Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCCCO.CCOC(C)=O>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Oc1ccnc(Cl)c1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(O)ccn2)CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
To a solution of 2-chloro-4-hydroxypyridine (12.9 g, 100 mmol) in n-BuOH (50 mL) was added t-butyl piperazine-1-carboxylate (46.5 g, 250 mmol). The mixture was heated at 140° C. for 3 days and then diluted with EtOAc (2 L) at ambient temperature. The organic phase was washed with saturated NH4Cl solution and then brine. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (5%-20% MeOH/CH2Cl2) to give 12.2 g (44%) of t-butyl 4-(4-hydroxypyridin-2-yl)piperazine-1-carboxylate as a white solid. MS m/z 280.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (1H, d, J=6.62 Hz), 6.20 (1H, dd, J=6.31, 2.21 Hz), 6.02 (1H, d, J=1.89 Hz), 3.56 (4H, m), 3.42 (4H, m), 1.50 (9H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=c1ccc(Br)c[nH]1
Product: N#Cc1ccc(N(CCOc2ccc(Br)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 5-bromo-2(1H)-pyridinone using dry DME as the reaction solvent: MS (ESI) m/z 468 (M+1, 79Br), 470 (M+1, 81Br).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][C:32]=1[CH2:42][CH2:43][C:44]([OH:46])=O.Cl.[CH3:48][N:49]1[CH2:55][C:54]2[CH:56]=[C:57](/[CH:60]=[CH:61]/[C:62](O)=O)C=N[C:53]=2[NH:52][C:51](=O)[CH2:50]1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:2]([CH3:1])[CH2:3][C:4]2[N:5]([CH3:13])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:41])=[CH:33][C:32]=1[CH2:42][CH2:43][C:44](=[O:46])[N:52]([CH3:53])[CH2:51][C:50]1[N:49]([CH3:48])[C:55]2[C:61]([CH:62]=1)=[CH:60][CH:57]=[CH:56][CH:54]=2
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CCC(=O)O
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CCC(=O)N(C)Cc2cc3ccccc3n2C)c1
Yield: 28 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[6-amino-5-(2-carboxy-ethyl)pyridin-3-yl]acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.37 g, 28%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.75-7.68 (m, 1H), 7.49-7.34 (m, 5H), 7.11-6.98 (m, 5H), 6.39-6.12 (m, 4H), 4.95-4.68 (m, 4H), 3.69 (s, 3H), 3.61 (s, 3H), 3.02-2.71 (m, 10H); MS (ESI) m/e 549 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>ClCCl.C(Cl)(Cl)Cl>[C:35]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27])(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)Cl
Reactant: NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-aminomethyl-3-chlorophenyl)-5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (70.0 mg) and triethylamine (15.0 mg) in dichloromethane (2 mL) was added butyryl chloride (15.4 mg) at 5° C. The reaction mixture was then stirred at room temperature for 1 hour. The resulting mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (3 mL) and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by liquid chromatography (medium pressure collection apparatus: Purif-α2 manufactured by Moritex Corporation) eluted with ethyl acetate-hexane (1:10) to afford the title compound as a colorless resin (42.0 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 4-benzyl-2-hydroxymethylmorpholine (118.8 g.) in dry pyridine (250 ml.) toluene-p-sulphonyl chloride (120.2 g.) is added gradually at 18°-25° C. The mixture is stirred for 20 hours at ambient temperature (ca. 20° C.) and the pyridine is removed under diminished pressure. The residue is diluted with water, the mixture made alkaline by the addition of sodium hydroxide solution, and the product is then extracted into ether. The ethereal solution is dried (MgSO4) and filtered, the ether is evaporated and the residual solid is crystallised from cyclohexane or petroleum ether (b.p. 60°-80° C.) to give 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine, m.p. 78°-79° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34]Cl.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][CH2:41][N:36]1[CH2:34][CH2:33][CH2:39][CH2:38][CH2:37]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (67 mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare a solution. Potassium carbonate (225 mg) and 1-bromo-2-chloroethane (0.15 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Potassium carbonate (300 mg) and piperidine (0.5 ml) were added to the reaction solution, and the mixture was further stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (69 mg, yield 78%) (2 steps).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 8 h
Yield: 200.1 %

Procedure:
