Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].N[C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1
Reactant: Nc1nnc(-c2ccc(Cl)cc2)s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc(-c2nnc(Cl)s2)cc1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
Stirred 37% hydrochloric acid, 225 ml, was cooled in a salt-ice bath, and 2-amino-5-(4-chlorophenyl)-1,3,4-thiadiazole (18.3 g, 0.087 mole) was added. The mixture was cooled to -5° C., and a solution of sodium nitrite (25.0 g, 0.338 mole) in 100 ml of water was added dropwise during a one hour period. Upon complete addition, the reaction mixture was allowed to warm to room temperature, where it was stirred for 16 hours. The reaction mixture was heated for one hour on a steam bath, cooled, then filtered to isolate the precipitated solid. The solid was recrystallized from ethanol to give 2-chloro-5-(4-chlorophenyl)-1,3,4-thiadiazole (6.0 g, mp 125°-127° C.).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[C:33](=[C:34]([CH:38]=O)[CH:35]=[CH:36][CH:37]=3)[N:29]2[CH2:28][CH2:27][CH2:26]1>O1CCCC1.O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](/[CH:38]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:33]=3[N:29]2[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% in oil, 230 mg, 5.76 mmol) was added to a stirred solution of ethyl (diethoxyphosphoryl)acetate (1.94 g, 8.67 mmol) in tetrahydrofuran (14 mL) at 0° C. After stirring 10 min, 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.88 mmol) in tetrahydrofuran (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (908 mg, 2.18 mmol, 76%).
Reaction SMILES: C(OC(=O)[N:7]([C:18]1[N:23]=[CH:22][C:21]([CH:24]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]([S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:27]=2)O)=[CH:20][N:19]=1)[CH2:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:40]1([S:37]([N:28]2[C:29]3=[N:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[C:34]3[C:26]([CH2:24][C:21]3[CH:22]=[N:23][C:18]([NH:7][CH2:8][C:9]4[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=4)=[N:19][CH:20]=3)=[CH:27]2)(=[O:39])=[O:38])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cnc2c(c1)c(C(O)c1cnc(N(Cc3cc(F)cnc3OC)C(=O)OC(C)(C)C)nc1)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(c1)c(Cc1cnc(NCc3cc(F)cnc3OC)nc1)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
To {5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyrimidin-2-yl}-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (124, 1 equivalent) in 10.0 mL of acetonitrile, triethylsilane (15.6 equivalents) and trifluoroacetic acid (16.9 equivalents) are added. The reaction is heated at 80° C. for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound, which is used in the next step without further purification.
Reaction SMILES: I[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Cl:11]
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)O

Procedure:
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid (3.12 g, 10 mmol) of Example 20, Step A in N,N-dimethylformamide (100 mL) was added 2-chlorophenyl boronic acid (5.07 g, 32.4 mmol) and potassium carbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen and then treated with tetrakis(triphenylphosphine) palladium(0) (0.58 g, 0.5 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide a nearly quantitative amount of the title acid which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30](=N)OCC.C(=O)([O-])O.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:29]3[CH:35]=[CH:36][CH:37]=[C:27]([O:26][CH3:25])[CH:28]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: CCOC(=N)c1cccc(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in methanol (5 mL) was added ethyl 3-methoxybenzimidate hydrochloride (153 mg, 0.711 mmol), and this was stirred at room temperature for 8 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (216 mg, 79% yield) as light brown crystals.
Reaction SMILES: [N+:1]([C:4]1([N+:10]([O-:12])=[O:11])[CH2:9][O:8]C(=O)[CH2:5]1)([O-:3])=[O:2].[N+](C(C)C(O)=O)([O-])=[O:14]>>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([CH3:5])[C:9]([OH:14])=[O:8])([O-:3])=[O:2]
Reactant: O=C1CC([N+](=O)[O-])([N+](=O)[O-])CO1
Reactant: CC(C(=O)O)[N+](=O)[O-]
Product: CC(C(=O)O)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A unique synthesis involving the latter substrates covers the synthesis of 3,3-dinitrobutyrolactone. 2-nitropropionic acid can be nitrated to provide 2,2-dinitropropionic acid, which is formylated to give the corresponding methylol derivative, which is then cyclized to the lactone.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:28][OH:29])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Yield: 86.6 %

Procedure:
12 g (35 mmol) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile were stirred at boiling temperature for 2 hours with 9.6 g (94 mmol) of sodium bicarbonate and 7.3 g (105 mmol) of hydroxylamine hydrochloride in 170 ml of ethanol and 40 ml of water. After evaporating the alcohol the suspension obtained was cooled and the crystallizate was filtered off under suction and dried. There were obtained 11.4 g (86%) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime of m.p. 235°-237°.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O-:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])=[CH:10][CH:11]=2)[CH2:6]1.[Na+].[Na+].Cl>O>[OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: O=C([O-])CCCCCc1ccc2c(c1)C[C@@H](NCC(O)c1ccc([O-])c(CO)c1)CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CO)c1)CC2
Yield: 66.2 %

