Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][C:17]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:19])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12
Reactant: COc1cc(OCC(=O)O)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCC(=O)NCCN(C)C)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Temperature: 25 °C

Procedure:
A mixture of {[3-amino-7-methoxy-2-(2-methylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl]oxy}acetic acid (80 mg), N,N-dimethylethylenediamine (33 μl), (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (58 mg), 1-hydroxybenzotriazole (41 mg), triethylamine (43 μl) and N,N-dimethylformamide (2 ml) was stirred at room temperature for one night. The reaction mixture was concentrated under reduced pressure, and the residue was purified with column chromatography to obtain the target compound (61 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=[CH:14][C:4]=1[O:5]/[C:6](=[CH:10]\[C:11](O)=[O:12])/[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([C:3]1[C:4]2[O:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11](=[O:12])[C:14]=2[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH3:31])[CH3:2]
Reactant: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)O)C(=O)O)c1CC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1CC
Temperature: 25 °C

Procedure:
A mixture of 1.07 parts of 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumaric acid and 1 part of concentrated sulphuric acid was shaken at room temperature for seventeen hours, then 25 parts of water were added. The resulting solution was made basic by addition of excess sodium carbonate, then re-acidified with 2N hydrochloric acid and extracted with ethyl acetate. Evaporation of the ethyl acetate under reduced pressure gave an oil which on trituration with acetone gave 0.674 parts of 8-ethyl-4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 198°-199°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][C@:45]([C:50]#[C:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=2)([OH:49])[CH2:44]1>CC(N(C)C)=O>[Cl:58][C:54]1[CH:53]=[C:52]([C:51]#[C:50][C@:45]2([OH:49])[CH2:46][CH2:47][CH2:48][C@H:43]([NH:42][C:37](=[O:39])[C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:41][CH:40]=3)[CH2:44]2)[CH:57]=[CH:56][CH:55]=1
Reactant: N[C@H]1CCC[C@@](O)(C#Cc2cccc(Cl)c2)C1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N[C@H]2CCC[C@@](O)(C#Cc3cccc(Cl)c3)C2)cc1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate)(29.9 mg, 0.093 mmol) in DMA (0.23 ml) and DIPEA (36 μl, 0.213 mmol) was added to solid 4-methylbenzoic acid (11.6 mg, 0.085 mmol) under argon atmosphere at room temperature. After stirring for 20 min., a solution of (1S,3S)-3-amino-1-(3-chloro-phenylethynyl)-cyclohexanol (21.2 mg, 0.085 mmol) in DMA (0.43 ml) was added and the crude reaction mixture was purified without further treatment after stirring for 24 h on a preparative LC/MS system, yielding the title compound (25.1 mg, 0.068 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][S:8](O)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][S:8]([Cl:16])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CS(=O)(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
5 g (22.83 mmol) of 4-cyanobenzylsulfonic acid, sodium salt, were moistened with approx. 20 ml of phosphoryl chloride after which 5.2 g (25.11 mmol) of PCl5 were added and the mixture was stirred for 15 min while being cooled with ice. The mixture was then heated at 80° C. for 4 h. After that, the mixture was poured onto ice and this fresh mixture was stirred vigorously for 30 min; the product then separated out on the ice as a white solid. After the ice had partially thawed, the mixture was filtered through a frit and the product/ice mixture which remained was washed several times with water. The crystals which remained were dried in vacuo and used directly for the next step in the synthesis.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:39][CH2:38][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:21][N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]2=[O:37])[CH2:17][CH2:16]1)=O)(C)(C)C>C(OCC)C>[CH2:30]([N:20]1[C:19](=[O:37])[C:18]2([CH2:38][CH2:39][NH:15][CH2:16][CH2:17]2)[N:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccc(F)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(Cc2ccccc2)CN(c2ccc(F)cc2)C12CCNCC2
Reaction time: 1 h