To a solution of L-tert-leucine (5.12 g, 39 mmol, 1 equiv) in 1,4-dioxane (80 mL) and 1 M NaOH (39 mL, 39 mmol, 1.0 equiv) at 0° C. was added benzyl chloroformate (6.24 mL, 43.68 mmol, 1.12 equiv). The reaction mixture was stirred at 23° C. overnight, then concentrated, poured into 1 M HCl (80 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over Na2SO4 and concentrated to give crude CBZ-L-tert-leucine (20.7 g) as a clear oil: IR (cm1) 3336, 1715, 1521, 1232; 1H NMR (CDCl3) δ 1.02 (s, 9H), 4.21 (d, 1H, J=9.9), 5.11 (s, 2H), 5.35 (d, 1H, J=9.0), 7.34-7.37 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[CH:14]([N:16]([CH:18]3[CH2:20][CH2:19]3)[CH3:17])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=[C:8]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:27][CH:26]=2)[CH:7]=1)=[O:5])[CH3:2].[OH-].[Li+]>C(O)C.O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[CH:14]([N:16]([CH:18]3[CH2:19][CH2:20]3)[CH3:17])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=[C:8]([C:23]#[C:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of 8-(cyclopropyl-methyl-amino)-3-(4-methoxycarbonylmethyl-phenylethynyl)-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 78, 0.09 g, 0.19 mmol) in ethanol (2 mL), tetrahydrofuran (3 mL) and water (1.5 mL) was treated with lithium hydroxide (0.11 g, 2.62 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (0.085 g, 94%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=1[C:5]1([C:3]([OH:4])=[O:2])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C#N)cc2Cl)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.6 g, 2.0 mmol) is dissolved in THF/water 3:2 (20 mL) and to it is added LiOH (0.17 g, 4.0 mmol). The mixture is stirred at room temperature for 2 h before being neutralized to pH 6 with 1M HCl. The solution is evaporated to dryness to give acid, 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid as a solid. MS (ESI) m/z 288.2, 290.2 (M+H); 1H NMR (400 MHz, MeOD) (ammonium salt) δ ppm 2.64-2.74 (m, 1 H), 2.77-2.86 (m, 1 H), 2.94-3.02 (m, 1 H), 3.74 (ddd, J=13.1, 9.1, 8.0 Hz, 1 H), 6.74 (d, J=8.1 Hz, 1 H), 6.85 (s, 1 H), 7.59 (dd, J=8.1, 1.5 Hz, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.91 (s, 1 H).
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (106 mg) in benzene (5ml) is added silica gel F-254 (500 mg) distributed by E. Merck Ag., and the mixture is shaken at room temperature for 1 hour. The insoluble material is removed by filtration, and washed several times with chloroform. The filtrate and washed solution are combined and evaporated under reduced pressure to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (60 mg). Yield: 66.3%. m.p. 95.5°-99.5° C IR: νmaxCHC13 3400, 1785, 1685, 1605. NMR: δCDC13 2.03s2H, 4.60s2H, 5.07+5.37ABq(4)2H, 5.37d(4)1H, 5.68dd(9;4)1H, 6.83-8.32m9H.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Compound 2 (150 mg, 0.41 mmol) was dissolved in DCM and cooled to 0° C. Ethanesulfonyl chloride (62.2 mg, 0.49 mmol) was added, followed by DIEA (0.21 mL, 1.22 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was diluted with DCM and washed with saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by normal phase chromatography eluting with 10-50% methanol/DCM gradient to provide Compound 91 as a white solid (0.13 g, 69%). MS: m/z 462.34 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:19].[Na+]>CO.O1CCCC1.[Ag]=O>[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]2[O:7][C:3]([C:1]([OH:19])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:18]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)c2ccccc12
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 1-(5-formylfuran-2-yl)-1H-indole-3-carbonitrile (0.085 g) in methanol (4 mL) and tetrahydrofuran (4 mL) were added silver oxide (0.1 g) and 2 mol/L aqueous sodium hydroxide solution (0.27 mL), this mixture was stirred at room temperature for 6 hours. The insoluble material of reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. To this residue were added water (15 mL) and 2 mol/L hydrochloric acid solution (2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.023 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH2:14][CH3:15].[N+:20](NC1C=CC=CC=1)([O-])=[O:21].S(=O)(=O)(O)O>CO>[CH2:13]([N:16]([N:20]=[O:21])[C:17]([NH:19][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:18])[CH2:14][CH3:15]
Reactant: O=[N+]([O-])Nc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCNC(N)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -1 °C
Reaction time: 2 h

Procedure:
