Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(C(C)C)C(C)C>>[CH2:32]([S:34]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:10]1)(=[O:36])=[O:35])[CH3:33]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCCC(Nc2nc(C)ccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(1-Ethanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine, and ethanesulfonyl chloride, using 3 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:14])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 gms of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid and 5.6 gms of triethyl amine was added to 25 ml of toluene. 5.1 gms of Pivollyl chloride was added and stirred the reaction mass at room temperature for about 2 hours. 4 ml of Morpholine in 25 ml of toluene was added to the reaction mass at 0° C. Stirred the reaction mass for about 30 minutes at 0-5° C. and 20 ml of water was added. To the reaction mass 30 ml of brine solution was added and organic layer was separated. Dried the separated organic layer over sodium sulfate. Distill off the solvent completely under reduced pressure at 50-55° C. The resulted oily mass was dissolved in 12 ml of toluene and 60 ml of hexane. Cooled the reaction mass and 12 ml of toluene was added. Stirred the reaction mass for about 1-2 hours at 0-5° C., filtered, washed with 5 ml of hexane and dried at 40-45° C. to get 10 gms of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CN(C)C=O.O1CCCC1>[CH2:1]([S:3]([CH2:5][C:6]([NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(=[O:40])=[O:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g of 1-[4-(N-ethylsulfinylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 46) are dissolved in 50 ml of dimethylformamide, and a solution of 3-chloroperbenzoic acid (85%) in 30 ml of tetrahydrofuran is added dropwise at RT. The clear solution is stirred overnight at RT. The mixture is concentrated by evaporation, the residue is dissolved in water and the solution is rendered neutral, extracted with dichloromethane, chromatographed over silica gel and crystallised from ether/petroleum ether/alcohol, yielding 1-[4-(N-ethylsulfonylacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 135°-136°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10]2([CH2:26][CH:27]=[CH2:28])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:11]2=3)=[CH:6][CH2:5]1)(=[O:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:38].[Na+].OO>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10]2([CH2:26][CH2:27][CH2:28][OH:38])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:11]2=3)=[CH:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCC1(C2=CCN(C(C)=O)CC2)c2ccc(Cl)cc2CCc2cccnc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CC=C(C2(CCCO)c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.6 %

Procedure:
Dissolved 1-acetyl-4-(8-chloro-5, 6-dihydro-11-(2-propenyl)-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6-tetrahydropyridine(1.0 g, 2.5 mmol) in 50 mL of dry THF, and cooled to 0° C. under a nitrogen atmosphere. Added 9-borabicyclo-[3.3.1]nonane (12.5 mL of 0.5M, 6.25 mmol) via syringe. Warmed slowly room temperature, and stirred for 4 hours. Added 25 weight % NaOH (7.8 mL, 20 mmol) and 30 weight % hydrogen peroxide (4.9 mL, 17.5 mmol), and stirred at room temperature for 16 hours. Added dichloromethane, and washed with saturated NaHSO3, water, and then saturated NaCI. Dried organic solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% MeOH-EtOAc. Combined appropriate fractions, and evaporated to give 0.16 g (16% yield) of 1-acetyl-4-(8-chloro-5,6-dihydro-11-(3-hydroxypropyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6-tetrahydropyridine as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of rac-1-(4-Fluoro-phenyl)-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (850 mg, 2.54 mmol) in THF (15 ml) was treated with 1M LHMDS in THF (3.30 ml, 3.30 mmol) followed by the addition of iodomethane (0.238 ml, 3.81 mmol). The solution was stirred at RT. After 4 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]=[O:17])=[CH:4][CH:3]=1.[CH3:18][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH:16]([OH:17])[CH3:18])=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Product: CC(O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 218A (3.52 g) in tetrahydrofuran (30 ml) was slowly added methylmagnesium chloride (3 M in tetrahydrofuran, 7.08 ml) at −78° C. After the addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and ice-water was added. The resulting mixture was extracted with dichloromethane and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-methylphenyl isocyanate (0.150 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 158 mg (51.1%) of the desired product as a solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:21][C:22](=[O:25])[NH:23][OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCOCC>[CH2:12]([O:21][C:22](=[O:25])[NH:23][O:24][C:8](=[O:10])[CH3:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCOC(=O)NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCOC(=O)NOC(C)=O
Reaction time: 2 h

