Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]2.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5]3)=[CH:20][CH:21]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)c1cc2cc(Br)ccc2nc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)c1cc2cc(-c3ccc(C)cc3)ccc2nc1C
Temperature: 25 °C
Yield: 100.6 %

Procedure:
Under argon atmosphere, a solution of methyl 6-bromo-2-methylquinoline-3-carboxylate (1.22 g), 4-methylphenyl borate (0.65 g) and potassium carbonate (1.18 g) in toluene-ethanol-water (40-4-4 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.15 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:1) to give methyl 6-(4-methylphenyl)-2-methylquinoline-3-carboxylate (1.27 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[CH:10]=[N:9]2)=[C:5]([CH3:19])[O:4][N:3]=1.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:15]1[CH2:16][CH2:17][N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:19])[CH:12]=2)[C:14]1=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2CCNC2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCN(Cc3ccccc3)C2=O)cn1
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (example 10-88a) (50 mg, 0.19 mmol) and 60% sodium hydride (8 mg, 0.21 mmol) in DMF (3 mL) were stirred at room temperature for 15 minutes then cooled to 0° C. Benzyl bromide (33 mg, 0.19 mmol) was added to the mixture and allowed to warm up at room temperature for 2 hours. The reaction was quenched with methanol and concentrated on the rotovap. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (21 mg, 31%) as a white solid. MS M+H calculated 352.17; found 352.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.71 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].CO.C[O-].[Na+]>>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(CBr)OC
Reactant: COc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(SCC(OC)OC)cc1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-methoxybenzenethiol (3.07 ml, 25.0 mmol) and 2-bromo-1,1-dimethoxyethane (3.25 ml, 27.5 mmol) were added to a sodium methoxide methanol solution (0.5 M, 80.0 ml, 40.0 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes, and then heated to reflux for five hours. The reaction mixture was concentrated under reduced pressure and cold water was added. The resulting mixture was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (5.30 g, 93%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:17]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCCC(CCCc2ccccc2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCCc2ccccc2)CCCCC1