A mixture of 3.6 g of D-glucose, 2.3 g of propylurea, 0.2 g of nitroaniline and 0.1 ml of a concentrated sulphuric acid is heated at reflux for 10 minutes in 15 ml of methanol. The residue in the amount of 2.6 g is separated, added with 15 ml of glacial acetic acid, 8 ml of distilled water, 1.8 g of sodium nitrite and stirred at the temperature of -1° C. for 2 hours. The solution is evaporated, the residue is recrystallized from methanol to give 2.32 g (80% of the theoretical) of the product. M.p. 110° C. (decomposition), [α]D -5° (CH3OH), Rf =0.81. Found, %: N 14.12. Calculated, %: N 14.33.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:28])[CH2:19][C@@H:20]([NH:27][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[N:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:16]
Reactant: O=[N+]([O-])c1cnc(C2CC2)nc1Cl
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Chloro-2-cyclopropyl-5-nitro-pyrimidine (597 mg, 3 mmol) in DMF (10 ml) was added (R)-3-Amino-3-phenyl-propionic acid ethyl ester hydro chloride (582 mg, 3 mmol). The mixture was stirred on ice for 5 minutes the DIPEA (580 mg, 4.5 mmol) was added. The solution was stirred at room temperature for one hour. TLC showed disappearance of the starting material. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, evaporated to dryness to give oil, which was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1ccc(CCNC(=O)Cc2cccc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (41) was prepared as follows: A solution of 3-bromo-phenylacetic acid (2.0 g, 9.3 mmol) and oxalyl chloride (36.4 g, 0.287 mol) in 80 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 3-bromo-phenylacetic acid (1.1 eq.) in CH2Cl2 was added to mixture of 100 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (1.31 g, 7.22 mmol) in 100 mL of CH2Cl2. The reaction mixture was stirred overnight at r.t. Another portion of acid chloride (0.1 eq.) in 10 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixtures. Yield is 2.59 g (95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:18]([O:19][CH3:20])=[N:17][S:16](=[O:21])[N:15]=2)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH3:22].[CH:23](Cl)(Cl)Cl>>[CH3:23][CH2:20][O:19][CH2:18][CH3:14].[NH2:1][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:18]([NH2:22])=[N:17][S:16](=[O:21])[N:15]=2)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N
Reactant: N
Reactant: ClC(Cl)Cl
Product: CCOCC
Product: NC1=NS(=O)N=C1NCCCCc1ncc(Br)cc1N

Procedure:
Reaction of 3-[4-(3-amino-5-bromopyrid-2-yl)butylamino]-4-methoxy-1,2,5-thiadiazole-1-oxide (0.56 g) with methanolic ammonia solution (50 ml) at room temperature overnight gave after chromatography on silica in chloroform and trituration with ether 3-[4-(3-amino-5-bromopyrid-2-yl)butylamino]-4-amino-1,2,5-thiadiazole-1-oxide (0.19 g) m.p. 105°-109° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11]([O-:13])[CH3:12].[Na+].C(O)C>>[CH2:11]([O:13][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH3:12]
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nnc(N)c(C)c1C
Yield: 50 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17 mmol, 1.0 eq) and sodium ethanolate in ethanol (16 mL, 21 w/w-%, 53.9 mmol, 17 eq) were heated for 2 h to 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 28 g NH2-cartridge: hexane→hexane/EtOAc 1/1) to give 267 mg (50% yield) of the title compound.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: C1COCCN1
Reactant: N#CC=Cc1ccccc1
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 64 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and morpholine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [O-]CC.[Na+].C([O:7][CH:8]=[C:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.O.[NH2:21][NH2:22].Cl>C(O)C.O>[CH2:13]([O:12][C:10]([C:9]1[C:8](=[O:7])[NH:21][NH:22][CH:15]=1)=[O:11])[CH3:14]
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH][nH]c1=O
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a solution of sodium ethoxide (20.8 g, 0.31 mol) and diethyl ethoxymethylenemalonate (20 mL, 0.10 mol) in ethanol (400 mL), was added hydrazine monohydrate (10.0 mL, 0.20 mol) with cooling in an ice-cold water bath. The mixture was then heated at 80° C. for 3 h. The resulting mixture was diluted with water (200 mL) and neutralized with 10M HCl solution until pH 6. The mixture was extracted several times with chloroform. The aqueous layer was acidified to pH 2 and extracted again with chloroform. The combined organic layers were dried (Na2SO4) and concentrated to a solid which was washed with methanol and ether and dried to give the product (13.2 g, 80%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.89 (s, 1H), 4.15 (q, 211, J=7.12 Hz), 1.23 (t, 3H, J=7.11 Hz).