Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C=O)c1
Yield: 88 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.22 g, 10 mmol) in anhydrous acetone (50 mL) was treated with K2CO3 (2.76 g, 20 mmol) and Mel (0.9 mL, 15 mmol) at room temperature for 12 hours. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by flash column chromatography (0–15% EtOAc in hexanes, 1.2 g, 88% yield). 1H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3 H), 7.17–7.21 (m, 1 H), 7.38–7.42 (m, 1 H), 7.45–7.47 (m, 2 H), 9.99 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. To a solution of 2,6-dicholoro-5-methoxy pyrimidine (100 g, 0.55 mol) in dry tetrahydrofuran (THF) solvent was added, dropwise, 1M vinyl magnesium bromide in THF solvent (124 g, 0.94 mol) for one hour at room temperature. The mixture was then stirred for 4 h at room temperature. Excess Grignard reagent was quenched by addition of acetone (200 mL) while the temperature of the mixture was maintained at a temperature below 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated out. The solid was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 L). The resulting undissolved, dark, semi-solid was separated by filtration using ethyl acetate. It was further concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in hexane mixture to provide the title compound (70 g, 60% yield): mp 60-61° C.; 1H NMR (CDCl3) δ 3.99 (s, 3H), 5.85 (d, 1H). 6.75 (d, 1H), 6.95 (dd, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:9]([F:8])([F:20])[F:19])[CH:17]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1CCC[C@H]1O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H]1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Trans-2-Methylcylopentanol (50 mg, 0.5 mmol) was added to a flame dried round bottom flask under nitrogen containing 0.5 mL of dry tetrahydrofuran (“THF”) and cooled to 0° C. A 1.0 M solution of potassium t-butoxide in t-butanol (0.5 mL) was added dropwise and the reaction mixture stirred at 0° C. for 0.5 h. The above solution was then transferred via syringe to a flask containing 2-Trifluoromethyl-4-fluoro-benzonitrile (95 mg, 0.5 mmol) in 0.5 mL of THF at 0° C. The mixture was stirred at 0° C. for 3 h, warmed to room temperature and stirred for 16 h. The reaction mixture was then cooled to 0° C., poured into a seperatory funnel containing 8 mL of water, and extracted with 10 mL of methyl tert-butyl ether. The organic phase was washed with water, brine, dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 112 mg 4-(trans-2-Methyl-cyclopentyloxy)-2-trifluoromethyl-benzonitrile. GC/MS: 269 (M/Z for C14H14F3NO).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][Cl:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCCCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
3-(4-Benzyloxyphenyl)propanol produced in Example 193-(1) (1.5 g) was dissolved in toluene (30 ml). To the solution were added thionyl chloride (0.88 g) and pyridine (0.1 ml). The mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled, to which was added saturated sodium hydrogencarbonate to cause decomposition, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 3-(4-benzyloxyphenyl)propyl chloride (1.3 g) as a colorless crystalline product. m.p.: 34-35° C.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[N:24]2[CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C>CC(C)=O>[CH:3]([O:37][C:36](=[O:38])[CH2:35][O:34][CH2:33][CH2:32][CH2:31][CH2:30][N:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C@@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:4])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Solvent: CC(C)I
Solvent: CC(C)=O
Product: CC(C)OC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 16 μL, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid (29 mg, 0.071 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 17 h, the reaction mixture was concentrated in vacuo, EtOAc (15 mL) was added and the resultant mixture was washed with 0.5 M aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2<5% MeOH/CH2Cl2, gradient) afforded 16 mg (50%) of the title compound.
Reaction SMILES: N1(C2N=CC(CC(O)=O)=CC=2)C=NN=N1.[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=2)[CH:20]=[N:19][N:18]=[N:17]1.[Cl:31]C1C(Cl)=CC([N+]([O-])=O)=CN=1>>[Cl:31][C:23]1[C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=[C:21]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:22]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: O=C(O)Cc1ccc(-n2cnnn2)nc1
Product: O=C(O)Cc1ncc(-n2cnnn2)cc1Cl

