Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:16](=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][C:20]=4[Cl:21])[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1.[CH2:25]([Mg]Br)[CH3:26]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([OH:23])[CH2:25][CH3:26])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
To a solution of 1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.352 mmol) in tetrahydrofuran (12.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 1.18 mL, 3.528 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (925.8 mg, 2.034 mmol, 87%).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>>[CH3:18][C:12]([O:11][C:10]1[CH:20]=[CH:21][C:7]([CH2:6][CH2:5][N:4]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[C:2]2[S:3][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[N:1]=2)=[CH:8][CH:9]=1)([CH3:19])[C:13]([OH:15])=[O:14]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(C(F)(F)F)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-bromo-1,1,1-trifluoroacetone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10][C@H:11]([CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10][C@H:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCc1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 316 mg (0.59 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{(E)-3-[4-(3-hydroxypropyl)phenyl]prop-2-en-1-yl}-L-glutamate in 29 mL of methanol, palladium (10% on charcoal, 126 mg) was added and the suspension was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered over celite, and the solvent was evaporated. The remaining material was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]1=[O:14].C1C(=O)N([Br:25])C(=O)C1>ClCCl>[Br:25][C:8]1[C:7](=[O:14])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)[C:11]([CH3:12])=[CH:10][C:9]=1[OH:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Solvent: ClCCl
Product: Cc1cc(O)c(Br)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A mixture of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.8 g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL) was stirred at room temperature, under argon atmosphere. After 1.5 h, the reaction mixture was diluted with dichloromethane (15.0 mL), cooled and filtered the solids. The residue was washed with dichloromethane and dried in vacuo to give 0.93 g of the title compound as a white powder: 1H-NMR (CD3OD/400 MHz) δ 7.33 (m, 1H), 7.2-6.8 (m, 3H), 6.07 (s, 1H), 5.34 (s, 2H), 2.26 (s, 3H); ESHRMS m/z 312.0016 (M+H C13H12NO2BrF requires 312.0035).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6]Br.[C:13]1([N:19]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:20](=O)[CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6][N:27]1[CH2:28][CH2:29][CH:24]([N:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][CH3:22])[CH2:25][CH2:26]1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: Cc1cccc(C)c1OCCBr
Product: CCCN(c1ccccc1)C1CCN(CCOc2c(C)cccc2C)CC1
Yield: 79.7 %

Procedure:
Using the procedure described in Example I and starting from 12.7 g (2,6-dimethylphenoxyethyl) bromide and 12.8 g 4-(N'-phenyl-N'-propionylamino)-piperidine, 16.1 g of the title product are obtained melting at 82° after recrystallization from hexane. Mixing the compound with 4-(N'-phenyl-N'-propionylamino)-piperidine depresses the melting point.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[C:24]1([C@H:34]([N:36]([CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH:46]2[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[C:39]([O:38][C:37]([N:36]([CH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:11]2[C:10]([F:13])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[F:1])[CH2:47][CH:46]1[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C@@H:34]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:35])=[O:43])([CH3:40])([CH3:41])[CH3:42]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(F)c(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 116 mg of methyl 3,4,5-trifluorobenzoate, 113 mg of potassium carbonate, and 2.0 mL of DMSO was added 181 mg of a solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate in 3.0 mL of THF at room temperature. It was stirred at 100° C. overnight, and then cooled. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 248 mg of methyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoate as a crude product. FAB+: 615
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(F)c1
Yield: 100 %

