Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:2]1[C:39]2[C:38](=[CH:37][CH:36]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:40]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and aniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (d, 1H, J=5.2 Hz), 6.76 (d, 1H, J=7.3 Hz), 7.00-7.08 (m, 4H), 7.13-7.31 (m, 5H), 7.40-7.63 (m, 6H), 7.88 (d, 1H, J=8.2 Hz), 7.98 (s, 1H), 8.02 (s, 1H), 8.25 (d, 1H, J=5.2 Hz), 8.52 (d, 1H, J=8.3 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.41 (s, 1H), 10.97 (s, 1H); ESIMS (M+H)+=610.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18]I>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:18])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(-c2ccc(Cl)cc2)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, room temperature solution of 5-(4-chlorophenyl) -2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (6.00 g, 2.68×10-2 mole) and 1 molar aqueous NaOH (30.0 ml, 3.00×10-2 mole) was added a solution of methyl iodide (2.5 ml, 4.0×10-2 mole) and ethanol (10 ml). After stirring overnight at room temperature, the reaction mixture was transferred to a separatory funnel where it was extracted three times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which slowly solidified. Chromatography and crystallization from cyclohexane gave small colorless needles: 3.4 g (53%), Mp 73°-75° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[CH:42][C:41]=1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[C:45]([C:2]2[C:10]3[C:9]([NH:11][CH:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:44][CH:43]=[CH:42][C:41]=1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2O)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc(C(C)Nc3ncnc4c3c(-c3cccc(NS(C)(=O)=O)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 17.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (61 mg, 0.10 mmol) was treated with N-(2-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (200 mg, 0.26 mmol, prepared from N-(3-bromo-2-hydroxyphenyl)-methanesulfonamide and bis(pinacolato)diboron according to Preparation 19b), sodium carbonate (27 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (25 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 12 mg (15% yield) of the title compound. Purity 90%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:40]=2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([CH3:48])(=[O:46])=[O:47])[CH:40]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH2Cl2 (5 ml) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by prep-TLC (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:16]([O:15][C:13]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of ethyl 2-hydroxyimino-2-cyanoacetate (8.5 g). water (30 ml) and acetone (4 ml) is stirred at 0°C, and benzyl chloroformate (9.4 g) is added thereto. The resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred for 3 hours and then filtered. The residue is washed with water and dried to give ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate (12.2 g) as crystals. M.P. 101° to 102.5°C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Cl-].[NH4+]>CS(C)=O>[C:1]([O:4][CH2:7][C:8]1[CH:17]=[CH:16][C:15]([CH2:18][O:4][C:1](=[O:3])[CH3:2])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(CBr)ccc1CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(COC(C)=O)ccc1COC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Sodium acetate (10.4 g, 126.8 mmol) was added to a solution of methyl 2,5-bis(bromomethyl)benzoate (described in J. Am. Chem. Soc., 121, 1192 (1999); 12.65 g, 39.3 mmol) in dimethyl sulfoxide (80 ml), and the mixture was stirred at room temperature for 1 hour. After a saturated aqueous solution of ammonium chloride (150 ml) was added thereto, the product was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure. The obtained oily residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:5˜1:2) to afford the title compound (7.72 g, 70% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)=S)=[CH:4][CH:3]=1.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: C[C@H]1CN(C(=S)c2ccccc2F)c2cc(Br)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(c2noc3ccccc23)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charged with a solution of (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanethione (0.021 g, 0.057 mmol) in dimethylsulfoxide (0.5 mL) and hydroxylamine (50% in water, 0.035 mL, 0.575 mmol). The vial was capped, and the solution heated to 100° C. for 90 min. Heating was increased to 150° C. for 3 h, and then the solution was stirred at rt overnight. Additional hydroxylamine (50% in water, 0.035 mL, 0.575 mmol) was added and heating resumed at 150° C. for 5 h. Potassium carbonate (ca. 10-15 mg) was added and heating resumed at 100° C. for 5 h. The mixture was diluted with water (1 mL) and extracted with dichloromethane. The dichloromethane extract was washed with 5% aqueous sodium chloride solution (1 mL) and concentrated. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 4:1 hexanes-ethyl acetate). The major band was isolated to afford (S)-3-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]isoxazole (0.010 g, 51%). MS (ESI, pos. ion) m/z 344, 346 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([O:40][C:41](=[O:45])[CH:42](Br)[F:43])[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:45])[C@@H:42]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][CH:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1)[F:43])[CH3:39]
Reactant: CCOC(=O)C(F)Br
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](F)Oc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Reaction time: 8 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (202 mg, 0.46 mmol) was dissolved in DMF (2 mL) at room temperature. Cs2CO3 (760 mg, 2.33 mmol) was added followed by bromo-fluoro-acetic acid ethyl ester (0.070 mL, 0.583 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (2/1 hexanes/ethyl acetate) to afford the product.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([N:36]1[CH2:37][CH2:38][N:33]([C:30]2[CH:31]=[CH:32][C:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in dichloromethane (2 mL) was added pyridine (23 μL, 0.28 mmol) followed by acetyl chloride (17 μL, 0.24 mmol). The mixture was stirred (rt) overnight. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (20 mL), brine, and was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 28 mg (26%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.97 (d, 2 H), 7.94 (s, 1 H), 7.81 (d, 1 H), 7.66-7.64 (m, 1 H), 7.36-7.26 (m, 5 H), 7.19 (dd, 1 H), 7.06-7.01 (m, 3 H), 5.66 (s, 2. H), 3.62-3.55 (m, 4 H), 3.26-3.21 (m, 2 H), 3.20-3.14 (m, 2 H), 2.05 (s, 3 H); ES-MS m/z 543.33 [M+H]+, HPLC RT (min) 2.65.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([N:29]=[C:30]=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CCCCCC.CN(C)C=O>[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([NH:29][C:30]([NH:1][C:2]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C=C(NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 3.55 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of n-hexane is added dropwise with stirring and at 0°-3° C. during 15 minutes to 0.85 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide, and the mixture is stirred for a further 30 minutes. Then a solution of 5.0 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate in 100 ml of n-hexane is added dropwise during 5 minutes with stirring and cooling. The temperature of the reaction mixture rises to 10° C., and the mixture is thereafter stirred for one hour at room temperature. The isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-benzoate which is formed as an intermediate is not isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([O:17]COC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(OC(C)(C)C)OC(C)(C)C>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:15])[F:16])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(F)F
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(F)F)[C@H](O)C1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of (±)-trans-4-difluoromethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.52 mmol, 0.45 g) in DCM (2 mL) was added 4 N HCl in dioxane (3 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure. The crude amine hydrochloride was dissolved in DCM (3 mL), and saturated NaHCO3 (3 mL). To this suspension was added di-tert-butyl carbonate (4.12 mmol, 0.90 g) and the reaction was stirred for 30 minutes at room temperature. The layers were separated and the DCM layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified on a 12 g SiO2 cartridge using a 0-30% ethyl acetate/hexanes gradient to give (±)-trans-4-difluoromethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.14 g).
Reaction SMILES: [C:1]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: O=C1CCCCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)C(=CNC1=CCCCCCCCC1)C(=O)OCC