Procedure:
The title compound was prepared in an analagous fashion to that described for the syntheses of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Steps B-F) and [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid (Steps A-E) starting from 2,3-dichloro-5-nitropyridine. LC/MS: [(M+1-28)]+=212.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[C:35]([O:36][CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])[O:27]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1ccc(OC)c(C=O)c1O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 21.8 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.30 mL, 60.37 mmol), 2-nitro benzoic acid (1.852 g, 10.98 mmol), and pyrrolidine (0.91 mL, 10.98 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-3,6-dimethoxy-benzaldehyde (10.0 g, 54.89 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes (1:1.2) as eluents, yielding 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (3.5 g, 62.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:18]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: O=C(CCCCCBr)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a solution of 2-nitroaniline (13.82 g, 100 mmol) in pyridine (120 mL) at 0° C. was dropwise added 6-bromohexanoyl chloride (22.6 mL, 32 g, 150 mmol) over 15 minutes. The resulting mixture was stirred for 1.5 hours at the same temperature, then poured into ice-water (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with aqueous citric acid solution (2×100 mL), water (100 mL) and brine (50 mL). After removal of the solvent, the crude product was passed through a silica gel pad (100 g) and washed with 1:1 mixture of hexane and diethyl ether. Concentration of the appropriate fractions gave 28.4 g of 2 as yellow solid. LC-MS (M++1) 315
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[CH3:18])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:16][C:17]([F:20])([F:19])[CH3:18])=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Product: Cc1cc(Cl)ncc1OCC(C)(F)F
Yield: 98 %

Procedure:
The title compound is prepared in 98% yield (4.52 g, pale yellow oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (11.9 g, 52.2 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C[O:21][C:22]([CH2:24][CH:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=O.C[O-].[Na+]>CS(C)=O.O=[Pt]=O>[O:21]=[C:22]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[N:30]2[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:25]2[CH2:24]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=[Pt]=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Temperature: 95 °C
Reaction time: 54 h

Procedure:
Diisopropylethylamine (3.03 mL, 17.34 mmol) was added to a mixture of 2-chloro-3-nitropyridine (2.75 g, 17.34 mmol) and the product of Example 22B (4.48 g, 17.34 mmol) in dimethyl sulfoxide (20 mL). The mixture was heated at 95° C. under nitrogen for 7 hours and then cooled to room temperature. Ice water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated brine (60 mL), dried (MgSO4) and concentrated under vacuum to an oil (6.81 g). This material was dissolved in methanol (400 mL), and PtO2 (25 mg, 0.11 mmol) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles). The suspension was stirred under hydrogen (1 atm) for 54 hours. The flask was evacuated and purged with nitrogen (3 cycles) and the black suspension was filtered through diatomaceous earth with a methanol (2×10 mL) rinse. Sodium methoxide (Aldrich, 25% in methanol, 12.01 g, 55.6 mmol) was added to the filtrate, and the mixture was heated at reflux for 41 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with methanol-CH2Cl2 (0:100-5:95), followed by crystallization from ethanol (10 mL) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.27-2.40 (m, 1H), 2.78 (dd, J=13.5, 5.9 Hz, 1H), 2.91-3.20 (m, 3H), 3.55-3.68 (m, 1H), 3.69-3.80 (m, 1H), 3.99-4.19 (m, 2H), 6.95 (dd, J=7.7, 5.0 Hz, 1H), 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCC(CCCCN)CCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C

Procedure:
To a solution of 2200 g or crude ethyl 8-amino-4-[3-(3-pyridyl)propyl]-octanoate in 28.8 l of dichloromethane is added 1377 g of triethylamine. The solution is cooled to 0° and a solution of 1435 g of p-chlorophenylsulfonyl chloride in 14.3 l of dichloromethane is added over a period of 45 min maintaining the temperature below 5°. The reaction mixture is allowed to slowly warm up to room temperature overnight. The reaction mixture is washed 3 times with 15 l of aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated to dryness to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (compound of example 4b) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Cl:8].O>CN(C=O)C.[Cu]I>[Cl:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=12
Reactant: Cc1cc(Cl)c(N)c(C#Cc2ccccc2)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Temperature: 110 °C
Yield: 48.5 %

Procedure:
3-Amino-4-chloro-6-methyl-2-(2-phenyl ethynyl)pyridine (1.24 g, 5.1 mmol) was dissolved in anhydrous DMF (90 mL), CuI (150 mg, 0.8 mmol) was added and the mixture was heated at 110° C. for 18 h. The cooled mixture was poured into H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with H2O and brine, dried over MgSO4 and filtered through a plug of silica using CHCl3. The crude product was triturated with 20:1 hexanes:EtOAc, filtered, and dried under high vacuum to afford 600 mg (48%) of 7-chloro-5-methyl-2-phenyl pyrrolo-[3,2-b]pyridine. 1H NMR (DMSO-d6; 500 MHz): δ 2.40 (s, 3), 7.05 (s, 1), 7.16 (s,1), 7.38 (t, 1, J=5.2), 7.49 (m, 2), 8.02 (d, 2, J=7.2). MS m/z: 243 (M+H). This intermediate chloride (273 mg, 1.1 mmol) was taken up in 4:1 o-xylene/piperidine (10 mL) and heated to 140° C. in a Teflon-capped pressure tube for 7 d. The mixture was cooled to room temperature, diluted with H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O and brine, dried over MgSO4 filtered, and concentrated in vacuo. Chromatography on silica gel eluting with 10:1 CHCl3:MeOH afforded 244 mg (75%, 36% overall) of the title compound as a pale yellow solid. The product's 1H-NMR was identical to that obtained using Method A.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][NH:1]2
Reactant: Oc1cccc2[nH]ncc12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.75 mmol) of 1H-indazol-4-ol (from example XXIV), 94 mg (0.64 mmol) of 3,4-difluoronitrobenzene and 103 mg (0.75 mmol) of potassium carbonate are suspended in 2 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted 2× with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and nitrogen inlet, was placed 411 g of the previously prepared methyl 3-bromomethyl-4-nitrobenzoate, 441 g of anhydrous potassium acetate and 2 1 of glacial acetic acid. The resulting mixture was refluxed for 4 hours, cooled to room temperature and stirred overnight. The solvent was removed in a rotary evaporator and the resulting light yellow solid treated with a mixture of 2 l of ethyl acetate and 1 l of water. The organic phase was separated, washed with water (3×400 mL), brine (1×400 mL) dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator. The crude reaction mixture was triturated with hexane and filtered yielding 318 g of the expected methyl 3-acetoxymethyl-4-nitrobenzoate. This compound was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1>ClCCl.CO>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cnc(N)cc2C(F)(F)F)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(C(F)(F)F)c(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine with reaction time of 15 h. Chromatography (dichlormethane/methanol 97:3) gave the title compound as an colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][CH2:13][Mg+].[Br-].[NH4+].[Cl-]>CCOCC>[OH:9][C:3]([C:2]([F:10])([F:11])[F:1])([CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(O)(CC)C(F)(F)F

Procedure:
To a −78° C. solution of ethyl trifluoropyruvate (129.0 g 758 mmol) in ether was added dropwise within 90 min a solution of EtMgBr 3.0 M in ether (252 mL). The solution was brought over one 1 h to ca. −10° C. and poured over 2 L of saturated NH4Cl. The layers were separated and the aqueous phase extracted with ether (3×500 mL). The organic phases were combined, dried over MgSO4 and the solvent removed. Distillation at 50-65° C. (30 mm Hg) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 5.4 (s, 1H), 4.35 (q, 2H), 2.07 (m, 1H), 1.83 (m, 1H), 1.3 (t, 3H) and 0.93 (t, 3H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].[H-].[Na+].S(OCC)(O[CH2:25][CH3:26])(=O)=O.Cl>CN(C)C=O>[CH2:25]([N:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18])[CH3:26]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCC2(CCC(=O)c3ccccc32)C1=O
Reaction time: 0.08 h
Yield: 128.8 %

Procedure:
To 24.3 grams (0.1 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione in 300 milliliters of dry dimethylformamide maintained under nitrogen atmosphere was added with stirring 4.37 grams (0.1 M) of a 55 per cent suspension of sodium hydride in mineral oil. After stirring for five minutes, 16.0 grams (0.1 M) of diethyl sulfate were added in one portion. The slightly exothermic reaction mixture was allowed to stir for a short time and concentrated hydrochloric acid was added dropwise until the reaction mixture was slightly acidic. The reaction solvent was removed under reduced pressure at steam bath temperature and the resulting oil extracted into ether. The ether extracts were washed with 5 percent sodium hydroxide solution, water, and then dried (MgSO4). After filtration, the ether was removed, leaving a residue, which was recrystallized from diethyl ether to give 34.9 grams (64%) of 1'-ethyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 85.5°-89° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Cl:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (64 mg, 0.19 mmol, prepared as described for Example 8) and N-chlorosuccinimide (27 mg, 0.20 mmol) were dissolved in DMF (0.9 ml) and the solution stirred overnight at 50° C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([CH3:13])[CH:3]=1.[CH2:14](I)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][N:7]([CH:8]2[CH2:9][CH2:10]2)[CH2:14][CH3:15])=[C:4]([CH3:13])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Br)ccc1CNC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(Cc1ccc(Br)cc1C)C1CC1
Temperature: 60 °C

Procedure:
A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), and K2CO3 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60° C. for 18 hours. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (2.5% EtOAc-hexanes).