Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C=O)C>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[CH:3]=2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccccc3)n2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccccc4)n3)c2)cc1

Procedure:
A solution of [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5) (50 mg), 4-tert-butyl-benzoyl chloride (0.83 mL of a 0.2M solution in toluene), and triethylamine (0.034 mL) in toluene (1 mL) and N,N,-dimethylformamide (1 mL) is stirred at room temperature for 16 hr. The mixture is purified by preparative thin layer chromatography over silica gel, eluting with diethyl ether/dichloromethane (1:1) to afford 4-tert-butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide (6) as a cream foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([CH3:17])=[C:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:18][CH2:17]/[C:9](/[C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1)=[C:10](/[F:16])\[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(F)=C(C)C1(C(=O)OCC)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C(\CBr)C1(C(=O)OCC)CC1
Yield: 49.8 %

Procedure:
To a solution of ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (152.78 g, 0.625 mol) in chloroform (1500 ml) were added N-bromosuccinimide (111.33 g, 0.625 mol) and a catalytic amount of 2,2′-azobis(isobutyronitrile) and then the resultant mixture was heated under reflux for 16 hours. Then, the liquid reaction mixture was cooled and concentrated under reduced pressure. After adding benzene (300 ml), insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain 100.5 g (49.7%) of the title compound as a yellow oily substance. On the other hand, 75 g (37.1%) of (Z)-ethyl 4-bromo-3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (the geometrical isomer of the title compound) was obtained as a yellow oily substance with the use of another eluent (n-hexane:ethyl acetate=2:1).
Reaction SMILES: C1(N2C(=O)C3=CNC4C=[CH:15][C:16]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[CH:29]=1.CN1CCNCC1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([N:39]2[C:38](=[O:49])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:16][CH2:15]5)=[CH:29][C:30]=4[C:31]3=[N:40]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(-n2nc3c4cc(N)ccc4[nH]cc-3c2=O)cc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4cc(N5CCN(C)CC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 7a using 6c and 1-methylpiperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.45 (3H, s), 3.50 (4H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 390.4 (MH+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:40]1[CH:41]=[C:42]2[C:59](=[N:60][CH:61]=1)[NH:58][C:57](=[O:62])[C:44]1([CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)[CH2:43]2>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:40]1[CH:41]=[C:42]2[C:59](=[N:60][CH:61]=1)[NH:58][C:57](=[O:62])[C:44]1([CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:46][CH2:45]1)[CH2:43]2)[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2

Procedure:
Ethyl acrylate (2.3 mL, 21.2 mmol), diisopropylethylamine (3.7 mL, 21.2 mmol) and P(o-tolyl)3 (323 mg, 1.06 mmol) were successively added to a suspension of tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (2.10 g, 5.3 mmol) in propionitrile (20 mL) and dimethylformamide (5 mL) in a sealed tube. The resulting mixture was then purged with argon prior to the addition of palladium acetate (120 mg, 0.53 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in dichloromethane (100 mL). The resulting solution was washed with a saturated solution of ammonium chloride (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was precipitated in dichloromethane/diethylether/pentane, the title product was obtained as an off-white solid (1.52 g, 70%).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:33]=[CH:32][C:22]3[NH:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH2:26][CH2:27][C:21]=3[CH:20]=2)[CH2:14][CH2:13]1.CO>ClC(Cl)C>[CH:1]([N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][C:21]2[CH:20]=[C:19]([CH2:18][N:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]3)[CH:33]=[CH:32][C:22]1=2)=[O:3]
Reactant: O=CO
Reactant: CN1CCN(Cc2ccc3c(c2)CCc2ccccc2N3)CC1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CN1CCN(Cc2ccc3c(c2)CCc2ccccc2N3C=O)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Formic acid (99%; 300 ml) was added dropwise to 600 ml of acetic anhydride, the internal temperature being maintained at 45° C. followed by stirring for one hour To this solution was added, in small portions, a suspension of 375 g of Compound 30-1a in 500 ml of dichloroethane under ice cooling, followed by stirring at room temperature for 8 hours. After cooling, 400 ml of methanol was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and adjusted to pH 9-10 with a 10N aqueous solution of sodium hydroxide. The organic layer was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent:ethyl acetate/methanol/triethylamine (300/20/1)] to give 106.8 g (23%) of the product as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:29][OH:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]>C(Cl)Cl.O1CCOCC1.O=[Mn]=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:29]=[O:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CO)nc3Cl)c2F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C=O)nc3Cl)c2F)c1
Reaction time: 66 h
Yield: 30 %

Procedure:
MnO2 (2.5 g, 29 mmol) was added to a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxamide (428 mg, 0.91 mmol) in DCM (30 mL) and 1,4-dioxane (5.0 mL). The mixture was stirred for 66 h and then the MnO2 was filtered off by through a pad of celite. Resin with 10% MeCN in DCM and the filtrates were concentrated, dried in vacuo to give the crude product (128 m, 30%) which was used for the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]1[N:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([C:12]1[N:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C#CC[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Yield: 111.3 %

