Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:21]C(=O)C1C=CC=CC=1)=[N:9]2.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:18])([F:19])[F:20])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 65 °C
Yield: 97.5 %

Procedure:
To a solution of N-((4aS,5S,7aS)-7a-(2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (250.2 g, 589.5 mmol) in methanol (1.25 L) was added K2CO3 (81.5 g, 590.0 mmol). The suspension was heated to 65° C. for 6 h. Upon cooling to ambient temperature, the solvent was evaporated under vacuum. To the resulting residue, was added 1.0 N aq NaOH (1.18 L) and THF (502 mL). The heterogeneous mixture was heated to 45° C. for 1 h. The mixture was cooled to ambient temperature, and EtOAc (1.38 L) was added. The aqueous layer was extracted with EtOAc (0.75 L). The organics were combined, washed with saturated aq. NaHCO3 (500 mL) and saturated aq. NaCl (500 mL). The organics were concentrated under vacuum to afford the title compound as a brown oil (184.1 g, 91.6% yield accounting for residual solvents). 1H NMR (500 MHz, DMSO) δ ppm 7.49-7.42 (m, 1H), 7.40-7.33 (m, 1H), 7.26-7.15 (m, 2H), 6.26 (s, 2H), 4.77-4.54 (m, 1H), 4.40 (d, J=8.0 Hz, 1H). 3.80 (dd, J=7.9, 2.3 Hz, 1H), 3.24-3.17 (m, 1H), 3.00 (dd, J=13.9, 3.2 Hz, 1H), 2.85 (dd, J=13.9, 3.9 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 159.75 (d, JCF=245.1 Hz), 149.51, 131.31 (d, JCF=3.9 Hz), 130.13 (d, JCF=8.8 Hz), 128.08 (d, JCF=10.4 Hz), 128.28 (q, JCF=282.1 Hz). 124.87 (d, JCF=3.0 Hz), 116.80 (d, J=23.8 Hz). 78.77, 76.80 (q, JCF=30.8 Hz), 66.31, 36.37, 23.27.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1([C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[C:22]3[CH2:39][CH2:40][CH2:41][C:21]=3[N:20]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH:51]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C)C=O>[CH:51]1([NH:56][C:36]([C:32]2([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23]4[C:22]5[CH2:39][CH2:40][CH2:41][C:21]=5[N:20]=[C:19]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[N:24]=4)=[CH:31][CH:30]=3)[CH2:33][CH2:34][CH2:35]2)=[O:37])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: NC1CCCC1
Reactant: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCC1)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 16 h
Yield: 46.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.48 g, 2.5 mmol) was added to a mixture of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid (0.5 g, 1.2 mmol), 1-hydroxybenzotrialzole (0.09 g, 0.65 mmol), diisopropylethylamine (0.43 mL, 2.5 mmol), and cyclopentylamine (0.13 mL, 1.3 mmol) in anhydrous dimethylformamide and stirred at a temperature in the range of 15° C. to 25° C. under N2 for 16 hours. The reaction was quenched by addition of water. The precipitated solid was filtered, washed with water and dried in vacuo. The crude was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.26 g, 45% yield).
Reaction SMILES: [CH:1]1([C:5]2[C:10]([F:11])=[C:9]([NH:12]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C2CCC2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(C2CCC2)c1F
Yield: 89.3 %

