Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: CNc1cc(C)ccc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1ccc(C)cc1N(C)C=O
Reaction time: 1.5 h

Procedure:
A mixture of acetic anhydride (23.3 ml) and formic acid (15.9 ml) was stirred at 50 to 60° for 90 minutes and then cooled to 0 to 5° in an ice/salt bath. 4'-Methyl-2'-(methylamino)acetophenone (17.25 g) was added and the solution stirred at 20° for 3 hours. The reaction mixture was cooled to 0° and water (80 ml) added dropwise whilst maintaining the temperature below 8°. Aqueous sodium hydroxide (specific gravity 1.5, 60 ml) was added dropwise whilst maintaining the temperature below 10°. The mixture was extracted with dichloromethane (3×30 ml). The combined extracts were washed with aqueous sodium chloride (6M, 100 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (100:1) to give the novel compound 2'-acetyl-5'-methyl-N-methylformanilide, m.p. 58°-60°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.Cl.[CH3:37][C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1.COC1CNC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:40]3[CH2:41][C:38]([OH:42])([CH3:37])[CH2:39]3)=[O:30])=[C:16]2[N:15]=1
Reactant: CC1(O)CNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: COC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(O)CN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 22 mg, 0.066 mmol) was added CDI (22 mg, 0.13 mmol) at ambient temperature in one portion. After stirring two hours, 3-methoxyazetidine 3-methylazetidin-3-ol hydrochloride (18 mg, 0.13 mmol) was added in one portion, followed by addition of DIEA (0.035 mL, 0.20 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (21 mg, 71% yield). MS (apci) m/z=445.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[C-]#N.[Na+]>CCO.O>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: COc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Yield: 65.4 %

Procedure:
To a stirred solution of 4-methoxybenzaldehyde (2 g, 14.6 mmol) in EtOH (50 mL) was added a solution of NaCN (0.8 g, 16.3 mmol) in water (5 mL) and the reaction mixture was refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo to yield a crude material which was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone (1.3 g, 65%) as a solid.
Reaction SMILES: C(N(CC)CC)C.C[Si]([C:12]#[N:13])(C)C.[CH3:14][C:15]1[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]#[N:13])[CH:16]=1
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccnc(C#N)c1
Yield: 64.6 %