Procedure:
The product of Example 71 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12].C[O-].[Na+].Cl>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:2][C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Br)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(Br)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of 2-acetyl-5-bromothiophene (25 g, 122 mmol) and dimethyl oxalate (23 g, 194 mmol) in dry methanol (800 mL) was added a solution of NaOMe in MeOH (25%, 51 mL, 224 mmol) at ambient temperature. The reaction mixture was stirred at 20° C. for 4 h and then acidified to pH 1 with 6 N aqueous HCl. The yellow solid was collected by filtration, washed with H2O, and dried under high vacuum to afford 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (31.3 g, 88%). 1H-NMR (DMSO-d6): δ 8.14 (s, 1H), 7.46 (d, 1H), 7.05 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (5 mL) was added slowly to a solution of N′-(2-chloro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (1.26 g, 3.0 mmol) in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 19 h. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with water (2×50 mL) and brine (50 mL), dried (sodium sulfate), filtered, and evaporated to give a light yellow solid. The solid was stored in the freezer over the weekend, and then triturated with 50% hexanes/diethyl ether (10 mL) and the mixture sonicated. The solid was collected by filtration, washed with ether, an air-dried to give (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (790 mg, 86%) as an off-white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:19]=2)=[CH:16][C:15]([CH:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:52][C:53]1[CH:54]=[C:55]([NH2:61])[CH:56]=[N:57][C:58]=1[O:59][CH3:60].[NH4+].[Cl-]>C1COCC1>[F:52][C:53]1[CH:54]=[C:55]([NH:61][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH:19]=3)=[CH:16][C:15]([CH:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH3:45])=[CH:14][N:13]=2)[CH:56]=[N:57][C:58]=1[O:59][CH3:60]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(C(C)N4CCOCC4)cnc3F)nc(C)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(C(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in hexane, 0.592 mL, 0.592 mmol) was added to a solution of 6-(2-fluoro-5-(1-(4-morpholinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.110 g, 0.197 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.042 g, 0.296 mmol, Anichem, North Brunswick, N.J.) in THF (1.5 mL) at −10° C. After 1 h, more lithium bis(trimethylsilyl)amide (1.0 M solution in hexane, 0.592 mL, 0.592 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.042 g, 0.296 mmol) were added. After a further 1 h, saturated NH4Cl (aq.) was added. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane to give 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-(1-(4-morpholinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.104 g, 0.153 mmol, 78% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H); 8.26 (dd, J=12.72, 2.35 Hz, 1H); 8.11 (d, J=2.15 Hz, 1H); 8.02 (d, J=2.35 Hz, 1H); 7.56-7.61 (m, 1H); 7.18 (dd, J=8.61, 0.98 Hz, 4H); 6.82-6.91 (m, 4H); 6.53 (s, 1H); 4.80 (br s, 4H); 4.01 (s, 3H); 3.79 (s, 6H); 3.62 (t, J=4.69 Hz, 4H); 3.30 (q, J=6.65 Hz, 1H); 2.66 (s, 3H); 2.39-2.47 (m, 2H); 2.30-2.37 (m, 2H); 1.31 (d, J=6.85 Hz, 3H). m/z (ESI, +ve) 680.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH:13]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH:13]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
A solution of KOH (0.067 g, 1.03 mmol) in ethanol (3 mL) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid diethyl ester (0.44g, 0.96 mmol) in ethanol (3 mL) and methylene chloride (2 mL) at 0° C. The mixture was stirred for 48 h at room temperature. The mixture was concentrated under reduced pressure and ethyl acetate and 0.5 M HCl were added to the residue. The organic layer was washed with brine and dried. Filtration and evaporation in vacuo gave 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-malonic acid monoethyl ester (0.37, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25](Br)=[O:26]>C(#N)C.O>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH2:24][C:25](=[O:26])[NH:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.060 g, 0.214 mmol) in acetonitrile (3.88 mL) and water (1.21 mL) was treated with potassium carbonate (0.118 g, 0.857 mmol), followed by the addition of bromoacetyl bromide (0.0279 mL, 0.321 mmol), and the resultant reaction mixture was stirred at RT for 30 min, after which time additional bromoacetyl bromide (0.0186 mL, 0.214 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h, then warmed to 75° C. and stirred at that temperature for 30 min. The reaction mixture was concentrated and diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo the yield a crude product. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (59.5 mg, 87%) as a white solid. LCMS calculated for C14H11BrNO3 (M+H)+: m/z=320.0, 322.0. found: 319.9, 321.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18](N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])=[O:4].P([O-])([O-])([O-])=[O:34].C([BH3-])#N.[Na+]>>[CH2:12]([CH2:13][N:14]=[C:15]([NH2:16])[NH2:17])[CH2:11][CH:10]([NH:9][C:7]([CH2:6][NH:5][C:3]([CH2:2][NH2:1])=[O:4])=[O:8])[C:18]([OH:19])=[O:34]
Reactant: N=C(N)NCCC[C@H](NC(=O)CNC(=O)CN)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=P([O-])([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: NCC(=O)NCC(=O)NC(CCCN=C(N)N)C(=O)O
Temperature: 25 °C

Procedure:
Gly-Gly-Arg-Tyr*, prepared by the method of Section 9.2, was coupled to normal human IgG or LL 1151 or NS 4.1 antibody oxidized by the method of Section 12.1 infra, by incubating the antibody at a 300-fold molar excess of Gly-Gly-Arg-Tyr* in the 0.1 M phosphate buffer, pH 6.0. To reduce the imine, sodium cyanoborohydride (NaCNBH3) was added to a final concentration of 10 mM, and the reaction mixture was maintained at room temperature for 2 hours. Unreacted Gly-Gly-Arg-Tyr* was separated from theantibody conjugate by gel filtration. The sample was passed through a 5 ml Sephadex® G-50 column (Pharmacia Fine Chemicals, Piscataway, N.J.), which had been pre-coated with 1 ml of 10% BSA and run in PBS, pH 7.4. Theprotein fractions were pooled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 70%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH3:3].[H-].[Na+].Cl[CH2:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:32]([F:43])[CH:31]=2)=[CH:26][CH:25]=1.Cl>CN(C)C=O>[F:43][C:32]1[CH:31]=[C:30]([O:29][CH2:28][C:27]2[CH:44]=[CH:45][C:24]([CH2:23][N:4]([CH2:1][CH2:2][CH3:3])[C:5]3[S:6][CH:7]=[C:8]([C:10]4[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=4)[N:9]=3)=[CH:25][CH:26]=2)[CH:35]=[CH:34][C:33]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Reactant: CCCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-propyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (700 mg, 2.44 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (100 mg, in oil, 2.5 mmol) at room temperature and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (700 mg, 2.0 mmol) was added and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by preparative HPLC. The obtained fraction was concentrated, neutralized with 10% aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was filtered with a Presep Dehydration tube (Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(Cc3cnc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 46.5 %