Procedure:
Cool trifluoroacetic acid (20 mL) using an ice bath and add 8-tert-butoxycarbonyl-3-benzyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane (10 mmol). After 1 h, dilute with diethyl ether (150 mL), filter to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCOc1cccc(O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
A mixture of 11 g of resorcinol, 8.8 g of methyl 5-bromopentanoate, and 13.8 g of potassium carbonate in 150 mL of dimethylformamide was heated in an oil bath at 90° C. for 24 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether providing the title intermediate in 34% yield, NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:9][C:5]([CH3:10])([C:6]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(=O)NS(C)(=O)=O
Yield: 66.8 %

Procedure:
3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, 0.624 mmole) was added to a stirring suspension of 2.5 equivalents of PS-DCC from Argonaut and 3 equivalents of dimethylaminopyridine in DCM. To this was added methanesulfonamide (41.6 mg, 0.437 mmole). The solution was filtered of and concentrated to give 69.3 mg of ethyl 2,2-dimethyl-3-[(methylsulfonyl)amino]-3-oxopropanoate (67% yield crude). MS ES− 236 (M−H). 1H NMR (300 MHz, Chloroform-d) δ ppm 1.4 (t, J=6.7 Hz, 3H), 1.6 (s, 6H), 3.3 (m, 3H), 4.3 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(#N)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.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.[Pd]>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: OCCCC#Cc1ccccc1F

Procedure:
1-Bromo-2-fluorobenzene [1072-85-1](3.0 g, 17 mmol, 1.0 equiv) and pent-4-yn-1-ol [5390-04-5](2.3 mL, 25 mmol, 1.5 equiv) were dissolved in acetonitrile (40 mL). CuI (0.13 g, 0.68 mmol, 0.04 equiv) and TEA (3.4 mL, 25 mmol, 1.5 equiv) was added to the stirred solution followed by tetrakis(triphenylphosphine)palladium(O) (0.39 g, 0.34 mmol, 0.02 equiv). The solution was heated at reflux for 16 hours. The solution was cooled, filtered through Celite, the Celite pad rinsed with EtOAc and the solvent removed by rotoevaporation. Column chromatography (9:1 hexanes:ethyl acetate) of the residue afforded pure 5-(2-fluorophenyl)pent-4-yn-1-ol Intermediate 60 (1.3 g, 43%). 1H NMR (600 MHz, DMSO-d6) δ: 7.42 (t, J=7.48 Hz, 1H), 7.38-7.32 (m, 1H), 7.22 (t, J=9.10 Hz, 1H), 7.14 (t, J=7.56 Hz, 1H), 4.50 (t, J=5.21 Hz, 1H), 3.49 (q, J=5.92 Hz, 2H), 2.47 (t, J=7.12 Hz, 2H), 1.66 (quin, J=6.68 Hz, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].CO[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[O:10][CH3:11].C(N(CC)CC)C>CCCCCC>[Cl:1][C:2]1[C:3](=[O:4])[C:9]([O:10][CH3:11])([O:12][CH3:13])[C:8]=1[O:14][CH3:15]
Reactant: COC(OC)=C(OC)OC
Reactant: O=C(Cl)CCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC1=C(Cl)C(=O)C1(OC)OC
Temperature: 20 °C
Reaction time: 3 h
Yield: 0.5 %

Procedure:
A solution of 23.7 g (0.21 mole) of chloroacetyl chloride is added dropwise, in the course of 40 minutes, to a solution, cooled to 0°-5° C. and vigorously stirred, of 14.8 g (0.1 mole) of 1,1,2,2-tetramethoxyethylene and 23.2 g (0.23 mole) of triethylamine in 100 ml of absolute n-hexane. The greyish-brown suspension formed is stirred for 3 hours at 20° C.; the resulting salt is then filtered off with suction and washed with n-hexane, and the yellow filtrate is concentrated by evaporation. The intensive IR-absorption bands of the residue (30.4 g) confirm the formation of 2-chloro-3,3,4,4-tetramethoxy-1-chloroacetoxycyclobutene (5.71μ) and 2-chloro-3,4,4-trimethoxycyclobutenone (5.58; 6.1μ). According to the NMR spectrum, the reaction mixture contains 80±5% by weight of 2-chloro-3,3,4,4,-tetramethoxy-1-chloroacetoxybutene and 12±3% by weight of 2-chloro-3,4,4-trimethoxycyclobutenone, besides small amounts of unidentifiable by-products. By rapid separation by columnchromatography of 0.5 g of the crude residue, it is possible to obtain 0.1 g of pure 2-chloro-3,4,4-trimethoxycyclobutenone (eluant: hexane/diethyl ether in a volume ratio of 4:1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:37])[C:19](=O)[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[C:23]=1[OH:35])C>CO>[OH:35][C:23]1[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]1[C:17](=[O:16])[C:18](=[O:37])[C:19]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCCC3)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCCC4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 95.1 %