Procedure:
Triethylamine (13.4 mL, 91.9 mmol) and trimethylsilyl cyanide (25 mL, 187.5 mmol) were added sequentially to a solution comprising 4-methylpyridine N-oxide (5 g, 45.8 mmol) and acetonitrile (20 mL). The mixture was heated at reflux for 24 hours, cooled and diluted with methylene chloride (150 mL). Saturated sodium bicarbonate solution (100 mL) was added slowly to the mixture and then the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with water (2×150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide 4-methylpyridine-2-carbonitrile (3.5 g, 29.6 mmol) as a dark solid, 1H-NMR (300 Mhz, DMSO-d6): 2.4 (s, 3H), 7.6 (d, 1H, J=5 Hz), 7.8 (s, 1H), 8.6 (d, 1H, J=5 Hz), MS (ESI), Calculated for C7H6N2 : 228.24, Found (MH+): 119.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13]>O.CC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:5]2[C:4]([NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Oc1cccnc1O
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(Nc2cccc(Cl)c2)C(Nc2cccc(Cl)c2)=NC1=O
Reaction time: 2 h
Yield: 36 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), m-chloroaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(m-chlorophenylamino)-2,3-pyridindione in a yellow powder. The yield was 36%-57%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10]([C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2)CCCN(Cc2ccccc2)C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a stirred solution of 13 parts of 3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol in 270 parts of methylbenzene were added dropwise 10.9 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux temperature. After cooling to room temperature, the whole was washed with water and hydrochloric acid. The organic layer Was dried, filtered and evaporated, yielding 7 parts (58%) of ethyl 3-(3-chlorophenyl)-3-hydroxy-1-piperidinecarboxylate as a residue (intermediate 50).
Reaction SMILES: [CH2:1]([P:3]([CH2:9][OH:10])(=[O:8])[O:4][CH:5]([CH3:7])[CH3:6])[CH3:2].C([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])(C)C.[P].OO.[C:27](O)(=[O:29])C>CN(C1C=CN=CC=1)C.O.C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([P:3]([CH2:9][O:10][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:29][CH3:27])(=[O:22])=[O:21])(=[O:8])[O:4][CH:5]([CH3:7])[CH3:6])[CH3:2]
Reactant: CC(C)c1ccccc1S(=O)(=O)Cl
Reactant: CCP(=O)(CO)OC(C)C
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: OO
Agent: [P]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCP(=O)(COS(=O)(=O)c1ccccc1OC)OC(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 5.65 g of O-isopropyl P-ethyl(hydroxymethyl)-phosphinate, (Example 22, Method B), 7.0 ml of triethylamine and 25 ml of methylene chloride was added dropwise over 45 minutes to a mixture of 50 ml of methylene chloride, 8.03 g of crude 2-methoxybenzenesulfonyl chloride, (Example 4), and 0.1 g of DMAP. The reaction temperature was kept between 20° C. and 27° C. during the addition. The reaction was allowed to stir at room temperature for four days and was then diluted with 80 ml of water and 100 ml of methylene chloride. The phases were separated, the organic phase dried with magnesium sulfate, filtered and concentrated to yield 7.8 g of the crude product as a brown oil. Phosphorus NMR indicated two products in a 1:1 ratio. The crude product was dissolved in 35 ml of acetic acid and 12 ml of 30% hydrogen peroxide solution was added. After stirring for 10 minutes, the reaction temperature was slowly increased to 90° C. for 2.5 hours. The reaction was allowed to cool to room temperature and stand overnight and was then poured onto 100 g of ice and the mixture diluted with 100 ml of water. After the ice had melted, the aqueous mixture was extracted with 200 ml of ethyl acetate, the phases separated, the organic phase washed with 100 ml of saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated to yield the crude product as an oil. The oil was dissolved in 4 ml of methylene chloride and flash chromatographed on Merck silica gel (230-400 mesh) using blends of hexanes and ethyl acetate ranging from 30/70 to 10/90 hexanes and ethyl acetate, respectively. Similar fractions were combined and concentrated to yield 0.5 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccccc2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 18 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and benzoic acid (0.40 mmol) were mixed in THF (5 ml). Carbodiimde resin (495 mg, 0.5 mmol) was added and shaking continued for 18 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX) to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)benzamide. NMR; δH [2H6]—DMSO 10.25,(1H, s), 8.62,(1H, t), 7.95-7.92,(4H, m), 7.73,(1H, dd), 7.69,(1H, d), 7.60-7.50,(3H, m), 7.44,(2H, d), 7.28,(1H, d), 3.16,(2H, t), 2.20,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.41 min, MH+385.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: OCCc1ccccc1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenylethanol (0.61 g., 0.005 mole), 4-benzamidopiperidine (1.02 g., 0.005 mole) and Raney Nickel (W7, ca. 2g.) were stirred in xylene (50 ml.)and the mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. Filtration of the hot mixture provided a yellow solution which was stored at room temperature until crystallisation was complete. The title compound was obtained as cream needles (0.85 g.), m.p. 164°-7° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[N:7]=1.C(N(C(C)C)CC)(C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OCC)(=O)C>O1CCOCC1>[C:18]([N:25]1[CH2:26][CH2:27][N:28]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][CH:5]=2)[CH2:29][CH2:30]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: Clc1cnnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31.1 %

Procedure:
To a solution of 3,5-dichloro[1,2,4]triazine (0.34 g, 2.28 mmol.) in anhydrous dioxane (4 mL) was add diisopropylethylamine (0.44 g, 3.41 mmol.) and N—Boc-piperazine (0.424 g, 2.28 mmol.). The reaction mixture was stirred at room temperature for 40 minutes. Ethyl acetate (200 mL) was added. The organic solution was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporation under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 5-(4-Boc-piperazin-1-yl)-3-chloro[1,2,4]triazine 151 (0.212 g, 0.71 mmol.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][C:4]=2[N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:8]1[CH2:7][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccc2c(n1)CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 81.5 %

Procedure:
A mixture of 2-methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.063 ml), water (0.063 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2-methyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 82) (0.34 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@H:26]4[C@@H:30]5[O:31]C(C)(C)[O:33][C@@H:29]5[C@@H:28]([O:36][CH2:37][CH2:38][OH:39])[CH2:27]4)[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@@H:26]4[CH2:27][C@H:28]([O:36][CH2:37][CH2:38][OH:39])[C@@H:29]([OH:33])[C@H:30]4[OH:31])[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Yield: 23.9 %