Procedure:
Reaction of 3,4-difluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 85:15 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12-7.26 (2H, m, aromatics), 7.44-7.52 (1H, m, aromatic), 7.97 (1H, s, CH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]2[CH:9]=[C:10]([Br:16])[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:16][C:10]1[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=[C:8]([C:4]2[C:3]([CH3:17])=[C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: Cc1c(N)cccc1-c1cc(Br)c(=O)n(C)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Br)c(=O)n(C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A 25-mL round bottomed flask was cooled to 0° C. with an ice/water bath and charged with 5-(3-amino-2-methylphenyl)-3-bromo-1-methylpyridin-2-one (12) (0.71 g, 2.20 mmol), triethylamine (489 mg, 4.84 mmol), methylene chloride (10 mL) and 4-tert-butyl-benzoyl chloride (0.48 g, 2.42 mmol) and the reaction mixture stirred at room temperature for 18 h. After this time the reaction was partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL), brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was subjected to flash chromatography to afford 0.75 g (75%) of N-(3-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-tert-butylbenzamide (13) as a white solid: mp 149-151° C.; 1H NMR (300 MHz, CDCl3) 7.87 (dd, 1H, J=2.4 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.71 (br s, 1H), 7.54 (d, 2H, J=8.7 Hz), 7.30 (t, 1H, J=7.8 Hz), 7.27 (d, 1H, J=1.8 Hz), 3.75 (br s, 2H), 7.05 (dd, 1H, J=7.8, 1.5 Hz), 3.67 (s, 3H), 2.24 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 453 (M+H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH:13][CH2:14]C(CO)O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[C:14]([O:11][C:1](=[O:12])[C:2]=2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: [Ti+4]
Agent: CC(=O)[O-]
Agent: CCCC[O-]
Product: O=C(O)c1ccc2c(c1)C(=O)OC2=O

Procedure:
380 g of a terephthalic acid polyester of 1.0 mol of terephthalic acid, 0.38 mol of glycerol and 0.72 mol of glycol containing approximately 6.0% by weight of hydroxyl groups and catalytic quantities of lead acetate and butyl titanate are then introduced one after another and stirred homogeneously into the reaction mixture. After condensation for one hour at 170° C., 2 hours at 200° C. and 2 hours at 220° C.,
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:13][N:12]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10]
Reactant: NO
Reactant: N#CCC1CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCC1CCCCC1=NO

Procedure:
The product of Example 149 is reacted with hydroxylamine hydrochloride and sodium acetate in ethanol/water by the method of Example 1 to generate the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1>>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1

Procedure:
5-Chloro-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-N*2*-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-pyrimidine-2,4-diamine was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 322. Product isolated as a pale yellow solid (120 mg, 46%). m.p.=151-152° C.; LCMS (m/e) 519 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H, J=8.7 Hz), 8.02 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.23-7.16 (m, 1H), 7.04 (d, 1H, J=8.0 Hz), 6.89 (s, 1H), 6.56 (s, 1H), 6.55-6.49 (m, 1H), 3.94 (s, 3H), 3.91 (m, 4H), 3.45 (s, 2H), 3.21-3.15 (m, 4H), 2.98-2.89 (m, 4H), 2.82-2.70 (m, 4H), 2.25-2.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Cl:11][C:12]1[C:13]([F:20])=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Yield: 92.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chlorobenzyl cyanide (8.9 g, 59 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood) (10 g, 63 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (300 mL) at 40° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile as a white powder (16 g, 92%).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]>ClCCCl>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:1])=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1Cl
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)cc2)c(F)c(N)c1Cl
Temperature: 23 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
Bromine (47 μL, 0.92 mmol, 1.2 equiv) was added to a stirred solution of methyl 4-amino-3-chloro-5-fluoro-6-(4-(trimethylsilyl)phenyl)picolinate (270 mg, 0.77 mmol, 1.0 equiv) in 1,2-dichloroethane (5.1 mL) at 23° C. The resulting dark orange solution was stirred at 23° C. for 24 h. The reaction mixture was quenched with a saturated solution of sodium thiosulfate (5 mL) and then adjusted to pH 10 using 2 M sodium hydroxide. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the title compound as a tan powder (160 mg, 57%).
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2>CC(N(C)C)=O.C(OCC)(=O)C.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of Zn (990 mg, 15.1 mmol) in DMA (1 mL) A 7:5 v/v mixture of TMSCl/1,2-dibromoethane (0.12 mL) was added drop-wise at a rate to maintain the temperature below 65° C., then the mixture was stirred for an additional 10 min. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (3.17 g, 10.2 mmol) in DMA (2 mL) was added drop-wise and stirred at 40-45° C. for 30 min. The resulting mixture was added to a mixture of 5-bromo-1H-indazole (1.00 g, 5.08 mmol), CuI (80 mg, 0.42 mmol) and Pd(dppf)Cl2 (260 mg, 0.36 mmol) in DMA (1 mL) in a 50-mL round-bottom flask under a nitrogen atmosphere. The resulting mixture was stirred overnight at 85° C., then cooled and diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as the eluent to yield the title compound as a yellow solid (200 mg, 12%).
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[C:14]=2I)=[O:12])=[CH:6][C:5]=1[C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34]>[Cu]I.CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[C:14]=2[C:33]([F:35])([F:34])[F:32])=[O:12])=[CH:6][C:5]=1[C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1nc(OC(F)F)c(I)c1C(=O)Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(OC(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Temperature: 80 °C
Yield: 13.5 %