Procedure:
25 Parts of triethylamine are added over 30 minutes to a stirred solution of 19.6 parts of acetyl chloride and 50.6 parts of nonyl-N-hydroxycarbamate in 500 parts of ether at 0°-5° C. keeping the pH of the mixture in the range pH3 to pH6. The reaction is stirred for a further 2 hours at 0°-5° C. followed by 24 hours at 25° C. and is then filtered to remove amine hydrochloride. The filtrates are washed with water, dried, filtered and evaporated to constant weight at 30° C. under reduced pressure to give 61 parts of nonyl-N-(acetoxy)carbamate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[N:14]1[NH:15][N:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:15]2[N:16]=[CH:17][CH:18]=[N:14]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(I)c(C(=O)O)c1F
Reactant: c1cn[nH]n1
Product: COc1ccc(-n2nccn2)c(C(=O)O)c1F

Procedure:
The title compound was synthesized following the same general protocol as described in Example A11 using 2-fluoro-6-iodo-3-methoxybenzoic acid and 2H-1,2,3-triazole. ESI-MS (m/z): 238 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4](C(OCC(Cl)(Cl)Cl)=O)[CH2:3]1>C(O)(=O)C.[Zn]>[OH:1][C@H:2]1[C@H:7]([S:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Sc2ccccc2)[C@H](O)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: O[C@@H]1CNCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.0 g (0.036 mol) of trans-3-hydroxy-4-phenylthio-1-(β,β,β-trichloroethoxycarbonyl)-piperidine are dissolved in 140 ml of 90% acetic acid and the solution is treated with 9.5 g (0.14 mol) of zinc dust in portions. The reaction mixture is subsequently stirred for one hour at room temperature and then filtered through a layer of diatomaceous earth. The filtrate is evaporated under a high vacuum, the resulting residue is taken up in 500 ml of water, the solution is cooled to 0° in an ice-water bath and, at this temperature, rendered strongly alkaline with concentrated sodium hydroxide solution and the reaction mixture is extracted by shaking with 3 times 200 ml of methylene chloride. The combined organic phases are washed once with water, dried over sodium sulphate and evaporated under a water pump vacuum, whereupon trans-3-hydroxy-4-phenylthio-piperidine is obtained in the form of the crystalline crude base, which is recrystallised from methanol/ether; melting point 135°-136°. The neutral fumarate prepared from the base with fumaric acid crystallises from methanol/ether; melting point 171°-173°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34](=[O:38])[NH:35][CH2:36][CH3:37])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:23]([C:24]4[S:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:28]=4)=[CH:22][C:21]([NH:33][C:34]([NH:35][CH2:36][CH3:37])=[O:38])=[N:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cn3C(COC)COC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCNCC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
Tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate (Example 139, 260 mg, 0.33 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (195 mg, 1.68 mmol) was added to the mixture and it was stirred for 30 h at room temperature. The reaction mixture was concentrated, and the pH was adjusted to 8 with saturated sodium bicarbonate solution to give solid compound which was filtered and dried to afford 160 mg (72%) of 1-{5-[1-(1,3-dimethoxypropan-2-yl)-4-oxo-3-(piperazin-1-ylcarbonyl)-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(OCCN2CCCC2)cc1

Procedure:
Compound 27-6 (1.5 g, 6.0 mmol) was treated with 6N HCl for 48 hours at room temperature and 60° C. for 2 hours. The solvent was removed to give 27-7 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:25][CH2:26]Br>O>[CH3:12][O:11][C:8]1[C:9]2[O:10][CH2:25][CH2:26][O:1][C:2]=2[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1
Reactant: COc1cc(C=O)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc2c1OCCO2
Temperature: 100 °C
Yield: 42.9 %

