Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH2:49]>CN(C=O)C>[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH:49][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5-Fluoroindole-3-butyric acid (1.5 g, 6.8 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 8.2 mmole) and 1,3-diisopropylcarbodiimide (2.6 ml, 16.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.8 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions of the products were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3yl)-butanamide, as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])=O)=[CH:3][CH:2]=1.[O:13]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:11][CH:10]([CH3:12])[CH2:9][C:7](=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: NNC(=O)c1ccccc1Oc1ccccc1
Reactant: CC(C)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: CC(C)CC(=NNC(=O)c1ccccc1Oc1ccccc1)c1ccncc1

Procedure:
Following the general method of procedure 4 and making noncritical variations, except 12 drops of glacial acetic acid is added as a catalyst, 9.00 gm (0.055 mole) of isobutyl 4-pyridyl ketone and 12.59 gm (0.055 mole) of 2-phenoxybenzhydrazide yield 13.89 gm (67%) of the title compound having a melting point of 137.6° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15](=O)[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[BH3-]C#[N:22].[Na+]>CCO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([NH2:22])[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cn1
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1ncc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 120 °C
Yield: 100.3 %

Procedure:
1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977 mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) were taken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 262 mg crude yellow oil, which was carried forward without further purification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5].[Mg].[Cl:9][C:10]1[C:11]2[C:12](=[O:23])[C:13]3[N:14]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1.[Cl-].[NH4+]>CCOCC.ClCCCl>[Cl:9][C:10]1[C:11]2[C:12]([OH:23])([CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5])[C:13]3[N:14]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1C2=NCCCN2c2cccc(Cl)c21
Reactant: COC(C)CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COC(C)CCC1(O)C2=NCCCN2c2cccc(Cl)c21

Procedure:
A solution of 1-bromo-3-methoxybutane (6.0 g) in dry ether (20 ml) was added dropwise under a nitrogen atmosphere to magnesium turnings (0.9 g) at such a rate as to maintain gentle reflux. After stirring at reflux for 0.5 hour the reaction mixture was chilled in ice and a solution of 9-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.5 g) in dry 1,2-dichloroethane (100 ml) was added dropwise. After stirring the reaction mixture for one hour at room temperature it was cooled and excess saturated ammonium chloride solution was added dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform. The extracts were combined with the organic phase, dried (MgSO4) and the solution evaporated under reduced pressure to leave an oil which was triturated with ether to give a solid. Recrystallisation from ethyl acetate gave the title compound as colourless needles m.p. 164°-5°. Treatment of a solution of these needles in methanol with ethereal hydrogen chloride, followed by evaporation in vacuo gave a solid which was recrystallised from propan-2-ol to give the title compound as the hydrochloride, colourless crystals (2.81 g) m.p. 264°-5°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N(C1CCCCC1)C1CCCCC1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=1[C:54]#[C:55][C:56]([O:63][CH2:64][CH3:65])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=2[C:54]#[C:55][C:56]([O:57][CH2:58][CH3:59])([O:63][CH2:64][CH3:65])[O:60][CH2:61][CH3:62])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(Cl)cc2C#CC(OCC)(OCC)OCC)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 38.5 %

Procedure:
In a glovebox, ethyl 1-benzylpiperidine-4-carboxylate (2.0 g, 8.1 mmol), LiNCy2 (1.55 g, 8.3 mmol), and toluene (10 mL) were loaded sequentially into a 40 mL vial. In a separate vial, Pd(OAc)2 (22 mg, 0.1 mmol), P(t-Bu)3 (44 mg, 0.22 mmol), 1-bromo-4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)benzene (1.5 g, 4.1 mmol), and toluene (10 mL) were loaded sequentially and were then heated at 100° C. for 1 minute. The enolate solution in vial 1 was then added to the reaction mixture in vial 2 via a syringe. The combined mixture was heated at 100° C. for 40 minutes. The reaction mixture was cooled to 23° C. and passed through a short plug of silica gel eluting with EtOAc (20 mL). The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluant: 5-20% EtOAc/hexane+2% TEA), affording 833 mg of ethyl 1-benzyl-4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-4-carboxylate.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[NH3:12].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:12])[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C1CCOc2ccccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: NC1CCOc2ccccc21
Temperature: 0 °C
Yield: 87 %

Procedure:
Chroman-4-one (3 g, 20.1 mmol), titanium(IV) isopropoxide (12.0 mL, 40.2 mmol) and 2 M solution of ammonia in ethanol (60.6 mL, 121.2 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min (1.14 g, 30.2 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 60 mL), the precipitate that formed was filtered off and washed with ethyl acetate (15 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (15 mL×2). The combined organic extracts were washed with 1 M HCl (25 mL). The acidic aqueous extracts were washed with ethyl acetate (50 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (40 mL×3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford Chroman-4-amine as an oil (2.61 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 1H), 7.23 (m, 1H), 6.94 (m, 1H), 6.82 (d, 1H), 4.38 (m, 2H), 4.12 (m, 1H), 2.19 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[OH:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5]
Reactant: N#CC(C=O)c1cccc(Oc2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC(CO)c1cccc(Oc2ccccc2)c1
Yield: 89 %