Procedure:
36.2 mg (0.19 mmol) of copper(I) iodide and 8.8 mg (0.15 mmol) of potassium fluoride are initially introduced in a heat-dried vial under argon, and 4 ml of N,N-dimethylformamide and 70.0 mg (0.12 mmol) of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(difluoromethoxy)-4-iodo-1-methyl-1H-pyrazole-5-carboxamide and 36.0 mg (254 μmol) of trifluoromethyltrimethylsilane are added. The reaction mixture is degassed in the ultrasound, flushed with argon and the closed vial is heated at 80° C. for two hours. The reaction solution is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. Chromatographic purification on silica gel gives 8.00 mg of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(difluoromethoxy)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (13%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:19]1[C:24]([O:25][CH2:26][O:27][CH3:28])=[CH:23][CH:22]=[CH:21][C:20]=1[O:29][CH2:30][O:31][CH3:32].CCOCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:32][O:31][CH2:30][O:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][O:27][CH3:28])[C:19]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COCOc1cccc(OCOC)c1I
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCOc1cccc(OCOC)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
Anhydrous toluene (2.0 mL) was added to a flask charged with Pd2(dba)3 (56.3 mg, 0.062 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (50.5 mg, 0.12 mmol), phenylboronic acid (281 mg, 2.31 mmol), and potassium phosphate (979 mg, 4.61 mmol) at room temperature. After 15 minutes, a solution of 15 (500 mg, 1.54 mmol) in anhydrous toluene (1.0 mL) was added and the resulting solution was heated to reflux for 12 hours. Upon cooling to room temperature, ether was added, the solution was filtered through SiO2 and concentrated to give 16 as a colorless amorphous solid (418 mg, 99%): 1H NMR (CDCl3, 500 MHz) δ 7.35-7.28 (m, 2H), 7.28-7.25 (m, 2H), 7.18-7.15 (m, 2H), 6.83 (d, J=8.3 Hz, 2H), 4.96 (s, 4H), 3.24 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 155.3, 155.0, 134.3, 130.8, 129.5, 128.7, 128.0, 127.6, 126.8, 122.6, 109.4 (2C), 94.9 (2C), 56.0 (2C); IR (film) νmax 2955, 2928, 2901, 2359, 2341, 1587, 1466, 1439, 1400, 1244, 1153, 1099, 1080, 1041, 922, 764, 733, 700 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C16H18O4, 297.1103. found, 297.1052.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20]>C1C=CC=CC=1>[CH2:17]([CH:16]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:7][O:8]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC=O
Reactant: CC(CO)(CO)OCc1ccccc1F
Solvent: c1ccccc1
Product: CCCCC1OCC(C)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and valeraldehyde were reacted, using benzene as solvent, to give, after separation by column chromatography, r-2-butyl-t-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 105°/0.05 mm, nD25 1.4840; and r-2-butyl-c-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, b.p. 105°/0.025 mm, nD25 1.4865. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=1.[BrH:12]>>[BrH:12].[NH2:11][CH2:10][CH2:9][C:7]1[NH:8][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(CCN)n1
Agent: Br
Product: NCCc1cccc(=O)[nH]1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
To 700 mg of 2-(6-methoxypyridin-2-yl)ethylamine was added 10 ml of a 47% aqueous hydrogen bromide solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent, the residue was washed with diethyl ether to obtain 1.21 g of a 6-(2-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][C:13]1[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:12][C:13]1[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc(O)c1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 8.3 mg of potassium carbonate were added to 15 mg of 2-(3-acetoxybenzamido)-4-phenylbenzoic acid at room temperature sequentially and stirred at the same temperature for 2 hours. 10% citric acid aqueous solution was added to the reaction mixture and a solid substance was separated by filtration to obtain 12 mg of 2-(3-hydroxybenzamido)-4-phenylbenzoic acid as while solid.