Procedure:
In a vial was placed 0.5 g (3.0 mmol) of 3,4-dihydroxy-5-methoxybenzaldehyde, 414 mg (3.0 mmol) of K2CO3, and 3 mL of anhydrous DMF. To this mixture was added, 0.56 g (3.0 mmol) of 1,2-dibromoethane dropwise. The vial was sealed and heated to 100° C. overnight. Water was added to the reaction and the mixture was extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the crude product. The material was purified by silica gel chromatography using 50% ethyl acetate/hexane as the eluent to afford 0.25 g (43%) of the pure aldehyde 10.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(N(CC)CC)C>[NH2:8][C:7]1[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1.[F:9][C:5]1[CH:6]=[C:7]2[C:2]([CH:12]=[CH:11][C:10](=[O:13])[NH:8]2)=[N:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(F)cnc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ncc(F)cc1N
Product: O=c1ccc2ncc(F)cc2[nH]1
Temperature: 147.5 °C
Reaction time: 5 h

Procedure:
To 0.99 g of 2-bromo-5-fluoropyridin-3-amine, 0.67 mL of ethyl acrylate, 3.5 mL of triethylamine, and 0.13 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at an external temperature of 145 to 150° C. for 5 hours in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.37 g of ethyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate and 0.15 g of 7-fluoro-1,5-naphthyridin-2(1H)-one as light brown solids.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0 mg, 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 65.0 mg (89%) of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][CH2:27][O:28][C:29]1[CH:48]=[CH:47][C:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:40][C:35]([CH2:34][O:33][C:32]2[CH:47]=[CH:48][C:29]([O:28][CH2:27][CH2:26][O:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]3)=[O:13])=[CH:30][CH:31]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: BrCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Product: COC(=O)c1ccc(OCCOc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 4-{[4-(2-bromoethoxy)phenoxy]methyl}biphenyl.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([O:17]C)=[O:16])[CH:10]=2)=[N:6][CH:7]=1.[Li+].[OH-].O1CCCC1>O>[Cl:1][C:2]1[C:3]([NH:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNc1nc(Nc2cc(C(=O)OC)nn2C)ncc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(Nc2cc(C(=O)O)nn2C)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a 100 mL round bottom flask equipped with a stir bar was added 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate, 0.28 g of LiOH, 15 mL of tetrahydrofuran and 10 mL of water. The reaction was stirred at room temperature for 18 hours. The tetrahydrofuran was removed in vacuo and the aqueous layer was acidified to pH 5 with 1N HCl. The aqueous layer was partitioned with ethyl acetate and the organic layer washed with brine, dried over MgSO4, filtered and concentrated to give 0.58 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.[F-].[K+]>[Pd].C1COCC1>[CH3:9][N:10]1[CH:14]=[C:13]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:12]=[N:11]1
Reactant: O=C1C=C(Br)CCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=CC(=O)CCC2)cn1
Temperature: 60 °C
Yield: 29.4 %

Procedure:
To a 50 mL round bottom flask containing a stir bar was added 0.152 g of 3-bromocyclohex-2-enone (0.868 mmol), 0.216 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.04 mmol), 5 mL of THF, 4.0 mL of an aqueous solution of 2.0 M KF solution, and 0.139 g of 5% Pd on activated charcoal (Degussa type E105 CA/W, 7.5 mol %). The reaction was stirred, placed under nitrogen, and heated to 60° C. in an oil bath overnight. The reaction was not complete by TLC so the temperature was raised to 80° C. and heated an additional 18 hours. The reaction was worked up by filtering the crude mixture through a celite plug and extraction with methylene chloride (2 times with 5 mL). The organic phases were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was passed through a Fisher Prep Sep SCX column eluting with 8 mL of CH2Cl2 followed by 5 mL of methanol/ammonia (7N). The fractions were not pure so purification was accomplished using flash chromatography on the Biotage system utilizing gradient elution (0% to 80% ethyl acetate/hexanes). The product fractions were combined and concentrated to give a white powder (45 mg, 29%). 1H NMR (CDCl3, 300 MHz): δ 2.09 (quintet, J=6.3 Hz, 2H), 2.41-2.46 (m, 2H), 2.63 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 6.26 (t, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.69 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.5, 27.9, 37.4, 39.4, 121.5, 128.6, 137.6, 151.9, 199.3. LCMS (ESI): mass calcd for (C10H12N2O) m/z 176.09; measured [M+H]+: m/z 177.08.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Br)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 7 h
Yield: 94.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56.1 mg), 5-bromo-2-hydroxybenzophenone (361 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (110 mg, yield 94%).