Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18](I)[CH3:19]>>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18]([N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1)[CH3:19]
Reactant: CCI
Agent: COc1cc2ccccc2c2c1C(C)(C)CN2
Product: CCN1CC(C)(C)c2c(OC)cc3ccccc3c21

Procedure:
The 4-methoxybenzoindoline 25 was synthesized as described above in Example 6. Compound 25 was alkylated by the general amino group alkylation procedure described in Example 3 employing ethyl iodide as the alkylating agent to give the N-ethyl-3,3-dimethyl-4-methoxybenzoindoline intermediate 28 (1HNMR: CDCl3 d 7.90 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.32 (bt, 1H, J=7.5 Hz), 7.22 (bt, 1H, J=6.9 Hz), 6.69 (s, 1H), 3.83 (s, 3H), 3.52 (q, 2H J=7.5 Hz), 3.38 (s, 2H), 1.46 (s, 6H), 1.27 (t, 3H, J=7.5 Hz). Subsequent methoxy group deprotection of compound 28 by the general boron tribromide procedure described in Example 1 yielded the N-ethyl-3,3-dimethyl-4-hydroxy-benzoindoline 29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:17][CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2 ml (0.02 mole) of 40% methylamine in water. After 3 hr, the reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (2.6 g). Recrystallization from benzene/methanol yielded 2.4 g (93.8%) of fine white crystals, m.p. 161°-162° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[S:11][C:12]([C:16]([C:18](=[C:37](SC)SC)[C:19]([C:21]2[CH:22]=[C:23]([S:27]([NH:30][C:31](=[NH:36])[C:32]([OH:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:17])=[C:13]([CH3:15])[N:14]=1>CCO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:37]1=[C:18]([C:16]([C:12]1[S:11][C:10]([CH3:9])=[N:14][C:13]=1[CH3:15])=[O:17])[C:19]([C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31](=[NH:36])[C:32]([OH:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: Nc1ccccc1N
Reactant: CSC(SC)=C(C(=O)c1cccc(S(=O)(=O)NC(=N)C(C)(C)O)c1)C(=O)c1sc(C)nc1C
Solvent: CCO
Product: Cc1nc(C)c(C(=O)C(C(=O)c2cccc(S(=O)(=O)NC(=N)C(C)(C)O)c2)=C2Nc3ccccc3N2)s1
Yield: 81.9 %