Procedure:
A 175 mg (0.738 mmol) sample of the above 3-oxo-2-(3-phenoxyphenyl)propanenitrile was reduced using sodium cyanoborohydride (51 mg, 0.81 mmol) in ethanol (1.25 mL) and acetic acid (90 μL) using the procedure described in Example 17 to give 158 mg (89% yield) of 3-hydroxy-2-(3-phenoxyphenyl)propanenitrile as a pale yellow viscous oil.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]=[C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH:22]([CH3:24])[CH3:23]>CO.[I-].[Na+]>[CH2:25]([C:20]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH2:18][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CC(=CCBr)CC(C)C
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CC(C)CC(=CCS(=O)(=O)c1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
55 gm of sodium phenyl sulfinate were dissolved in 500 cc of methanol and then 8 gm of potassium carbonate, 1 gm of sodium iodide and finally 71 gm of 1-bromo-3-isobutyl-5-methyl-2-hexene were added to the solution, which was then agitated for 15 hours at room temperature. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure and water was added thereto. The aqueous phase was extracted with methylene chloride and the methylene chloride extracts were combined. The organic solution thus obtained was washed with water, dried and concentrated to dryness under reduced pressure. The residue was subjected to chromatography through an alumina column to obtain 62.32 gm of the (3-isobutyl-5-methyl-2-hexenyl)phenylsulfone. This product is not described in the literature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6].Cl.[CH3:31][NH:32][CH3:33]>C(O)C>[CH3:31][N:32]([CH3:33])[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccnc(Br)c2)cc1NC(=O)c1cc2nccnc2s1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccnc(N(C)C)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 150 °C
Yield: 49.3 %

Procedure:
To a solution of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 30 (25 mg, 0.053 mmol) in ethanol (1 mL) was added dimethylamine HCl (24.07 mg, 0.534 mmol) and TEA (10 eq). The resulting mixture was heated at 80° C. overnight and 2 h at 150° C. in microwave. Quenched in 3% citric acid solution and extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4 and evaporated. Triturating with ethyl acetate/heptane gave the title compound N-(5-(2-(dimethylamino)isonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 31a (11.3 mg, 49%). NMR (400 MHz, DMSO-d6) 2.26 (s, 3H), 3.11 (s, 6H), 7.03 (d, J=5.1 Hz, 1H), 7.10 (br s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.2 and 1.9 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.56 (br s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.39 (br s, 1H), 10.54 (br s, 1H). (m/z)=433 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:58])([F:57])[O:46][C:47]1[CH:48]=[C:49]([CH2:53][C:54](O)=[O:55])[CH:50]=[CH:51][CH:52]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][C:45]([F:57])([F:44])[F:58])[CH:48]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(OC(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-trifluoromethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-trifluoromethoxy-phenyl)-acetamide (0.8 g, 74%) as a white solid: mp 178-180° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.32 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.83 (s, 2H), 4.72 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.23-8.10 (m, 7H), 8.74 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.84, 48.83, 118.96, 121.43, 121.93, 127.15, 128.29, 130.07, 131.53, 133.15, 134.61, 138.80, 139.00, 148.24, 166.88, 167.41, 169.77, 169.96, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.44; H, 3.44; N, 8.46; F, 11.89.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].O.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5])[O:10][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: CN(C)C(=O)CCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (250 mg, 1.31 mmol) and 2-chloro-N,N-dimethylacetamide (238 mg, 1.97 mmol) in DMF (10 mL) was added CsCO3 (854 mg, 2.62 mmol) and the suspension was stirred at ambient temperature overnight. The reaction mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. The material was purified by flash chromatography using heptane/EtOAc (1:3) as eluent to give 2-(3,5-dichloro-4-formylphenoxy)-N,N-dimethyl-acetamide as a yellow solid.
Reaction SMILES: C1(O)CCCCC1.CN(C)[C:10]1[CH:11]=[C:12](CO)[CH:13]=[CH:14][CH:15]=1.[Br:19][C:20]1[C:21]([Cl:27])=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:21]=1[Cl:27]
Reactant: Oc1cccc(Br)c1Cl
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: OC1CCCCC1
Product: Clc1c(Br)cccc1OC1CCCCC1

Procedure:
The title compound was prepared by substituting for cyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-chlorophenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:6][O:5]1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC1COC(C)(C)O1
Reaction time: 72 h
Yield: 56.5 %