Procedure:
To a mixture of (R)-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-carbamic acid tert-butyl ester (5.35 g, 12.2 mmol) in methanol (65 ml) was added HCl in dioxane (4M, 20 ml). The resulting solution was stirred and the reaction completion was monitored using HPLC/LCMS. The solvent was then removed and the mixture was triturated with diethyl ether to afford 2-((R)-1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one (4.60 g, 100%) as off-white solid. M.p. 175-180° C. LCMS: m/e 339 [M+H]. 1H NMR: (DMSO d6) δ 9.27 (s, 1H), 8.73 (s, br, 3H), 8.15 (d, J=8.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0 and 8.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 6.92 (t, J=7.6 Hz 1H), 6.68 (m, 2H), 4.90, 4.58 (m, 1H, rotomers), 3.18 (m, 1H), 3.08 (m 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7].[I:17][CH3:18]>CC(C)=O>[I-:17].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][N+:11]([CH3:18])=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1cccc(C(=O)c2ccncc2)c1
Reactant: CI
Solvent: CC(C)=O
Product: COc1cccc(C(=O)c2cc[n+](C)cc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A mixture of 4-[3-methoxybenzoyl]pyridine(790 mg, 3.7 mmol) and iodomethane (1.15 ml, 18.5 mmol) in acetone (10 mL) was stirred at room temperature for 48 h. The precipitate was filtered, washed with diethyl ether and dried in vacuo to give 1.2 g (91%) of an orange powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[N:25]([CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:40])[C:23]2=[O:41].ClCCl>O1CCCC1>[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]2[C:26]3[C:22](=[CH:21][CH:20]=[CH:19][C:18]=3[F:17])[C:23]([OH:41])([C:8]3[C:9]([OH:11])=[CH:10][C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=3)[C:24]2=[O:40])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C1(O)c1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a cooled (0° C.) suspension of 2,3-dihydro-1,4-benzodioxin-6-ol (0.47 g, 3.0 mmol) in anhydrous tetrahydrofuran (12 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 1.7 mL, 3.3 mmol). The reaction mixture was stirred at 0° C. for 1 h, and 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione (1.0 g, 3.0 mmol) and anhydrous dichloromethane (10 mL) were added. The reaction mixture was allowed to stir for 19 h at ambient temperature. The reaction mixture was concentrated in vacuo and was diluted with saturated aqueous ammonium chloride (30 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 8% to 66% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.22 g, 84%) as an off-white solid: MS (ES+) m/z 475.0 (M−17).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.[CH3:23][N:24]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH2:41]([O:43][C:44]1[C:52]([O:53][CH3:54])=[CH:51][CH:50]=[CH:49][C:45]=1[CH2:46]CN)[CH3:42].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:24]([CH2:46][C:45]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:44]=2[O:43][CH2:41][CH3:42])[CH3:23])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CCOc1c(CCN)cccc1OC
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)cccc1OC
Yield: 25 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (177 mg, 25%) was prepared as a pale, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.4 (s, 1H), 8.28-8.19 (m, 2H), 7.73 (s, 1H), 7.47 (d, J=15.3 Hz, 1H), 7.21 (dd, J=14.9, 5.4 Hz, 1H), 7.05-6.94 (m, 2H), 6.64 (dd, J=7.2, 7.2 Hz, 1H), 4.78-4.63 (m, 2H), 4.03-3.93 (m, 2H), 3.79 (s, 3H), 3.55-3.33 (m, 7H), 3.09-2.85 (m, 7H), 2.74 (s, 3H), 1.31-1.25 (m, 3H); MS (ESI) m/e 454 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH3:19].CC(C)([O-])C.[K+].O1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(OCC)C.O>[CH2:16]([C:5]1([CH2:27][CH2:28][CH2:29][CH3:30])[C:4]2[CH:3]=[C:2]([I:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:18][CH3:19]
Reactant: C1CCOC1
Reactant: CCCCI
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 0.58 parts of 2-iodo-9H-fluorene, 1.10 parts of 1-iodobutane, and 0.67 parts of potassium tert-butoxide were added into 15 parts of dry tetrahydrofuran, followed by stirring and mixing. Then, the reaction mixture was heated to 50° C. and reacted for 12 hours. After the reaction mixture was cooled, poured the water into the reaction mixture for quenching the reaction, using the diethyl ether to extract the product, and magnesium sulfate was used for dehydration. After removing the solvent, the residual was purified with column chromatography method by using hexane as an eluent, to obtain a compound (32) of the present example. This compound was in a form of a light yellow solid, and the yield of this compound was 94%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:34])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)N3CCOCC3)ccc2C)cc1