Procedure:
1,2-Phenylenediamine (81 mg) was added to an EtOH (20 mL) solution of N-[(3-{2-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-3,3-bis(methylthio)acryloyl}phenyl)sulfonyl]-2-hydroxy-2-methylpropanimidamide (370 mg), followed by heating under reflux for 13 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2,4-dimethyl-1,3-thiazol-5-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (310 mg).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1.[C:30](#[N:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:23]([O:22][C:17]1[C:16]2[N:15]([N:14]=[CH:32][C:31]=2[C:30]#[N:33])[CH:20]=[C:19]([Cl:21])[N:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC#N
Reactant: N[n+]1cc(Cl)nc(OCc2ccccc2)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
1-amino-3-(benzyloxy)-5-chloropyrazin-1-ium 2,4,6-trimethylbenzenesulfonate (5.34) (657 mg, 1.51 mmol) was suspended in 1,4-dioxane (5.75 mL) and acrylonitrile (0.23 mL, 3.5 mmol) was added followed by iPr2NEt (0.32 mL, 1.9 mmol). The resulting mixture was stirred for 1.75 h at r.t. and DDQ (720 mg, 3.2 mmol) was added in one portion. The resulting mixture was stirred an additional 1 h and was then partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carbonitrile. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.18 (s, 1H), 7.61-7.55 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 5.67 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CI>O>[CH3:3][O:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(OC)c1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0° C. is added dropwise a solution of 0.01 moles of ethyl 3-hydroxy-4-cyclohexylphenylglyoxylate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 3-methoxy-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N+:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:40]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (380 mg, 1 mmol) was mixed with K2CO3 (280 mg, 2 mmol), 3-nitro-phenylboronic acid (334 mg, 2 mmol), Pd(Ph3)4 (115 mg, 0.1 mmol), 4 mL of 1,2-dimethoxyethane and 5 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 3 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 310 mg (88% yield) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[CH:2]=[CH2:3].C1(C)C=CC(S(NN)(=O)=O)=CC=1.CC([O-])=O.[Na+]>C(COC)OC.O>[CH3:12][O:11][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCc1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution of 123 mg (0.75 mmole) of 4-allyl-2-methoxyphenol (eugenol) and 1.4 gm (7.5 mmole)of p-toluenesulfonhydrazide in 15 ml of dimethoxyethane under reflex was added a solution of 1.7 gm of NaOAc in 15 ml water over a 4 hour period. The mixture was cooled to room temperature, poured into 20 ml of water, and extracted three times with 30 ml of CH2Cl2. The combined organic layers were washed with 50 ml of water, dried over MgSO4, and concentrated under vacuo. The resulting solid was flash chromatographed over silica gel using 10% ethyl acetate in hexane to afford 60 mg of 2-methoxy-4-propylphenol in 48% yield.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Diethylazodicarboxylate (0.839 mL, 5.50 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.00 g, 3.55 mmol), (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.96 g, 5.50 mmol), triphenylphosphine (1.40 g, 5.50 mmol) and benzene (15 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 19 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (60 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (2.48 g, 94 %): mp 140-143° C.: [a]D25=-56.87° (10.02 mg/mL CHCl3); NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.49 (m, 2 H), 7.46-7.27 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (dd, J =8, 6 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (31%), 724 (94%) 726 (100%) 728 (40%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.99, H, 2.85, N, 0.03.
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.Cl.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][C:47]([Cl:49])=[O:48]>ClCCl>[ClH:49].[Br:2][C:3]1[N:4]=[C:5]([C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][N:32]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12
Reactant: COCC(=O)Cl
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Agent: Cc1nccn2c([C@H]3CCNC3)nc(Br)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CC[C@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-Bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride was prepared in a similar way as (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride. To (S)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.31 mmol, 100 mg) in dichloromethane (5 ml) and N,N-diisopropylethylamine (1.778 mmol, 0.311 ml) at 0° C. was added a solution of methoxyacetyl chloride (0.534 mmol, 0.049 ml) in dichloromethane (0.5 ml). After stirring for one hour at room temperature the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (S)-1-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-methoxyethanone (80 mg).
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:41][CH3:42])=[C:38]([Pb+3])[CH:39]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:41][CH3:42])=[C:36]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])[CH:35]=1
Reactant: CC12CCC(C(=O)CC1=O)C2(C)C
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.22 g, 1.22 mmol) (preparation described by H. Favre et al., Can. J. Chem. (1956), 34 1329-39) in dry chloroform (10 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is then added 4-dimethylaminopyridine (0.744 g, 6.15 mmol) and anhydrous toluene (3 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (0.673 g, 1.18 mmol) is added portionwise over 10 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (10 ml) is added, and the resulting biphasic mixture is filtered to remove any inorganic salts (washing with additional dichloromethane, 10 ml). The organic phase separated, and the aqueous phase is extracted again with dichloromethane (10 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give an orange gum. This crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.04 g, 9%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:30])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][CH:27]([NH:30][C:34]([C:33]3[C:32]([CH3:31])=[N:40][CH:39]=[CH:38][CH:37]=3)=[O:35])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 4-(2-amino-butyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (100 mg, 0.233 mmol) in pyridine (4 mL) was added 2-methyl-nicotinic acid (38.4 mg, 0.280 mmol) and EDCI (71.5 mg, 0.373 mmol). The solution was stirred overnight at room temperature, then diluted with water (5 mL). The mixture was poured into a separatory funnel and diluted further with water (20 mL). The mixture was extracted with EtOAc (2×20 mL), then the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield a yellow-brown oil which was purified via column chromatography. The resulting yellow solid was dissolved in methanol (2 mL) and HCl in Et2O (2M, 2 mL) was added. The mixture was stirred for 5 minutes, then concentrated to yield 103 mg of 6,6-dimethyl-4-{2-[(2-methyl-pyridine-3-carbonyl)-amino]-butyl}-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (71% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (37.9 mmol) of 3,5-dibromobenzaldehyde and 5 g (45.5 mmol) of 2-aminophenol were dissolved in 200 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 20.2 g (45.5 mmol) of lead (IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was added to the acquired reactant. The mixture was extracted with ethyl acetate and treated under reduced pressure to remove the solvent, obtaining 5.7 g (Y=42%) of a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26].C(OCC)(=O)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:10]2[C:8]3[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=3[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11]2=[O:22])=[CH:29][CH:28]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 7 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 0.64 mmol). The mixture was heated at 40° C. to 50° C. for 20 minutes, resulting in a clear solution. Methyl 4-(bromomethyl) benzoate (206 mg, 0.90 mmol) was added, and the reaction mixture was heated at 40° C. to 50° C. for 15 minutes, then poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to 1:2 hexane: ethyl acetate, then dried in vacuo to provide 204 mg of 4-[2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-ylmethyl]-benzoic acid methyl ester containing 0.16 equivalents of ethyl acetate; mp 235°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[O:21].N.O>C1COCC1>[C:20]([O:19][CH2:18][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[O:21])[NH2:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
In a 250 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-o-fluorophenylalaninol (0.096 mole, 2.15 g) was dissolved in 200 ml of THF and was added with 1,1'-carbonyldiimidazole (0.010 mol, 1.62 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture of n-hexane and diethyl ether, to produce 1.93 g of O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol: Yield 75%.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:2][CH2:3][S:4][CH2:5][CH2:6]1
Reactant: O=Cc1csc(N2CCSCC2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCSCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 0.85 g of 2-(thiomorpholin-4-yl)thiazole-4-carbaldehyde, 0.76 g of rhodanine-3-acetic acid, 0.4 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia and 30 ml of ethanol, giving the title compound as yellow crystals.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1[CH:16]=[C:17]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:18]=[C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH:2]1([N:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[C:17]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:16]=[C:15]([CH3:14])[CH:20]=3)[CH:25]=[N:24]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3C=CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromocyclohexene (0.18 mL, 1.57 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to an oven-dried flask containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.57 mmol) dissolved in DMF (5 mL). The mixture was warmed to 80° C. and stirred overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with 1:1 water:brine (3×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford racemic N-{3-[1-(cyclohex-2-en-1-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calcd. for C21H21F3N5 [M+H]+ 400. found 400.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([S:10]([CH2:13][S:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:13]([S:14]([CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[N+:35]=[N-:36])(=[O:12])=[O:11])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCC)CC2)CC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCC)CC2)CC1
Yield: 49 %

Procedure:
Synthesis was conducted as in Synthesis Example 8 using 8.0 g (0.020 mol) of the bis(4-n-propylcyclohexyl-sulfonyl)methane prepared above, 6.1 g (0.030 mol) of p-toluenesulfonylazide, 73 g of dichloromethane and 3.1 ml (0.020 mol) of DBU. There was obtained 4.1 g of the desired bis(4-n-propylcyclohexylsulfonyl)diazomethane. The yield was 48%.