Procedure:
Disodium 6-[(2S)-2-[[(2RS)-2-hydroxy-2-(3-hydroxymethyl-4-oxidophenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yl]hexanoate (Compound 11) (20 mg) was dissolved in water (192 μl), and 1 N hydrochloric acid (77 μl) was added to the solution under ice-cooling with stirring. After reaction for 2 hours, the reaction mixture was concentrated in vacuo, and methanol was added to the residue. The insoluble material was filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by medium pressure liquid column chromatography on octadecyl silica gel (eluent: water/acetonitrile=2/1) gave 6-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yl]hexanoic acid (Compound 12) (12 mg) as an amorphous.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH:3]([OH:15])[CH2:4][O:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:13])=[N:10][C:11]=1[Cl:12].C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:13][C:9]1[N:10]=[C:11]([Cl:12])[C:6]([O:5][CH2:4][CH:3]([OH:15])[C:2]([CH3:1])([CH3:17])[CH3:16])=[C:7]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:8]=1
Reactant: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 3,3-dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol (275 mg, 1.05 mmol) in IMS (3 mL) was added triethylamine (291 μL, 2.09 mmol) followed by morpholine (100 μL, 1.15 mmol) and stirred at RT for 2 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution then extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) then concentrated in vacuo giving 1-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-3,3-dimethyl-butan-2-ol (255 mg, 77%). LCMS: RT=3.57 min, [M+H]+=350/352/354.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21].[OH-].[K+]>O>[CH3:5][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[C:10]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:11]1
Reactant: COS(=O)(=O)OC
Reactant: CS(=O)(=O)Cc1cnc2ccccc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl sulphate (3.0 ml) was added to a stirred solution of 4-hydroxy-3-methylsulphonylmethylquinoline (1.9 g.) and potassium hydroxide (1.4 g.) in water (20 ml.) at 5°. The mixture was stirred at room temperature for 4 hours, then filtered to give the novel 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 204°-205° (from acetone).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH3:25])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:5][CH:4]=1)#[N:2].[OH-].[K+].CO>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH3:25])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCCc1c(C)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3ccc(C#N)cc3)c(CCCCCC(=O)O)c(C)nn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 4.7 %

Procedure:
To a solution of ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (15 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4 ml), followed by methanol (7.4 ml). After stirring at 50° C. for 2 hours and 60° C. for 3 hours, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The precipitates were filtered and washed with ethyl acetate. The organic layer and the washings were combined, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ethyl acetate and the precipitates were filtered. The filtrate was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and hexane (1:1) and triturated with isopropyl ether to give 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid (650 mg) as an yellow crystals. The two precipitates were combined and recrystallized from ethyl acetate to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (550 mg, 37.6%) as an yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>[H-].[Na+]>[C:9]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:10])[CH2:8][C:7]([CH3:6])=[O:11]
Reactant: OCC1CC1
Reactant: C=C1CC(=O)O1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCC1CC1
Yield: 92.8 %

Procedure:
0.1 g of sodium hydride (50%) was added to 25 g of cyclopropylmethanol and then 29 g of diketene was added dropwise thereto at a temperature of 50° to 60° C. with stirring. After completion of the addition, the mixture was heated at that temperature for 1 hour. The resulting oil was distilled under reduced pressure to obtain 50 g (93% yield) of cyclopropylmethyl acetoacetate as a colorless oil having a boiling point of 78° C. (4 mmHg).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2OC)=[CH:6][CH:5]=[CH:4][C:3]=1[S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18].[CH3:23][C:24]1[O:28][C:27]([CH:29]([NH2:35])[C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[CH:26][CH:25]=1>CO>[OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:35][CH:29]([C:27]2[O:28][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:30]2([CH3:34])[CH2:31][O:32][CH2:33]2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18]
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COc1c(Nc2cccc(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(S(=O)(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A mixture of 284 mg (0.87 mmol, 1 eq) of 2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)-N,N-dimethylbenzenesulfonamide and 318 mg (1.75 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 20 ml of methanol was heated at 50° C. for 3 days. The reaction medium was concentrated. The residue was taken up in ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 0.29 g of product was obtained in the form of an ochre solid. Yield=70%, HPLC=98.68%, Mp=123° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](C)([C:14](OC)=O)[C:11](=[O:19])[C:10](C)([C:20](OC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CN(Cc2ccccc2)CC(C)(C(=O)OC)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)C1=O
Temperature: 10 °C
Yield: 95 %

Procedure:
A mixture of the crude dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate (786.0 g, ca. 2.3 mol) and 1M hydrochloric acid solution (11.5 L) was refluxed for 24 hours. The reaction mixture was cooled to 10° C. and 25% wt. aqueous sodium hydroxide solution (1.92 kg) was added slowly. The mixture was extracted with dichloromethane (4×4 L), and the combined organic extracts concentrated to dryness to give the crude (3R,5S)-1-benzyl-3,5-dimethylpiperidin-4-one (475 g) as a light brown oil. The 1H NMR indicated that it was a 6:1 desired: undesired diastereomeric mixture.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=[O:17])[CH:14]([NH:18][C:19](=[O:38])[C@@H:20]([C@H:23]4[C@@H:28]([OH:29])[C@@H:27](/[CH:30]=[CH:31]/[C:32]([CH3:35])([CH3:34])[CH3:33])[O:26]C(C)(C)[O:24]4)[O:21][CH3:22])[CH2:13][CH2:12][C:11]=3[CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=[O:17])[CH:14]([NH:18][C:19](=[O:38])[C@H:20]([O:21][CH3:22])[C@H:23]([OH:24])[C@@H:28]([OH:29])[C@H:27]([OH:26])/[CH:30]=[CH:31]/[C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:13][CH2:12][C:11]=3[CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[C@@H](C(=O)NC1CCc2cc(-c3ccccc3)ccc2NC1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CCc2cc(-c3ccccc3)ccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C

