Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38](=[O:43])[C:37]=2[CH:36]=[CH:35][C:34]=1[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[Br:32][C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]([OH:43])([C:11]3[S:12][C:8]([C:6]4[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]5[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=5)[N:5]=4)=[CH:9][N:10]=3)[C:37]=2[CH:36]=[CH:35][C:34]=1[C:44]([O:46][CH3:47])=[O:45]
Reactant: COC(=O)c1ccc2c(c1Br)CCCC2=O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1Br)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To an oven-dried flask was added 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (300 mg, 0.892 mmol) and THF (7.1 mL) and the solution was cooled to −78° C. LDA (1.34 mL, 2.68 mmol) was slowly added, and the resulting mixture was stirred for 30 minutes at −78° C. In a separate oven-dried flask, methyl 1-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (316 mg, 1.12 mmol) was then dissolved in THF (5 mL), and this solution was added to the reaction mixture, which was then allowed to warm to rt. over a period of 3 hours. The reaction was then quenched with MeOH (5 mL) and concentrated. Purification by chromatography on silica gel furnished methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate 17A (210 mg, 38%) as a light yellow solid. MS ESI calcd for C27H22BrF3N4O3S [M+H]+ 619, found 619.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O.O1CCCC1>O>[C:21]1(=[O:30])[N:2]([CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1CCC(O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:8]([NH:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-])=O.O>[Fe].C(O)C>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[CH2:9][CH:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH3:2])[NH:23][CH3:24]
Reactant: CNC(Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1sccc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(Cc1ccc(C(F)(F)F)cc1N)c1sccc1C
Yield: 77.1 %

Procedure:
A mixture of 3.3 g of α-(3-methyl-2-thienyl)-N-methyl-2-nitro-4-trifluoromethylbenzeneethanamine hydrochloride, 4.8 g of iron powder, 13 ml of water, 50 ml of 95% ethanol, and concentrated 350 μl hydrochloric acid was refluxed for 1.5 hrs. The mixture was filtered through Celite, the filter cake washed with water, and the organic phase of the filtrate was concentrated in vacuo. The residue was diluted with 50 ml of water and basified with 10% (aq) sodium hydroxide solution. The aqueous phase was extracted with dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was triturated with hexane to afford 2.1 g of product, mp 52°-54° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Solvent: CCO
Product: CN1CCN(c2cc(C3CCCC3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (92 mg, 0.47 mmol), and N-methyl piperazine (0.15 mL, 1.4 mmol) in EtOH (2 mL) was heated at 70° C. for 2 h. The reaction was cooled to rt and concentrated and the crude residue chromatographed (2 M NH3 in MeOH/CH2Cl2) to yield an oil (81 mg, 66%). MS (ESI): mass calcd. for C14H23N5, 261.2; m/z found, 262.3 [M+H]+. 1H NMR (CDCl3): 5.85 (s, 1H), 4.78 (s, 2H), 3.59 (t, J=5.0, 4H), 2.81 (q, J=8.7, 1H), 2.44 (t, J=5.0, 4H), 2.32 (s, 3H), 2.04-1.89 (m, 2H), 1.82-1.59 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([CH2:39][CH:40]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)[OH:41])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:45]3[CH:46]=[CH:47][C:42]([CH:40]([OH:41])[CH2:39][CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:43][CH:44]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC1(C)OB(c2ccc(C(O)CC3CCCC3)cc2)OC1(C)C
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(O)CC4CCCC4)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (433 mg, 0.79 mmol) was coupled with 2-cyclopentyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ethanol according to general procedure G to give {-4-[2-[4′-(2-cyclopentyl-1-hydroxy-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester. The product benzyl alcohol was reduced according to general procedure AA and the reduced product was treated following general procedure F to give 5-{-4-[2-[4′-(2-cyclopentyl-ethyl)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidin-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([O:8][CH3:13])=[O:7])#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
To a solution of 3-cyano-5-fluorobenzoic acid (1.0 g, 6.1 mmol) in dichloromethane (5 ml) and methanol (0.5 ml), at 0° C., was added dropwise (trimethylsilyl)diazomethane (2M in hexanes, 3.6 ml, 7.3 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 18 h and then concentrated in vacuo to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17]>>[C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COC(=O)/C(C#N)=C/C=C/c1cc(OC)c(O)c(OC)c1