Procedure:
To NaH (1.85 g, 60% dispersed in mineral oil) under argon was added anhydrous N,N-dimethylformamide (DMF, 30 mL) at RT. Solketal (2.20 g, 16.7 mmol) in 10 mL anhydrous DMF was then added dropwise with constant stirring. 1-Bromohexadecane (5.10 g, 16.7 mmol), dissolved in anhydrous DMF (20 mL) was then added to the reaction mixture dropwise and stirred for 72 hours. The reaction was quenched by adding about 5 mL of methanol. It was then poured into cold ice water (100 mL) and extracted with hexane (100 mL, 3×). The solvent was removed under reduced pressure and the residue chromatographed on silica gel using hexane-dichloromethane to obtain 1a (3.363 g, 57% yield); 1H NMR (in CDCl3): δ in ppm 0.83-0.86 (3H, t, J=6.5 Hz), 1.22 (26H, m), 1.33 (3H, s), 1.39 (3H, s), 1.52-1.55 (2H, m), 3.37-3.48 (4H, m), 3.68-3.71 (1H, t, J=6.5 Hz), 4.01-4.03 (1H, t, J=6.5 Hz), 4.20-4.25 (1H, quintet, J=6.0 Hz); 13C NMR (in CDCl3): δ in ppm 14.3, 22.9, 25.6, 26.2, 27.0, 29.6, 29.7, 29.8, 29.9, 32.1, 67.1, 72.0, 72.1, 74.9, 109.5.
Reaction SMILES: [OH2:1].[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[C:20]([CH3:21])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1.Cl>O.C1COCC1.CCOC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[CH2:12][N:13]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:14]2[C:15]([OH:1])=[O:17])=[CH:7][CH:6]=1
Reactant: O
Reactant: Cc1ccc2n1CC(c1ccc(F)cc1)OC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
A solution of lithium hydroxide hydrate (103 mg, 2.4 mmol) in water (1 mL) was added to a solution of 3-(4-fluorophenyl)-6-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (200 mg, 0.8 mmol) in THF (9 mL) at room temperature. The reaction was stirred at room temperature for 2 days. The reaction mixture was then diluted with EtOAc (20 mL) and acidified to approx. pH 2 with 1 M HCl (aq). The organic layer was separated and the aqueous layer extracted further with EtOAc (2×20 mL). The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid as an off-white solid (211 mg, 98%). 1H NMR (400 MHz, CD3OD): δ 2.07 (s, 3H), 4.31 (dd, 1H, J 13.7, 7.9 Hz), 4.42 (dd, 1H, J 13.7, 4.9 Hz), 4.99 (dd, 1H, J 7.7, 5.1 Hz), 5.85 (dd, 1H, J 3.9, 0.7 Hz), 6.92 (d, 1H, J 3.9 Hz), 6.97-7.06 (m, 2H), 7.34 (dd, 2H, J 8.5, 5.5 Hz).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:20][CH2:19]4)[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:18]1([CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([C:9]3[N:10]=[C:6]4[N:7]([C:2]([NH:31][CH2:32][CH2:33][NH:34][C:35]5[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=5)=[N:3][C:4]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])=[CH:5]4)[N:8]=3)[CH2:16][CH2:15]2)[CH2:19][CH2:20]1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(CC5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC5CC5)CC4)nn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.10 mmol) of 5-chloro-2-[1-(cyclopropylmethyl)piperidin-4-yl]-7-(2,4-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 47A), 25 mg (0.12 mmol) of 6-[(2-aminoethyl)amino]-pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.110 ml (0.6 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 22 mg (38% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH:6]=[CH2:7])C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:4]2[CH2:1][CH:7]=[CH:6][C:5]2=[O:8])=[CH:14][CH:13]=1
Reactant: C=CCN(C(=O)C=C)c1ccc(OC)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: COc1ccc(N2CC=CC2=O)cc1
Temperature: 40 °C
Yield: 84.3 %

Procedure:
To a solution of N-allyl-N-(4-methoxyphenyl)acrylamide (150 mg, 0.69 mmol) in degassed methylene chloride (400 mL) was added Grubbs catalyst (58 mg, 0.069 mmol) and the mixture was heated to 40° C. overnight. All volatiles were removed and the resulting material was subjected to flash chromatography (Hexanes:EtOAc 1:1) to yield 1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (110 mg, 86%).
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][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of 4-methoxythiophenol (9.66 g), ethyl 4-bromobutyrate (13.5 g) and potassium carbonate (18.8 g) in DMF (200 ml) was stirred at room temperature for 4 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, into a solution of the residue in ethanol (200 ml) was added at room temperature a 1 N aqueous solution of sodium hydroxide (85 ml), and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to remove the ethanol and was then extracted with diethyl ether. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 4-[(4-methoxyphenyl)thio]butyric acid (13.09 g) as colorless crystals.