Procedure:
A solution of 0.95 g (0.00494 mol) of 1-(4-methoxy-phenyl)-piperazine in 30 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.00164 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol (1:1 ), digested in diethyl ether and subsequently filtered off under suction. 0.24 g (47%) of 5-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[OH2:12].[ClH:13]>Cl.Cl.CNNC.CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:12])[CH2:1]1.[ClH:13]
Reactant: O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: CNNC
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
A mixture of 83 g of acetonine, 167 g of acetone, 17 g of water and 4.2 g of N,N'-dimethylhydrazine dihydrochloride was reacted at 50°-55° C. for 15 hours and then stripped under reduced pressure, followed by addition of acetone to the light-red residue and hydrogen chloride gas to pH=7. The crystals precipitated were filtered, washed with acetone, and dried to give 72.2 g of triacetonamine hydrochloride.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([O:15]C)=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncn(-c2ccc(I)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ncn(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Methyl 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylate (830 mg, 2.5 mmol) was dissolved in MeOH (20 mL) and THF (10 mL). 1 M NaOH (2.5 mL, 2.5 mmol) was added and the mixture stirred at room temperature for 2 h. Additional 1 M NaOH was added (2.5 mL, 2.5 mmol) and the reaction was heated to 50° C. for 30 minutes. After cooling to room temperature, the pH was adjusted to 4 by the addition of 6 M HCl, MeOH and THF were removed under reduced pressure and the resulting white precipitate was collected by filtration and dried in vacuo to obtain 680 mg (86% yield) of 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1ccccc1C=O
Yield: 67.2 %

Procedure:
35.5 g (0.125 mol) of methyl alpha-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 500 ml of CCl4. 43.4 g (0.321 mol) of methylmorpholine N-oxide monohydrate are added, and the mixture is refluxed for 20 hours. The solid is filtered of f and the CCl4 phase is washed with water, with 2 N hydrochloric acid and again with water, dried and concentrated. 18.5 g (67%) of product are obtained as a reddish brown oil.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]([F:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[F:30][C:21]([F:20])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCC(F)(F)c1ccccn1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(F)(F)c2ccccn2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2,2-difluoro-2-pyridin-2-yl-ethylamine (example 59d) and DIEA to give 2-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. The product was dissolved in methanol (5 mL). 2 M HCl in ether (2 mL) was added. After adding ether, the solid was collected by filtration, washed with ether and dried to give 2-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one hydrochloride. LC-MS m/e 397 (MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][N:15]4[C:14](=[O:21])[CH2:13][CH2:12]3)[CH:18]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:40])[C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:27]=[N:28][CH:29]=1>>[O:21]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]13)[CH:18]=[C:9]([C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32]([C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:40])[CH:27]=[N:28][CH:29]=1)[CH:10]=2
Reactant: O=C(NCc1cncc(Br)c1)c1ncccc1Cl
Reactant: CC1(C)OB(c2cc3c4c(c2)CCN4C(=O)CC3)OC1(C)C
Product: O=C(NCc1cncc(-c2cc3c4c(c2)CCN4C(=O)CC3)c1)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 45, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one has been coupled to N-((5-bromopyridin-3-yl)methyl)-3-chloropicolinamide (intermediate A-56) to give the title compound as off-white solid. MS: 419.3 (M+H+).