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to methyl cyanoacetate (0.064 ml, 0.72 mmol). After refluxing for 1 h and recrystallization from ethanol an orange solid was obtained (0.2 g, 90%). The product gave the following analytical data:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]([CH3:4])[CH3:3].CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][NH:35][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Yield: 38.9 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (40.0 mg) was prepared by following General Procedure F starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.72 (1H, m), 7.54 (1H, m), 7.35 (1H, m), 4.00-3.99 (2H, m), 2.81-2.80 (3H, d), 1.23 (1H, m), 0.95-0.92 (6H, m), 2 —NH proton signals were not observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:25](Cl)[CH:26]=[CH2:27]>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][CH:26]=[CH2:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: C=CCCl
Reactant: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: C=CCOc1nc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)cc1C#N

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 5) (100 mg, 0.297 mMol), silver carbonate (82 mg, 0.297 mMol) and allyl chloride were stirred in a brown vessel in acetone (25 ml) for 48 hours. The reaction mixture was filtered. The filtrate was condensed to give the crude compound as a solid. 6-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-2-[(2-propenyl)oxy]-pyridine-3-carbonitrile was purified by silica gel chromatography and recrystallized from hexane. Anal. Calc'd. for C22H17N2OSF: C, 70.19; H, 4.55; N, 7.44. Found: C, 69.80; H, 4.60; N, 7.32.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].IC>CC(C)=O>[O:12]=[C:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:2])=[O:19]
Reactant: CC(=O)CCCCC(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCCCC(C)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.4 mL, 22.86 mmol) was added to a solution of 6-oxoheptanoic acid 23 (1.1 g, 7.63 mmol) in acetone (15 mL) at 23° C. After stirring for 15 min iodomethane (2.4 mL, 38.3 mmol) was added. The reaction was stirred for 1 h and then the solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 7:3 hex/EtOAc) to provide 1.18 g (95%) of the methyl ester 24 (see scheme 4).
Reaction SMILES: [H][H].[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH2:12][CH2:13][CH2:14][CH3:15]>CO.[Pd]>[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:10])([CH3:11])[CH:5]1[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1=C(C)CCCC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCC1C(C)CCCC1(C)C