Procedure:
A mixture of 25.0 g of cyclodecanone, 60.7 g of diethyl aminomethylenemalonate, 1.54 g of p-toluenesulfonic acid monohydrate in 500 ml xylene is refluxed 2 weeks under argon, collecting the distillate in a Dean-Stark trap. The solution is then decanted and solvent is removed. The residual oil is triturated twice with hexane and the combined hexane extract is concentrated to yield an oil which is flash chromatographed on 600 g of silica gel using 99:1 methylene chloride ethyl acetate as eluent. A forerun containing cyclodecanone is discarded and the fractions containing the product are combined and concentrated to dryness to give diethyl N-(1-cyclodecenyl)-aminomethylenemalonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[C:12]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH2:19]
Reactant: CSc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(SC)c(Cl)c1Cl)C1CCCC1

Procedure:
2',3'-dichloro-4'-methylthio-2-cyclopentylacrylophenone is prepared following substantially the same procedure described in Example 3, Step B, using the following substances: 2',3'-dichloro-4'-methylthio-2-cyclopentylacetophenone (54.5 g., 0.18 mole), paraformaldehyde (21.6 g., 0.72 mole), concentrated sulfuric acid (9.65 g.) and dioxane (450 ml.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCBr

Procedure:
A solution of 4-phenoxy-2-propylphenol (25.0 g, 0.11 mol), 1,4-dibromobutane ( 70.99 g, 0.33 mol) and cesium carbonate (39.28 g, 0.12 mol) in dry DMF ( 250 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (1:1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[O:19][CH3:22]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2c(=O)n1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(OC)c2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
A suspension of ethyl 6-chloro-4-hydroxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.41 g, 5 mmol), methyl iodide (0.47 ml, 7.5 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.11 g, 75.5%) as crystals.
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[Na].C(OC)(=O)[CH2:14][C:15]([CH3:17])=[O:16]>CO>[CH2:2]([CH:1]1[CH:6]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:17][C:15](=[O:16])[CH2:14]1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CC=C1CCCC1=O
Agent: [Na]
Solvent: CO
Product: CC(C)CC1CC(=O)C=C2CCCC21
Yield: 52 %

Procedure:
The procedure of Example 1 is repeated with 85 g (0.56 mol) of isopentylidene cyclopentanone, 1.61 g (0.07 g-atom) of sodium, 76.5 g (0.66 mol) of methyl acetoacetate and 300 ml of methanol. Upon distillation there are obtained 56 g (bp 97°-100° C. at 0.5 mm) of 5-isobutylbicyclo [4.3.0]-non-1-en-3-one having the structure: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1>O1CCOCC1.C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cn1cncc1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
Manganese (IV) oxide (1.17 g, 13.4 mmol) was added to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (1.03 g, 2.68 mmol, Intermediate 2: step a) in 1,4-dioxane (15 mL). The resulting black suspension was fitted with a reflux condenser and was refluxed for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and was filtered through Celite®, washing with DCM. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 1-3% MeOH-DCM, first column; 10-25% acetone-EtOAc, second column) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]#[CH:24])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[NH2:16])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 65 °C
Yield: 96.4 %

Procedure:
A multinecked flask as described in Example 1 was charged with 50.0 g (0.28 mol) of p-bromofluorobenzene, 200 ml of dried, degassed triethylamine, 35.0 g (0.30 mol) of 3-aminophenylacetylene, 0.23 g (0.29 mmol) of bis(triphenyl phosphine) palladium II chloride, 1.03 g (3.92 mmol) of triphenylphosphine, and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 48 hours at which point gas chromatography showed the reaction to be complete. The mixture was cooled to room temperature and diluted with 200 ml of toluene. The toluene/triethylamine solution was decanted and concentrated on the rotary evaporator to give 75 g (0.27 mol, 96% yield) of the product as a bright yellow solid.