Procedure:
150 mg of 15 (280 μmol) in 1,4 ml of THF and 2.78 ml of 1N hydrochloric acid are introduced into a 20 ml round-bottomed flask, with stirring and under argon. The stirring is maintained for 4 h at AT. The medium is neutralized with NaOH (1N), to pH 7, and extracted with 2 times 5 ml of EtOAc. The combined organic phases are dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed on a silica cartridge (10 g) with an eluent of CH2Cl2/MeOH (as an MeOH gradient of 1 to 10%). 85 mg of expected product Ex4 are recovered. 58 mg of Ex4 are separated by preparative chiral HPLC (Chirapad AD-H 5 μm 250×4.6 mm, flow rate 1 ml/min, mobile phase: 70% heptane-30% EtOH, 0.1% TEA), to give 16 mg of Ex4a (tr=13.42 min) and 40 mg of Ex4b (tr=18.96 min).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]([CH:12]=O)[C:10]#[N:11])[CH:6]=[CH:5][N:4]=1.[NH2:14][NH2:15].O.Cl>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:12]=[N:14][NH:15][C:10]=2[NH2:11])[CH:6]=[CH:5][N:4]=1
Reactant: NN
Reactant: CSc1nccc(C(C#N)C=O)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2cn[nH]c2N)n1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A suspension of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile (5) (100 g, 0.52 mol), NH2NH2—H2O (85%, 31.2 g, 0.62 mol) and conc. HCl (60 mL) in ethanol (1 L) was stirred at reflux for 5 h. After cooled to room temperature, the mixture was concentrated in vacuum, and the residue was washed with ether (200 mL×3) and suspended in H2O (200 mL). The mixture was basified with saturated aq. Na2CO3 to pH 9 and the precipitate was collected. The solid was washed with H2O (100 mL×3) and ether (200 mL×3), then dried in vacuum to give 4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-5-amine (6) (56.8 g, 51.8%) as a yellow solid. 1H NMR (400 MHz, CD3CN): δ 8.295 (d, 1H), 7.826 (s, 1H), 7.101 (d, 2H), 5.800 (d, 1H), 2.586 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[N:4]=1.N1(C2C=C[C:25]([CH:26]=[O:27])=CC=2)C=CC=N1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12](/[CH:13]=[CH:25]/[CH:26]=[O:27])=[CH:11][CH:10]=2)[N:4]=1
Reactant: COc1ccnc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: COc1ccnc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methoxy-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 13) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 241 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[C:9](C)([CH3:10])[NH:8][C:7](C)([CH3:12])[CH:6]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19])[CH:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[Cl:28])(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:32]1([C:38]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(C)C.C(OCC)C>[ClH:19].[C:1]([C:4]1[CH:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])[C:6]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:41]2[CH2:40][CH2:39][C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:43][CH2:42]2)=[C:7]([CH3:12])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(c2cccc(Cl)c2Cl)C(C(=O)CCCCCl)C(C)(C)NC1(C)C
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc(Cl)c1Cl

Procedure:
5 g (12 mmol) 5-acetyl-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-2,6-dimethyl-3-(5-chloropentanoyl)-pyridine are reacted first with 3.6 g (24 mmol) sodium iodide and then with 6.9 g (24 mmol) 4,4-diphenylpiperidine hydrochloride, as described for starting compound B. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=7/3. The product thus obtained is taken up in 20 ml isopropanol and the mixture is diluted with 5 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 2.3 g (30%). M.p. 258°-259° C. decomp. (acetonitrile).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:6]1=2>CCO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:13]=1
Reactant: COCCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: COCCN1C(=O)CCCc2cc(N)ccc21
Yield: 54 %

Procedure:
To a solution of the above 1-(2-methoxy-ethyl)-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in EtOH (10 mL) was sequentially added 10% Pd/C (120 mg) and hyrdrazine-monohydrate (1 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine. The residue was recrystallized from EtOAc/heptane to afford transparent prisms of 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (345 mg, 54%) that had the following properties: mp: 134-135° C.; LC/MS (ESI+): 235 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 7.08 (d, J=8.4, 1H), 6.60 (d, J=8.4, 1H), 6.51 (s, 1H), 4.20 (br s, 1H), 3.65 (m, 2H), 3.53 (m, 2H), 3.28 (s, 3H), 2.60 (br s, 1H), 2.27 (m, 2H), 1.58 (m, 3H).