Procedure:
18 g Of the mixture of alkenes obtained by dehydration of dihydro-β-ionol as described in example 1 was dissolved in 150 ml of methanol and hydrogenated at atmospheric pressure using 0.5 g of a catalyst consisting of 5% Palladium on charcoal. Hydrogenation was stopped when the uptake of hydrogen markedly slowed down. A 1:1 mixture of 1,3,3-trimethyl-2-(but-1-yl)-cyclohex-1-ene and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane was obtained. This mixture was oxidized with tert.butyl chromate as described in example 1, yielding a mixture of the title compound and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane. The mixture was fractionated yielding 6.75 g of the title compound boiling at 90°-92° C. (4 Torr).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline (34.0 mg, 0.120 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 7.97 (1H, d, J=7.6 Hz), 7.08 (1H, d, J=8.6 Hz), 6.67-6.82 (1H, m), 6.45 (1H, d, J=9.6 Hz), 6.06 (1H, d, J=2.2 Hz), 3.88 (4H, t, J=4.3 Hz), 3.70-3.82 (4H, m), 3.36 (4H, br. s.), 2.96-3.24 (4H, m), 2.70-2.97 (4H, m), 2.11 (3H, s), 1.58-1.92 (7H, m). Mass Spectrum (ESI) m/e=524.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2ccc(F)c3nc(C)ncc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 53 mg (0.3 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are reacted to give 4-(4-chloro-3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 140 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yield 3 mg of product and 16 mg of the dihydroxy compound Ex. 18.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[O:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:60]1[CH2:66][CH2:65][CH2:64][C@@H:61]1[CH2:62][OH:63]>CN(C=O)C>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:6]1[O:7][C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:60]3[CH2:66][CH2:65][CH2:64][C@@H:61]3[CH2:62][OH:63])=[O:15])=[CH:17][CH:18]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: OC[C@H]1CCCN1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCC[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
To a solution of 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.040 g, 0.111 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.042 g, 0.111 mmol), and diisopropylethylamine (0.038 mL, 0.222 mmol) in DMF (0.35 mL) was added D-prolinol (0.011 mL, 0.111 mmol) and the reaction mixture stirred at room temperature for 6 hours. The reaction was reduced in vacuo. The residue was purified by preparative HPLC to afford the white solid (R)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)phenylamino)oxazole-4-carboxamide (0.018 g, 0.040 mmol, 36%). 1H NMR (DMSO) δ 1.68 (1H, m), 1.90 (3H, m), 3.61-3.32 (4H, m), 4.13 (1H, br s), 4.75 (1H, t), 7.50-7.31 (8H, m), 7.64 (1H, m), 9.50 (1H, br s). LCMS (2) Rt: 2.10 min; m/z (ES+) 443.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C@@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]2[NH2:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1N
Reactant: N[C@@H]1CCCC[C@@H]1N
Product: N#Cc1ccc(N[C@@H]2CCCC[C@@H]2N)cc1N
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 2-amino-4-fluorobenzonitrile (5.0 g, 37 mmol) and cis-cyclohexane-1,2-diamine (12.6 g, 111 mmol) was heated to 120° C. After 48 hours, the reaction mixture was cooled to ambient temperature and purified directly via silica gel chromatography (1-5% methanol/dichloromethane, linear gradient) to afford rel-2-amino-4-{[(1R,2S)-2-aminocyclohexyl]amino}benzonitrile. MS ESI calc'd. for C13H19N4 [M+H]+ 231. Found 231. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=8.8 Hz, 1H), 6.01 (d, J=9.6 Hz, 1H), 5.85 (s, 1H), 4.68 (d, J=9.6 Hz, 1H), 4.22 (br s, 2H), 3.39-3.34 (m, 1H), 3.14-3.11 (m, 1H), 1.70-1.35 (m, 10H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].Br[C:18]([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[C:14]([CH:13]([C:12]#[N:16])[C:18]([CH3:24])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:15]
Reactant: CCOC(=O)C(C)(Br)c1noc(C)n1
Reactant: N#CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(c1noc(C)n1)C(C#N)C#N
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DBU (2.56 mL, 8.1 mmol) was added dropwise to a −78° C. THF (20 mL) solution of malononitrile (1.12 g, 17 mmol) and the intermediate from Step C (1.49 g, 5.66 mmol). The reaction solution was stirred at −78° C. for 15 minutes and then at room temperature for 1 hour. The solution was then concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 4.79 (1H, s), 4.30 (2H, dd, J=7.1, 2.6 Hz), 2.64 (3H, s), 2.02 (3H, s), 1.31-1.25 (3H, m).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 1.66 g (23.9 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 2.95 g (35.1 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (15.97 mmol) of octanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Nc1ccc2ncccc2c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4ncccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 173.8 mg (1.2 mmol) of 6-aminoquinoline and 115.6 mg (1 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was refluxed for 6 hr. The work up gave 212.5 mg (59.5%) of the product as a orange solid, m.p. 241-243° C., mass (electrospray, m/e): M+H 356.8. HRCIMS: calcd 356.127 for C20H17N5O2 (M+), obsd 356.1275.
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:29][CH:4]1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[CH:9][CH:8]=1>C(O)C>[C:19]1([C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH:4]([OH:3])[CH2:29][NH:2][CH3:1])=[CH:8][CH:9]=3)[O:14][C:13]([CH3:18])([CH3:17])[CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h
Yield: 63 %

Procedure:
Methylamine (9.5 ml) was added to 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H chromene (4.5g., 0.013 moles) in ethanol (9.5ml) and the solution left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as an orange oil (3.2g., 63%). N.M.R. (τCDCl3) 8.54(s, 3H, CH3 --), 8.48(s, 3H, CH3 --), 7.06(s, 3H, N--CH3), 6.72(d, 2H, --CHCH2 --), 6.05(d, 2H, --CH2CH--), 4.51(s, 1H, vinylic CH), 3.40-3.80 (m, 3H, aromatic H's), 2.10-2.75(m, 7H, aromatic H's).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.OO.N[C:14](N)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:15][CH3:14])=[N:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CCOc1ccc(Br)cn1
Agent: OO
Solvent: ClCCl
Product: CCOc1ccc(Br)c(OC)n1
Temperature: 25 °C

Procedure:
To 5.00 g (24.7 mmol) 5-bromo-2-ethoxy-pyridine in 50 mL DCM are added 4.66 g (49.5 mmol) urea hydrogen peroxide. Then the mixture is chilled to 0° C. before 6.88 mL (49.5 mmol) TFA anhydride are added. Afterwards cooling is removed and the resulting mixture is stirred over night while the temperature raises to r.t. The solvent is removed in vacuo, water is added and the resulting mixture is extracted with DCM. The combined org. layers are dried over MgSO4, filtered and the sovent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH).