Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+]=[S:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)=[CH:17][CH:16]=2)[C:12]#[N:13])=[CH:7][C:6]=1[O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30].C1COCC1.O>CO.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)=[CH:19][CH:20]=2)[C:12]([NH2:13])=[S:2])=[CH:7][C:6]=1[O:27][Si:28]([CH:29]([CH3:30])[CH3:31])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]
Reactant: COc1ccc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
After adding 30.8 ml of a 20% aqueous solution of ammonium sulfide to a solution of 8.92 g of (4-methoxy-3-triisopropylsilanyloxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 300 ml of a methanol:THF=2:1 mixed solvent, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.59 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.[OH-].[Na+]>>[OH:8][C:7]1[C:2]2=[N:1][C:18]([CH3:20])=[CH:17][C:16](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)n2cccc(O)c2n1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a suspension of 2-amino-3-benzyloxypyridine (5.01 g) in polyphosphoricacid (40 ml) was dropwise added ethyl acetoacetate (6.51 g) at 60° C., and the mixture was warmed at 100° C. for 3 hours. The mixture was poured into ice water, neutralized with sodium hydroxide and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (methanol-chloroform) to give 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (880 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110 %

Procedure:
To a solution of 1-(6-bromo-pyridin-3-yl)-ethanone (20.3 g, 101 mmol) and aluminum chloride (200 mg, 1.5 mmol) in chloroform (288 mL) was added bromine (5.23 mL, 101 mmol). The mixture was stirred at rt for 16 h. Upon completion of the reaction as judged by LC/MS analysis, the solution was diluted with sat aq NaHCO3 and extracted with DCM. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to 31 g 2-bromo-1-(6-bromopyridin-3-yl)ethanone, which was taken on immediately. LC/MS: m/e 277.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O[Li].O>CO.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COC(=O)C1(c2ccc3onc(C)c3c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1noc2ccc(C3(C(=O)O)CC3)cc12
Yield: 32.2 %

Procedure:
To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (0.80 g, 19 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature overnight before the MeOH was removed by evaporation under vacuum. Water and Et2O were added and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 1H NMR (400 MHz, DMSO) δ 12.40 (br s, 1 H), 7.76 (s, 1 H), 7.60-7.57 (m, 2 H), 2.63 (s, 3 H), 1.52-1.48 (m, 2 H), 1.23-1.19 (m, 2H). MS (ESI) m/z (M+H+) 218.1.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH:19]([CH3:21])[CH3:20])(OCC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)CCCCn1c(C(C)C)nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2ccccc2n1CCCCCO
Temperature: 0 °C
Yield: 84 %

Procedure:
Part B. A solution of the ester obtained in Part A above (9.54 g, 33.1 mmol) in tetrahydrofuran (30 mL) was added to a solution of lithium aluminum hydride (80 mmol) in tetrahydrofuran (80 mL) at 0° C. The mixture was heated to reflux overnight, then cooled back to 0° C. and quenched by the careful sequential addition of water (3 mL), then aqueous sodium hydroxide solution (10 mL of 15%), then water (10 mL). The mixture was filtered through celite with copius tetrahydrofuran washing, and the liquid was dried over anhydrous potassium carbonate, filtered and evaporated. The residual oil was separated by flash chromatography (ethyl acetate) to afford the product, 1-(5-hydroxypentyl)-2-(1-methylethyl)-1H-benzimidazole (6.82 g, 27.7 mmol, 84%) as an oil. 1H NMR (CDCl3) : 7.78-7.70 (1H, m); 7.32-7.22 (3H, m); 4.90 (1H, br d, J=2.2 Hz); 4.12 (2H, t, J=7.5 Hz); 3.64 (2H, t, J=6.0 Hz); 3.18 (1H, m, J=6.6 Hz); 1.93-1.45 (6H, m); 1.44 (6H, d, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:19]1([CH2:20][CH2:21][CH3:22])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:17][CH3:16]
Reactant: CCCC(=O)CCC
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1(CCC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.120 g, 0.550 mmol), 4-heptanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (1.5 mL) was stirred for 1 h at 100° C. in a sealed tube. Then, this mixture was stirred for 2 h at 120° C. and stirring was continued for 2 h at 110° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. This solid was triturated with dichloromethane (10 mL), and the precipitate was collected by filtration. Then, the obtained solid was stirred at 60° C. in ethyl acetate (5 mL). After 10 min, the mixture was cooled, and the precipitate was collected by filtration to afford the title compound (0.0406 g, 23%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.78 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH2:13][Cl:14])[N:3]=1.O.[NH2:16][NH2:17].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Cl:14][CH2:13][C:4]1[N:3]=[C:2]([NH:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1
Reactant: NN
Reactant: Cc1ccc2nc(CCl)nc(Cl)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(CCl)nc(NN)c2c1
Temperature: 10 °C
Reaction time: 0.13 h

Procedure:
3. 63.5 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline are dissolved in 630 ml of absolute tetrahydrofuran at room temperature and then cooled to 10° C. 27.2 ml of hydrazine hydrate are added dropwise thereto within 8 min., whereby a solution results and the temperature rises to 15° C. The reaction mixture is stirred at 5° to 15° C. for 4 h. and then poured into a solution of 40 g of sodium hydrogen carbonate in 5 l of water. The mixture is extracted five times with 1.5 l of dichloromethane each time. The combined organic phases are washed with water, dried and concentrated (T<40° C.) in a vacuum to a volume of 0.5 l. 0.5 l of ethyl acetate is added thereto and the dichloromethane is evaporated completely in a vacuum, whereby the product crystallizes out. The mixture is left to stand at -25° C. overnight and the crystals are filtered off, washed with diethyl ether and dried at room temperature in a vacuum. There are obtained 38 g of 2-(chloromethyl)-4-hydrazino-6-methylquinazoline of m.p. above 140° C. (dec.).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:8]([F:20])[C:7]([CH:21]=[O:22])=[CH:6][CH:5]=1>C1COCC1.CO>[Br:3][C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:8]([F:20])[C:7]([CH2:21][OH:22])=[CH:6][CH:5]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(C=O)c2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CO)c2F)c1
Reaction time: 12 h
Yield: 47.2 %

Procedure:
NaBH4 (0.64 g, 1.5 equiv) was added portionwise to a stirred solution of 105 (4.0 g, 11.3 mmol) in a mixture of THF (20 mL) and MeOH (10 mL) at RT. The reaction mixture was stirred for 12 h, and quenched by the addition of saturated aqueous NH4Cl. The aqueous mixture was extracted with EtOAc, and the organic solution was washed with water and evaporated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20% to 50% EtOAc) to afford 1.9 g (47%) of 3-(6-bromo-2-fluoro-3-hydroxymethyl-phenoxy)-5-chloro-benzonitrile (107) as a yellow oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[Cu](C#N)[C:21]#[N:22]>CN(C=O)C>[C:21]([C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)#[N:22]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(C#N)nc1-2
Yield: 74.3 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740, 2.3 mmol) and copper cyanide (537 mg, 6.9 mmol) were mixed in DMF (8 mL). The reaction was microwaved on 200 watts, 150° C. for 40 minutes. The reaction mixture was partitioned between 15% ammonia in water and EtOAc. The aqueous layer was extracted with EtOAc three times, combined organic extracts were washed with water, brine and dried over MgSO4 to produce 0.46 g (74% yield) of methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate.
Reaction SMILES: C12CC3CC(CC(C3)C1)C2.FC(F)(F)C1C=CC2N=NN([OH:21])C=2C=1.O=O.[C:27]12([OH:37])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C(O)(=O)C>[C:29]12([OH:21])[CH2:30][CH:31]3[CH2:32][CH:33]([CH2:34][C:27]([OH:37])([CH2:36]3)[CH2:28]1)[CH2:35]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: On1nnc2ccc(C(F)(F)F)cc21
Agent: C1C2CC3CC1CC(C2)C3
Agent: O=O
Solvent: CC(=O)O
Product: OC12CC3CC(C1)CC(O)(C3)C2

Procedure:
A mixture of 10 mmol of adamantane, 0.8 mmol of 6-trifluoromethyl-1-hydroxybenzotriazole, 0.06 mmol of acetylacetonatocobalt(III), and 25 ml of acetic acid was stirred at 90° C. in an oxygen atmosphere (1 atm) for 8 hours. A gas chromatographic analysis of products in a reaction mixture found that 1-adamantanol and 1,3-adamantanediol were formed in yields of 38% and 4%, respectively, with a conversion rate from adamantane of 48%.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:12])([F:11])[C:6](OCC)=[O:7])[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:4][C:5]([F:12])([F:11])[CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)CC1CC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
A solution of ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, 0.244 mol), prepared as in Example 1, in absolute ethanol (100 mL) was added drop wise to a stirred slurry of sodium borohydride (9.45 g, 0.25 mol) in absolute ethanol (150 mL). The temperature of the mixture was allowed to rise to 35° C., whereupon cooling (ice/acetone bath) was applied and the temperature was maintained at 5° C. by controlling the rate of addition of the ester over 2 hours. The mixture then was stirred in an ice bath for 3 hours and then for 17 hours at room temperature. The reaction was quenched at 0° C. with 2M hydrochloric acid (180 mL) and the mixture was stirred for 30 minutes. The resulting homogenous mixture was poured into water (1000 mL) and extracted with diethyl ether (4×300 mL). The combined extracts were washed with 2M hydrochloric acid, water, 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure. Distillation of the residue under reduced pressure gave 3-cyclopropyl-2,2-difluoro-1-propanol (28.3 g, 85% over 2 steps), as a colorless oil, b.p. 48-50° C./5 mbar. 1H-NMR (400 MHz, CDCl3): δ=6:15-0.23 (m, 2H), 0.49-0.60 (m, 2H), 0.77-0.90 (m, 1H), 1.77 (bs, 1H), 1.80-1.90 (m, 2H), 3.83 (t, J=14 Hz, 2H); 1H-NMR (400 MHz, CD3SOCD3): δ=0.08-0.28 (m, 2H), 0.39-0.55 (m, 2H), 0.70-0.86 (m, 1H), 1.70-1.87 (m, 2H), 3.53-3.73 (m, 2H), 5.36 (t, J=4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:7]=2[CH:22]=1.O=[C:26]([CH2:30][CH2:31][N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])[C:27]([OH:29])=[O:28]>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([C:27]([OH:29])=[O:28])[CH2:30][CH2:31][N:32]([CH2:36][CH2:37][CH3:38])[CH2:33][CH2:34][CH3:35])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:7]=2[CH:22]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1
Reactant: CCCN(CCC)CCC(=O)C(=O)O
Product: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-(trifluoromethyl)-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine can be stirred with 2-oxo-4-(dipropylamino)-butyric acid at room temperature to give 7-(trifluoromethyl)-2-[[1-carboxy-3-(dipropylamino)propylidene]-hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][N:28]1C(=O)C2C(=CC=CC=2)C1=O)=[O:5].CN>>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5]
Reactant: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: CN
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C

Procedure:
Phthaloyl amlodipine (100 g, 0.18 M) was reacted with monomethyl amine (500 g, 40% solution) in denatured spirit at room temperature for 8 hrs, cooled to 0° C., filtered, washed with distilled water up to neutral pH and dried at 60-65° C. for 8 ills. Yield 58 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.Cl.C(N=C=NCCCN(C)C)C.C1C=C2N=NN(O)C2=CC=1.N.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>O.ClCCl.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:15]([C:3]2[CH:4]=[N:5][N:6]([CH:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[C:2]=2[CH3:1])=[O:17])=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)cnn1C(C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnn(C(C)c3ccccc3)c2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A mixture of 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid (49 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.5 mmol), N-hydroxybenzotrizole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) was stirred at 25° C. for 0.5 hours. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 ml) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide as a white solid (43 mg, 56%). LRMS (M+H+) m/z: calcd 364.19. found 364. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.34 (s, 1H), 7.70 (t, J=5.1 Hz, 1H), 7.35-7.18 (m, 5H), 5.84 (s, 1H), 5.49 (q, J=7.2 Hz, 1H), 4.20 (d, J=4.8 Hz, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H), 1.73 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([F:19])=[C:21]([S:28]([N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:30])=[O:29])[CH:22]=1
Reactant: COc1ccc(CNc2cccnn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Product: COc1ccc(CN(c2cccnn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 14 using N-[(2,4-dimethoxyphenyl)methyl]pyridazin-3-amine (Preparation 19) and 2,4-difluoro-5-chlorobenzenesulfonyl chloride.
Reaction SMILES: [CH3:1][N:2]([O:7][CH3:8])[C:3](=[O:6])[CH2:4]Br.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][N:2]([O:7][CH3:8])[C:3](=[O:6])[CH2:4][O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CON(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CON(C)C(=O)COc1ccc(NC(C)=O)cc1
Yield: 74 %

Procedure:
This bromoacetamide was dissolved in acetonitrile and to the solution were added 10.75 gm (71.15 mMol) 4-acetamidophenol followed by 23.10 gm (71.1 mMol) cesium carbonate. The reaction mixture was heated at reflux for 3 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and 1N aqueous sodium hydroxide. The organic phase was separated, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 10.34 gm (74%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[CH:11]1[CH:16]=[N:15][C:14]2N(O)N=N[C:13]=2C=1.C(Cl)CCl.N(CC)CC>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:15]([CH2:16][CH3:11])[CH2:14][CH3:13])=[O:10])[N:6]=1
Reactant: On1nnc2cccnc21
Reactant: Nc1nc(CC(=O)O)cs1
Solvent: CCNCC
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)Cc1csc(N)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2-aminothiazol-4-yl)acetic acid (1 eq), HOAT (1 eq), EDC (1.1 eq), TEA (1 eq) and HNEt2 (1 eq) in DMA was stirred at room temperature for 6 hours. The reaction mixture was then quenched with H2O and concentrated. The residue was dissolved in a stirred 4:1 mixture of EtOAc and NaHCO3(sat.). The two phases were separated and the organic solution was washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting solid was washed twice with Et2O and dried to yield the desired product as a white solid. LC/MS (m/z): 214.0 (MH+), Rt 1.13 minutes.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:6](=[O:15])[NH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Br:4][C:5]1[C:6]([O:15][CH2:2][CH3:3])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CCOc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 64 h
Yield: 59.8 %

Procedure:
Iodoethane (1.33 ml, 16.6 mmol) was added to a suspension of 3-bromo-5-trifluoromethyl-2(1H)-pyridone (2.0 g, 8.3 mmol) and silver carbonate (1.16 g, 4.2 mmol) in hexane (50 ml) and the mixture stirred for 64 h at room temperature. The resulting suspension was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel to give the product as a colourless oil (1.34 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: C1=COCCC1
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCCC#N)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC2CCCCO2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 19 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4 -(3-nitrophenyl )pyridine-3-carboxylic acid in 0.5 ml of tetrahydrofuran were added 5 mg of p-toluenesulfonic acid, and then 0.138 ml of 3,4-dihydro-2H-pyran. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified using preparative TLC to obtain 16.4 mg of the objective compound.