Procedure:
Using the Procedure of Example 12, 2-cyclobutyl-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.298 g, 4.5 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-cyclobutyl-5-fluoropicolinaldehyde (0.780 g, 88%) as a white solid: mp 134-135° C.; 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.22 (d, J=6.7 Hz, 1H), 4.34 (s, 2H), 3.90 (m, 2H), 2.51 (pd, J=9.3, 2.4 Hz, 3H), 2.32 (qt, J=8.5, 2.7 Hz, 3H), 2.03 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 193.39, 151.45 (d, J=14.5 Hz), 148.62 (d, J=5.4 Hz), 148.24 (d, J=253.9 Hz), 141.03 (d, J=12.5 Hz), 107.43 (d, J=3.6 Hz), 35.38 (d, J=2.0 Hz), 27.00 (d, J=1.6 Hz), 18.64; 19F NMR (376 MHz, CDCl3) δ −144.82; HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O, 194.0855. found, 194.0855.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19]I>CN(C)C=O>[CH3:19][N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 60% sodium hydride (0.14 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.6 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methyl iodide (0.44 g) in dimethylformamide (1 ml) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.57 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]1[NH:20][C@@H:19]([C:21]([OH:23])=[O:22])[C:18]([CH3:25])([CH3:24])[S:17]1>O>[C:1]([N:20]1[C@@H:19]([C:21]([OH:23])=[O:22])[C:18]([CH3:25])([CH3:24])[S:17][C@H:16]1[C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])(=[O:3])[CH3:2]
Reactant: CC1(C)SC(c2ccc(Cl)cc2Cl)N[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
5.56 ml of acetic anhydride are given to a hot suspension containing 2-(2,4-dichlorophenyl)-5,5-dimethylthiazolidine-4(S)-carboxylic acid in 5.56 ml of water. The mixture is heated at 100° C. for 6 minutes, then cooled down and diluted with 10 ml of water. The crystalline precipitate is filtered to give the title compound in a yield of 2.57 g (73.8%). After recrystallization from a mixture of methanol and water, this acid melts at 233°-235° C., [α]d22 =-142.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)=[CH:5][CH:4]=1.Br.[CH3:19]I>C(O)(=O)C>[OH:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CSc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1
Temperature: 35 °C

Procedure:
5-(4-Methoxybenzyl)-2-thiouracil (105 g) was refluxed in glacial acetic acid (800 ml) and 48% aqueous hydrobromic acid (400 ml) for 3 hrs. The solution was cooled to ca. 35° C., methyl iodide (53 ml) was added and the solution was refluxed for a further 2 hours. The mixture was evaporated to dryness in vacuo and water (500 ml) added to the residue. Sodium hydroxide was added to raise the pH to ca. 5. The solid which formed was filtered off and recrystallised from ethanol giving 4-hydroxybenzyl-2-methylthio-4-pyrimidone (43.1 g) m.p. 243°-4° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)=O>N1C=CC=CC=1>[CH2:8]([NH:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)O
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(CC(=O)O)NCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
3-Methylcrotonic acid (12.0 g) was dissolved in pyridine (40 ml), and benzyl amine (12.8 g) was added thereto, and the mixture was stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, and after acetone was added to the resulting suspension, crystals were collected by filtration and washed. The crystals were dried under reduced pressure to give 3-benzylamino-3-methylbutanoic acid (10.3 g, Y.:42%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:49]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][C:47]=1[Cl:48]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:46]5[CH:45]=[C:44]([C:49]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)=[O:50])[CH:43]=[CH:42][C:47]=5[Cl:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(c1ccc(Cl)c(Br)c1)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCOCC4)ccc3Cl)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (3-bromo-4-chloro-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-chloro-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-310) as a pale brown powder (16 mg, 24%).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[CH3:19][O-].[Na+].CI.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([CH3:19])[C:4]#[N:5]
Reactant: C[O-]
Reactant: CSC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSC(C)(C#N)c1cccc(Oc2ccccc2)c1
Yield: 82 %

Procedure:
956 ml of alpha-(methylthio)(m-phenoxyphenyl)-acetonitrile was dissolved in 5 ml of anhydrous methanol, and 1.7 ml of a 2.5 M methanol solution of sodium methoxide was added at room temperature in an atmosphere of argon. The mixture was stirred, and 0.34 ml of methyl iodide was added dropwise. The mixture was further stirred for 1 hour at room temperature. An aqueous solution of ammonium chloride (3 g/20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 25 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 817 mg (yield 82%) of alpha-(methylthio)-alpha-(m-phenoxyphenyl)-propionitrile as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[CH2:1]([O:8][C@@H:9]([C:10]1[O:11][C:20](=[O:21])[NH:13][N:12]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](OCc1ccccc1)C(=O)NN
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)c1n[nH]c(=O)o1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(benzyloxy)propanehydrazide (194 mg, 1 mmol) in anhydrous THF (2 mL) was added CDI (178 mg, 1.1 mmol) and the resulting mixture was allowed to stir one hour. Solvent was removed under reduced pressure and the residue was purified on silica gel. Elution with EtOAc yielded title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][N:11]([CH3:29])[C:12]([C:14]1[S:18][C:17](CNC(=O)OC(C)(C)C)=[CH:16][C:15]=1[CH3:28])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:33](CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH3:30][N:8]([CH2:9][CH2:10][N:11]([CH3:29])[C:12]([C:14]1[S:18][C:17]([NH:33][CH3:31])=[CH:16][C:15]=1[CH3:28])=[O:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CNc1cc(C)c(C(=O)N(C)CCN(C)C(=O)OC(C)(C)C)s1
Yield: 98.6 %