Procedure:
A solution of 2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (450 mg, 0.80 mmol, 1.00 equiv.) in methanol (4 mL) and 12N hydrochloric acid (1.5 mL) was stirred at ambient temperature for about 3 hours. The pH value of the solution was adjusted to 8-9 by adding potassium carbonate. Following standard extractive workup with ethyl acetate (3×20 mL), the resulting crude residue was purified by silica gel column chromatography (dichloromethane/methanol (50:1)) to give a semi-crude product (200 mg; yield=48%). The semi-crude product, which contained about 5% of other diastereoisomers, was then further purified by chiral-prep HPLC (column: Chiralpak IA2×25 cm, 5 umChiral-P(IA)004IA00CJ-MB003) to afford the title compound (100 mg). [α]D24.1-43.2° (c, 0.2 g/100 mL in MeOH). LC-MS: m/z=523.0 (MH)+, Retention time: 1.58 minute. 1H NMR (300 MHz, CD3OD) δ: 7.08-7.23 (m, 3H), 5.13 (q, 1H), 4.75-4.79 (m, 1H), 4.17-4.20 (m, 1H), 3.91-3.95 (m, 1H), 3.63-3.73 (m, 4H), 3.06-3.26 (m, 2H), 2.90-3.00 (m, 1H), 2.70-2.80 (m, 1H), 2.05-2.29 (m, 2H), 1.60-1.88 (m, 2H), 1.38-1.59 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:5][CH:6]=1.[CH3:13][I:14]>C(O)C>[I-:14].[CH3:13][N+:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:8]=1
Reactant: CI
Reactant: Cc1coc(-c2cccnc2)n1
Solvent: CCO
Product: Cc1coc(-c2ccc[n+](C)c2)n1
Product: [I-]
Yield: 83.5 %

Procedure:
10.8 g of 3-(4-methyloxazol-2-yl)-pyridine and 19.4 g of methyl iodide are mixed together in 140 cm3 of ethanol, then heated under reflux for 6 hours. The solvent is evaporated, the residue is crystallized from a mixture of ethanol and ether and 17 g of expected product is obtained, which is recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][C:5]2[N:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1ccccc1Oc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ncccn3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H14FN5O, 359.12; m/z found, 360.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J=4.8, 2H), 8.43 (d, J=1.4, 2H), 7.58-7.46 (m, 3H), 7.42-7.27 (m, 4H), 7.20 (t, J=4.8, 1H), 6.88 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:33]([O:35][CH3:36])=[O:34])[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:23])([CH3:22])[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]1)=[O:9].C(O)C.Cl.C(OC(C)C)(C)C>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:33]([O:35][CH3:36])=[O:34])[CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:22])([CH3:23])[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C=O)CC2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Yield: 80.5 %

Procedure:
460 mg of 3-(4-formyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in 1.5 ml of methanol and 0.3 ml of an ethanol solution of 9.9H hydrogen chloride was added. After stirring the mixed solution for one night, isopropyl ether was added. The solid which separated was collected by filtration, dissolved in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After washing with saturated solution of sodium chloride, the extract was dried with anhydrous sodium sulfate; then, the solvent was evaporated under reduced pressure to give 350 mg of the subject compound (yield: 81%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])[CH2:14][C:15](=O)[CH3:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH3:30]>O1CCCC1>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])/[CH:14]=[C:15](\[NH2:30])/[CH3:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CC(=O)CC(=O)N1CCN(C2CCCCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C/C(N)=C/C(=O)N1CCN(C2CCCCC2)CC1
Reaction time: 8 h

Procedure:
0.1 mol of crude 3-oxo-butyric acid 4-cyclohexylpiperazide is dissolved in 150 ml of tetrahydrofuran and, under reflux, after addition of 0.5 g of p-toluenesulphonic acid, ammonia is passed in for 4 hours. The mixture is allowed to stand at room temperature overnight, the solvent is removed by distillation in vacuo, and the residue is crystallized from toluene/petroleum ether.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:26])[CH2:19][C@@H:20]([OH:25])[CH2:21][C:22]([OH:24])=[O:23])=[C:14]([CH:27]([CH3:29])[CH3:28])[N:13]=[C:12]([N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])[N:11]=2)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:26])[CH2:19][C@@H:20]([OH:25])[CH2:21][C:22]([O-:24])=[O:23])=[C:14]([CH:27]([CH3:29])[CH3:28])[N:13]=[C:12]([N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])[N:11]=2)=[CH:6][CH:5]=1.[CH3:1][NH3+:2]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: CN
Solvent: CO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Product: C[NH3+]
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A solution of methylamine in methanol (1.4 ml of a 40% solution) was added with stirring to a solution of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid (obtained as described below) at −5° C. The mixture was stirred at 30° C. for 90 minutes and then cooled to 3° C. The crystalline product was collected by filtration, washed with acetonitrile and dried under vacuum at 40° C. to give methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (3.85 g; 87.9% yield) as white crystals. (The same crystalline salt was obtained when a 40% solution of methylamine in water (1.1 ml) was used). The X-ray powder diffraction spectra (XRD) for a typical sample of the crystalline methylammonium salt is shown in FIG. 2 hereinafter. The ten most prominent peaks in the XRD occur at about 2-theta=8.2, 12.3, 15.7, 16.5, 17.6, 18.7,19.9, 21.0, 24.3 and 25.9°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32]>C(N(CC)CC)C>[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reactant: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.8 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.6 g HOBtxH2O and 15.0 ml triethylamine is stirred at ambient temperature for 0.5 h. Then 6.04 g EDCxHCL are added and the suspension is stirred again for 0.5 h. Finally 1.23 g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 4.6 g of a yellow foam are obtained.