Procedure:
385 mg (2.12 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in solution in 3 ml of methanol were added to a solution of 443 mg (1.40 mmol) of 3-ethoxy-4-[2-hydroxy-3-(pyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione in 42 ml of methanol. The reaction medium was heated at 50° C. for 13 hours. The reaction medium was concentrated. The residue was taken up with ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 0.62 g of product were obtained in the form of a beige solid. Yield=95%, HPLC=94.06%, Mp=210° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH:19](O)[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[H][H]>C(O)(=O)C.[Pd]>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2O
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2
Temperature: 25 °C

Procedure:
Pd/C (0.015 g, 10% w/w) and catalytic amount of perchloric acid was added to a solution compound of Example 203 (0.11 g, 0.3 mmol) in acetic acid (60 ml). The reaction mixture was subjected to hydrogenation at 100 psi of hydrogen at 65° C. for 6.5 h. The reaction mixture was cooled to 25° C. and filtered through high flow bed. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, ethyl acetate and pet ether) to obtain the title compound. Yield: 0.05 g (47%); 1H NMR (CDCl3): δ 3.8 (s, 2H, CH2), 3.9 (s, 3H, CH3), 4.32 (s, 2H, CH2), 7.38 (m, 5H, Ar), 8.09 (d, 1H, Ar), 8.61 (s, 1H, Ar); MS: m/e (CI+) 303 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18]C.B(Br)(Br)Br>>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[OH:18]
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Agent: BrB(Br)Br
Product: Oc1cc(C=Cc2ccccc2)cc(O)c1Br
Yield: 90 %

Procedure:
This material was synthesized from 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (21B) and BBr3 in 90% yield by the same method as described in Example 6. 1HNMR (CDCl3, ppm): δ 5.39 (s, 2H), 6.81 (s, 2H), 7.06 (d, J=17 Hz, 1H), 7.11 (d, J=17 Hz, 1H), 7.28 (m, 1H), 7.37 (m, 2H), 7.55 (m, 2H).
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:22]([Cu])#[N:23].O>CN(C=O)C>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([CH:16]=2)[C:22]#[N:23])=[CH:13][N:12]=1
Reactant: N#C[Cu]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Temperature: 120 °C
Yield: 43.3 %

Procedure:
A mixture of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.37 g, 0.925 mmol) and CuCN (0.12 g, 1.39 mmol) in DMF (5 ml) was heated at 120° C. for 3 hours. Water (100 ml) was added, and the precipitate was collected. The residue was triturated with methanolic dichloromethane (10% CH3OH in CH2Cl2 with 0.1% NH4OH) to release the product from its copper complex and filtered. The filtrate was concentrated and purified via flash chromatography (3%CH3OH in CH2Cl2 with 0.1% NH4OH) to give 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile as white solid (0.12 g, 44%): M+H 300.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH2:5].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.[I-].ClC1C=CC=C[N+]=1C.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH:5][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCNC(=O)c1cccnc1
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A mixture of 2 mmol of N-(3,7,11-trimethyl-2,6,10-dodecatrienyl)amine (hereinafter abbreviated as farnesylamine), 2.2 mmol of nicotinic acid, 562 mg (2.2 mmol) of 2-chloro-1-methylpyridinium iodide, and 444 mg (4.4 mmol) of Et3N in 20 ml of CH2Cl2 is heated with stirring for 3 hours. The reaction mixture is washed twice with 20 ml of saturated aqueous NaHCO3 and twice with 20 ml of water. The mixture is dried and evaporated under reduced pressure. The residual oil is purified by silica-gel column chromatography and eluted with AcOEt to give 426 mg of the titled compound I-85.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:36](N)([CH3:38])[CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:29][CH2:30][NH:31][CH:36]([CH3:38])[CH3:37])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isopropylamine instead of cyclopropylmethylamine. LC-MS: (M+1=463, obsd.=463).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:11][NH2:16])[S:9][CH:10]=1
Reactant: O=Cc1cc(Oc2cccc(F)c2)cs1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1cc(Oc2cccc(F)c2)cs1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-(3-Fluorophenoxy)thiophene-2-carbaldehyde described in Preparation Example 34 (210 mg, 0.95 mmol) was dissolved in 7N ammonia/methanol (30 mL), Raney nickel (500 mg) was added thereto, followed by stirring for 19 hours under hydrogen atmosphere at room temperature. The reaction mixture was filtered through Celite pad, Raney nickel was removed, silica gel was added to the filtrate, then, the solvent was evaporated in vacuo, for adsorption on silica gel, purification by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=4:1) was carried out, and the title compound (70 mg, 0.32 mmol) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12](I)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[F:17][C:18]([F:26])([F:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:24]4[N:20]([CH2:19][C:18]([F:26])([F:25])[F:17])[N:21]=[CH:22][N:23]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: FC(F)(F)Cn1cncn1
Product: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Yield: 10 %