Procedure:
The compound (418 mg, 0.947 mmol) obtained in Example 90a, triethylamine (0.658 mL, 4.74 mmol) and di-tert-butyl dicarbonate (248 mg, 1.14 mmol) were used to give the title compound (319 mg; yield, 99%) as a yellow oily substance according to the method described in Example 89c.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-N,N-dimethyl-benzamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=436.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[C:12](#[N:14])[CH3:13]>C1CCCCC1.O>[CH3:10][C:7]([CH3:8])([CH3:9])[C:6](=[O:11])[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)(C)C(=O)CC#N
Temperature: 80 °C

Procedure:
To a refluxed solution of sodium hydride (33.18 g, 553.03 mmol) in 275 mL of cyclohexane is added a mixture of 2,2-dimethyl-propionic acid ethyl ester (30 g, 230.43 mmol) in 79 mL acetonitrile (553.03 mmol) in 25 mL of cyclohexane. The mixture is maintained at 80° C. overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water, dried over sodium sulfate, filtered and concentrated to afford title compound which was used crude in subsequent reaction. ESI m/z 124=MH−
Reaction SMILES: [NH2:1][NH2:2].O[CH:4]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)[C:5](OCC)=[O:6]>C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:2]=[N:1][C:5]([OH:6])=[CH:4][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(O)CC(=O)c1ccc(OC)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2ccc(O)nn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
4.91 ml (98.0 mmol) of hydrazine was added to an ethanol solution (50 ml) of 20.62 g (82.0 mmol) of the obtained ethyl 2-hydroxy-4-(4-methoxyphenyl)-4-oxo-butyrate, and the reaction liquid was stirred at 60° C. for 4 h ours. The reaction liquid was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 16.18 g (yield: 80%) of 6-(4-methoxyphenyl)-pyridazin-3-ol as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 45.9 %

Procedure:
4-chloro-3-nitro-pyridine (1 g, 6.307 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.145 g, 6.938 mmol) and PdCl2(PPh3)2 (221.4 mg, 0.3154 mmol) in DME (20.00 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (9.460 mL of 2 M, 18.92 mmol) was added followed by further degassing and the reaction heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column, eluting with 0 to 70% EtOAc/Petroleum Ether, dry loaded) to give tert-butyl 3′-nitro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate as a pale yellow solid (884 mg, 46% Yield). MS (ES Na+) 328.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=3)[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=2)=[CH:4][CH:3]=1.[CH3:27][N:28](C)C=O.[C-]#N.[Na+].Cl>O>[C:24]([C:19]1[CH:18]=[C:17]([N:9]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:7][CH:6]=2)[CH:22]=[CH:21][C:20]=1[OH:23])([OH:26])=[O:25]
Reactant: O=C(O)c1cc(-n2c(-c3ccc(Br)cc3)cc3c2CCCC3)ccc1O
Reactant: CN(C)C=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2cc3c(n2-c2ccc(O)c(C(=O)O)c2)CCCC3)cc1