Procedure:
A stirred solution of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (520 mg) in dry THF (25 ml) containing triethylamine (0.57 ml) was treated with 4-morpholine-carbonyl chloride (0.26 ml). After 18 h. the mixture was partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1:1 gave the title compound as a yellow oil (416 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1([O:13][C:14](=O)[O:15][C:16]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:38]=3[N:37]=[CH:36][CH:35]=[CH:34]4)(=[O:28])=[O:27])[C:17]2=[O:39])C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Cl:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=1[N:37]=[CH:36][CH:35]=[CH:34]3)(=[O:28])=[O:27])[C:17](=[O:39])[C:16]2([O:15][C:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]
Reactant: COc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C1(OC(=O)N2CCCCC2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Piperidine (0.132 ml, 1.33 mmol) was added to a solution of the intermediate from step A (200 mg, 0.33 mmol) in THF (10 ml), and the reaction solution was stirred overnight. 2 M sodium hydroxide solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed three times with water and concentrated under reduced pressure. Recrystallization from dichloromethane/diethyl ether resulted in 112 mg of the desired product.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCC(=CC(=O)OCC)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.85 g (5.4 mmol) Ethyl 3-oxohexanoate, 1.0 g (6.21 mmol) 3-trifluoromethylaniline and 5 mg (0.08 mmol) acetic acid are dissolved in 15 ml ethanol, and 0.78 g (6.5 mmol) magnesium sulfate are added. The reaction mixture is stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane as eluent.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12][CH2:13]2)[CH2:9]1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH:10]12[CH2:16][CH:14]([CH2:15][NH:8][CH2:9]1)[CH2:13][S:12][CH2:11]2
Reactant: c1ccc(CN2CC3CSCC(C3)C2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: C1NCC2CSCC1C2
Yield: 57.9 %

Procedure:
A 50-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a heating mantle, a standard condenser with a N2 inlet and two glass stoppers. In one portion, anhydrous HCO2NH4 (1.11 g, 17.1 mmol) was added under N2 to a mixture of the amine (27, 0.90 g, 3.86 mmol) and 10% Pd/C (0.90 g) in anhydrous CH3OH (25 mL). With stirring, the mixture was brought to reflux for 30 min, filtered through a Celite pad on a fritted funnel (which was washed thoroughly with CH2Cl2), and then concentrated to give a gummy oil with suspended solid. This material was again dissolved in CH2Cl2 (~15 mL), and the suspension was filtered to remove any unreacted ammonium formate. The filtrate was then concentrated to near saturation and placed in a diffusion chamber of ether overnight. Crude amine (28) became an oil; however, the mother liquor, containing predominantly starting material, could be decanted. Chromatography of the oil employed a gradient elution of CH3OH/CH2Cl2 (300 mL of 10% CH3OH/CH2Cl2, 50 mL of 20% CH3OH/CH2Cl2, 100 mL of 50% CH3OH/CH2Cl2, and 100 mL of CH3OH) on silica gel (35 g, 1.5 cm×62 cm) and afforded 0.32 g (56.9%) of amine (28) (Rf =0.11, 10% CH3OH/CH2Cl2) as a light, gummy solid which was used without further purification. 1H NMR (DCCl3) δ1.84, 2.04 [two bd, 2H, H(9)], 2.31 [bs, 2H(1,5)], 2.80 [bd, 2H, H(2,4)ax, J=12.3 Hz], 3.20 [bd, 2H, H(2,4)eq, J=13.7 Hz], 3.45 [m, 2H, H(6,8)ax ], 3.73 [bd, 2H, H(6,8)eq, J=13.2 Hz], 7.59 (bs, 1H, N--H); 13C NMR (DCCl3) ppm 24.88 [d, C(1,5)], 29.79 [t, C(9)], 32.17 [t, C(2,4)], 47.8 [t, C(6,8)].
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:6]1[C:7]2[O:8][CH2:26][CH2:25][NH:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: BrCCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2NCCO3)c1=O
Yield: 6.5 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-primidinedione (0.4 g), 1,2-dibromoethane (0.26 g) and potassium carbonate (0.312 g) in acetone (30 ml) was heated at reflux for 6 hours. The insoluble precipitate was removed through Celite and the filtrate was concentrated to an oil. The oily substance was purified by column chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give the title compounds (0.028 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>C1COCC1>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 4-(chlorosulfonyl)-benzoic acid (0.5 g, 2.2 mmol) in THF (20 ml) was added morpholine (0.434 ml, 5 mmol) dropwise over 5 min, and this mixture stirred at r.t.for 1 h. Water (50 ml) was then addedand the mixture agitated, the phases were separated and the aqueous phase extracted with EtOAc (2×50 ml). The combined organic phases were washed with satd. aq. NaCl solution, dried, filtered and evaporated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with a CHCl3/(acetone+10% HCO2H) (9:1), the product fractions were pooled, evaporated and dried in vacuo (0.05 mmHg, 50° C.) to afford the title compound as a beige solid (270 mg, 20% yield), MS: m/e=271 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH:7]2[CH2:9][O:8]2)=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:9]([OH:8])[CH2:12][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(OC2CO2)cc1
Agent: [K+]
Solvent: CC#N
Product: OC(COc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(4-chlorophenoxy)oxirane (18.4g), potassium carbonate (13.8g) and 1,2,4 triazole (13.8g) in acetonitrile (130ml) was stirred at room temperature for 48 h. The acetonitrile was removed by concentration under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried and evaporated to dryness under reduced pressure. The residual yellow oil was purified by silica column chromatography, using 5% by volume methanol in chloroform as eluent, to give 1-(4-chlorophenoxy)-3-(1,2,4--triazol-1-yl)propan-2 ol) as a white solid, which was used without further purification.