Procedure:
Following the procedure for 184, 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and 1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole were reacted to give 9-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.109 g, 10%). 1H NMR (400 MHz, DMSO) δ 8.28 (t, J=21.9, 1H), 8.11 (t, J=7.9, 2H), 7.51-7.35 (m, 1H), 7.32 (d, J=2.0, 1H), 5.88 (q, J=8.8, 2H), 4.76-4.29 (m, 4H). MS (ESI(+)): m/z 413.9 (M+H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30]>C1COCC1>[CH2:33]([O:32][C:28](=[O:31])[CH:29]([OH:30])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:34]
Reactant: CCOC(=O)C=O
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)C(c1ccc(OC2CCCCC2)cc1)C(O)C(=O)OCC
Reaction time: 12 h

Procedure:
To a stirred solution of 1-(4-cyclohexyloxy-phenyl)-hexan-2-one (86.4 mmol, 23.7 g) and triethylamine (86.4 mmol, 12.1 mL) in THF (10 mL) was added a solution of ethyl glyoxylate (50% in toluene, 432 mmol, 86 mL) and continued stirring for 12 h during which time the starting material was fully consumed as judged by TLC. After removal of volatiles in vacuo, the crude product was purified on a 300 g SiO2 cartridge with 10-15% ethyl acetate in hexanes to afford 3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.O>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:2]=[O:3])[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, 263 g of methoxymethyl triphenylphosphonium chloride was suspended in THF (800 mL), and 90 g of potassium-tert-butoxide was added the resultant suspension at an inside temperature of 0° C. or less, followed by stirring at an inside temperature of 0° C. for 20 minutes. Then, a solution of 4-(3,5-difluorophenyl)cyclohexanone (119 g) in THF (300 mL) was added at an inside temperature of 5° C. or less, followed by stirring at an inside temperature of −5 to 8° C. for 30 minutes. After water (10 mL) was added, the solvent was distilled off under reduced pressure, and water (400 mL), methanol (400 mL), hexane (500 mL), and 7.3 g of a 70% aqueous tert-butyl hydroperoxide solution were added to the residue, followed by stirring at room temperature for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a 50% aqueous methanol solution and water two times in that order, and the solvent was distilled off under reduced pressure. Then, 10% hydrochloric acid (400 mL) and THF (400 mL) were added to the resultant residue, followed by heating under reflux for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with ethyl acetate. The ethyl acetate extract was combined with the organic layer and washed with saturated brine two times. The solvent was distilled off under reduced pressure, and methanol (300 mL) and a 10% aqueous sodium hydroxide solution (20 mL) were added to the resultant residue, followed by stirring at 5° C. to −15° C. for 1 hour. The mixture was neutralized with 10% hydrochloric acid, and then water (300 mL), THF (200 mL), and ethyl acetate (400 mL) were added to the mixture. An 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 112 g of trans-4-(3,5-difluorophenyl)cyclohexane carbaldehyde as a light yellow oil.