Procedure:
A mixture of 6.18 g. (0.015 mole) of 2-(4-bromophenyl)-1-(3-carboxy-4-hydroxyphenyl)-4,5,6,7-tetrahydroindole, 1.6 g. (0.018 mole) of cuprous cyanide, and 10 ml. of dimethyl formamide was heated under reflux for 6 hours, poured into a solution of 3 g. of sodium cyanide and 10 ml. of water, and after 5 minutes diluted with 46 ml. of water. The solution was acidified to pH 1-2 with hydrochloric acid and the solid which separated was collected. Recrystallization from acetic acid gave 1.21 g. (23%) of crystals, m.p. 242°-244°.
Reaction SMILES: O1CCCC1.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:47])=[C:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C@@H:27]([O:32][C:33]([O:35]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:28]([O:30][CH3:31])=[O:29])=[CH:20][C:19]=2[O:45][CH3:46])[N:15]=1.[NH3:48]>O>[C:33]([O:32][C@H:27]([CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:14]2[N:15]=[C:11]([C:7]3[O:6][CH:10]=[CH:9][CH:8]=3)[O:12][C:13]=2[CH3:47])=[C:19]([O:45][CH3:46])[CH:20]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:35])[NH2:48]
Reactant: N
Reactant: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(N)=O
Yield: 89 %

Procedure:
Into a tetrahydrofuran (THF) (80 ml) solution of methyl (R)-(+)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolyl methoxy]-3-methoxyphenyl]-2-(4-nitrophenoxycarbonyloxy)pentanoate (4.25 g) was introduced ammonia (gas) for 10 minutes at temperature ranging from -65 to -70° C. The reaction mixture was poured into water-6N HCl, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:1), was obtained methyl (R)-(+)-2-carbamoyloxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (3.0 g, 89%), which was recrystallized from acetone-isopropyl ether to give colorless needles, m.p.110-111° C. [α]D +5.30° (c=1. 0, CH3OH)
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[N:12][C:9]=3[C:10]=2[N:11]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]3[CH:15]=[CH:14][CH:13]=[N:12][C:9]=3[C:10]=2[N:11]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3cccnc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 500 mg (2,35 mmol) 2,3-dihydroxy-pyrido(2,3-f)quinoxaline in 25 ml sulfuric acid (95-97%) was ice-cooled, and 238 mg (2,35 mmol) potassium nitrate was added. Stirring was continued at 0° C. for 1/2 h and then at 25° C. for 4 h. The reaction mixture was poured into 100 ml ice-water. The precipitate was filtered off and washed with water. The crude product was recrystallized (dimethyl formamide - water) to give 425 mg (70%) of pure 2,3-dihydroxy-6-nitropyrido-(2,3-f)quinoxaline, m.p. >300° C.1H NMR (DMSO-d6): 13,7 (2H,broad s), 9,0 (1H,d), 8,8 (1H,d), 7,86 (1H,s), 7,6 (1H, double d).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([C:14](=[O:22])[CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:12][CH:11]3[CH2:23][CH2:24][CH2:25][N:10]3[CH2:9][C:8]=2[CH:26]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([C:14](=[O:22])[CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:12][CH:11]3[CH2:23][CH2:24][CH2:25][N:10]3[CH2:9][C:8]=2[CH:26]=1
Reactant: [H][H]
Reactant: O=C(CCN1CCCC1)N1CC2CCCN2Cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CN1CCCC1CN2C(=O)CCN1CCCC1

Procedure:
A mixture of 5 g. of 2,3,5,10,11,11a-hexahydro-7-nitro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c][1,4]benzodiazepine, 250 ml. of ethanol and 2 g. of 10% palladium on carbon catalyst is shaken under about 3 atmospheres of hydrogen pressure in a Parr hydrogenerator until hydrogen uptake is complete. The catalyst is filtered off and the mother liquor is concentrated to obtain the 7-amino-2,3,5,10,11,11a-hexahydro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine.
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C=O.[C:17]([O-])(=[O:19])C.[Na+].[OH-].[Na+]>C(O)(=O)C.ClCCl>[OH:19][CH2:17][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccn2c1CO
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (5.0 g) in acetic acid (30 ml) were added 37% formaldehyde (14 ml) and sodium acetate (8.0 g) at room temperature, and the reaction mixture was heated under reflux for 15 hr. The reaction mixture was cooled to room temperature and dissolved in dichloromethane. The mixture was adjusted to pH 8 with 10% aqueous sodium hydroxide solution at 0° C. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with dichloromethane-methanol (15:1) was concentrated under reduced pressure to give the object product (2.1 g).