) in TFA (20 ml) was heated at 80° C. for 5 hours and stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was suspended in water (50 ml). Solid sodium hydrogen carbonate was added until the pH was approximately 7. The precipitate was then collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methanol/methylene chloride (5/95). After removal of the solvent by evaporation, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-4-methylanilino)-7-hydroxy-methoxyquinazoline (1.04 g, 74%).
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH2:12][CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:25]C([N-]C(C)C)C.CI.O>C1COCC1>[C:1]([N:5]1[C:13]2[CH2:12][CH2:11][C:10]([CH3:25])([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:8]=2[C:7]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Temperature: -25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To methyl 1-tert-butyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (1.6 g, 5 mmol) in dry THF (20 mL) at −78° C. was added LDA (2 M, 5.5 mmol). The reaction temperature was increase to −25° C. for 1 h and was then cooled down to −78° C., MeI (16 mmol) was added and stood at r.t. for overnight, 20 ml water was added, most of the solvent was removed by distillation and the product was extracted with ethyl acetate, purified using silica chromatography (ethyl acetate/hexane) to give the desired product as yellow solid (1.1 g). LC-MS found 328.2 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[CH:28]=[C:29]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)[CH:30]=[CH:31][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:31]4[CH:32]=[CH:27][CH:28]=[C:29]([C:33]5[N:37]=[C:36]([CH3:38])[O:35][N:34]=5)[CH:30]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Reactant: Cc1nc(-c2cccc(Br)c2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccn2c(-c3cccc(-c4cccc(-c5noc(C)n5)c4)c3)cnc2n1
Temperature: 90 °C

Procedure:
To a degassed solution of 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) in 1,4-dioxane (3 ml) was added 3-(3-bromophenyl)-5-methyl-[1,2,4]oxadiazole (0.142 g, 0.59 mmol) (prepared as described in WO 95/27692), potassium phosphate (189 mg, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 μmol) and the mixture heated at 90° C. for 18 h. After cooling to ambient temperature the solvent was evaporated in vacuo and the residue stirred with 10% methanol in dichloromethane. The solid material was removed by filtration and the filtrate applied to two preparative TLC plates (silica gel) and eluted with 5% methanol in dichloromethane. The appropriate band was collected and processed, affording a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 7-methyl-3-[3′-(5-methyl-[1,2,4]oxadiazol-3-yl)biphenyl-3-yl]imidazo[1,2-a]pyrimidine as a cream coloured solid (32 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 2.68 (3H, s), 6.79 (1H, d, J 7), 7.60-7.80 (5H, m), 7.87 (1H, s), 7.92 (1H, m), 8.10 (1H, dd, J 7 and 1), 8.32 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 368 (M++H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH:22][C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:29]1[CH:30]=[C:25]([CH2:24][C:23]([NH:22][CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)Cc2cc(F)cc(F)c2)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCNCC1
Yield: 50 %

Procedure:
To a stirred solution of 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.09 g, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL, to give a 25% v/v solution). The mixture was stirred at room temperature for 3 h at which time TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL) then diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum for 1 h to yield 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine as a reddish solid (0.038 g, ˜0.08 mmol). MS (ESI): 471.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=O)C.[CH:16]([NH2:18])=O>>[N:11]1[C:10]2[S:9][C:8]3[CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[C:6]=2[C:4]([OH:3])=[N:18][CH:16]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: NC=O
Product: Oc1ncnc2sc3c(c12)CCCC3
Temperature: 25 °C

Procedure:
A solution of 10 millimol IV in 15 milliliter formamide was stirred at 100° C. for 3 hours then cooled down to room temperature. The reaction mixture was poured onto crushed ice with continuous stirring then collected by filtration. The product was washed with water and n-hexane, then dried.