Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:30]([C:27]3[CH:26]=[CH:25][C:24]([Br:23])=[CH:29][N:28]=3)=[O:31])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (264 mg, 0.865 mmol), 5-bromo-pyridine-2-carboxylic acid (192 mg, 0.951 mmol) and HOBT (172 mg, 1.124 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (112 mg, 0.865 mmol) and EDC (182 mg, 0.951 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc) to yield the title compound in the form of a colourless solid. 1H-NMR (400 MHz, DMSO-d6, 81° C.): 10.32 (1H, NH), 9.30 (br, 1H), 8.81 (s, 1H), 8.29 (dd, 1H), 8.08 (d, 1H), 7.81 (m, 2H), 7.33 (m, 1H), 7.19 (d, 1H), 4.40-4.30 (m, 2H), 3.75-3.55 (m, 2H), 1.53 (s, 3H), 1.45 (s, 9H); MS: 489 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[N:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)[N:12]=2)=[CH:4][CH:3]=1.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH:24]([OH:28])[CH:23]([NH:22][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[N:21][C:13]=1[C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[S:9][CH:10]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cccnc1-c1csc(-c2ccc(F)cc2)n1
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccc(F)cc2)n1
Yield: 93.7 %

Procedure:
Coupling of 2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinic acid (350 mg, 1.165 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (270 mg, 1.39 mmol) in an analogous manner as described for example 1.2 afforded 520 mg of the title compound as white amorphous solid; ESI-MS [M+H+]: 477.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl.[OH-].[Na+].C(O)CCC>CO>[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CO
Product: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After dissolving 4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 13.1 mmol) in methanol (10 mL), a 4N hydrogen chloride-1,4-dioxane solution (33 mL, 131 mmol) was added in small portions at a time in an ice bath, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice, 2N aqueous sodium hydroxide was added to adjust the pH to approximately 11. Salt was added to the aqueous solution to saturation, and the organic layer obtained by extraction with 1-butanol (100 mL×3 times) was washed with saturated brine and then dried over anhydrous sodium sulfate. The dried 1-butanol was concentrated under reduced pressure to obtain (1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1ncc(Br)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)c1ncc(Br)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
5-Bromo-N2,N2-dimethylpyridine-2,3-diamine (53 mg, 0.25 mmol) was taken into THF (2 mL) followed by addition of diisopropylethylamine (213 uL, 1.25 mmol) and methanesulfonyl chloride (95 ul, 1.25 mmol). The mixture was allowed to stir for 48 h at room temperature then partitioned with ethyl acetate and water. The organic phase was washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was taken into methanol (3 mL) followed by addition of potassium hydroxide (108 mg, 10 eq) in a minimum of water. The mixture was stirred for 15 minutes at room temperature then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give N-(5-bromo-2-(dimethylamino)pyridin-3-yl)methanesulfonamide (27.9 mg, 39%). MS (EI) for C8H12N3SO2Br: 294, 296 (MH+, Br pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.O.CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:25](=[O:26])[NH:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Reactant: CN(C)C=O
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 16 h

Procedure:
3 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine are dissolved in 40 ml of dimethylformamide. After adding 3.6 g of N,N'-carbonyldiimidazole, the mixture is stirred at 50° for 16 hours. The solution obtained is then poured into 700 ml of water and extracted with ethyl acetate. The organic extracts are washed with water and saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on 200 g of silica gel while eluting with chloroform/ethanol (98.5:1.5). After recrystallization from diisopropyl ether, there is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin -1-one of melting point 223°-225°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[S:34](=[O:38])(=[O:37])([OH:36])[OH:35].[O-2:39].[O-2:40].[O-2:41].[Cr+6:42].O>CN(C)C=O.CC(C)=O>[CH3:5][C:4]([CH3:22])=[O:39].[OH:37][S:34]([OH:38])(=[O:36])=[O:35].[O:39]=[Cr:42](=[O:41])=[O:40].[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH:27][C:28](=[O:33])[C:29]([F:31])([F:32])[F:30])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[O:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Reactant: [Cr+6]
Reactant: [O-2]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Product: O=[Cr](=O)=O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) was dissolved in a mixture of dimethylformamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25 ml.), which was prepared from conc. sulfuric acid (0.28 ml.), chromium trioxide (0.33 g.) and water (0.9 ml.), was dropwise added thereto over 2 minutes with stirring and cooling at 0° to 2° C. After stirring for 20 minutes at the same temperature, the reaction mixture was poured into ice-water (50 ml.). After acetone was distilled off, the residue was twice extracted with ethyl acetate (50 ml.). The extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}-acetamido]-3-formyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound can be represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione (syn isomer)](0.56 g.).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]1=[O:17].Br[C:19]1[N:23]([CH:24]2[CH2:26][CH2:25]2)[C:22]2[CH:27]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:28]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=3)[C:29](=[O:30])[C:21]=2[CH:20]=1.C(Cl)Cl.CO.N>>[Cl:37][C:35]1[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=[C:31]([N:28]2[C:29](=[O:30])[C:21]3[CH:20]=[C:19]([C:5]4[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:17])[CH:4]=4)[N:23]([CH:24]4[CH2:26][CH2:25]4)[C:22]=3[CH:27]2[C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[CH:36]=1
Reactant: Cn1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc(-c2cc3c(n2C2CC2)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 240 but using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Step 242.1) and 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-cyclopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 250.1). tR: 0.83 min (LC-MS 6); ESI-MS: 521.2/523.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH/NH3 94:5:1): Rf=0.18; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.450 (m, 1 H) 0.74-0.84 (m, 2 H) 1.12-1.25 (m, 1 H) 3.06-3.18 (m, 1 H) 3.41 (s, 3 H) 3.37 (s, 3 H) 6.30 (s, 1 H) 6.47 (dd, J=7.04, 1.95 Hz, 1 H) 6.52-6.61 (m, 1 H) 6.71 (s, 1 H) 7.30 (m, J=8.21 Hz, 2 H) 7.38 (m, J=8.60 Hz, 2 H) 7.62 (d, J=7.04 Hz, 1 H) 7.80-7.95 (m, 2 H).
Reaction SMILES: NC1C=C(C=CC=1)CN1N=NC(C2C=CC=[C:17]3[C:12]=2C[CH2:14][CH2:15][N:16]3[C:21](=[O:34])CCCOC2C=CC=C(C)C=2C)=N1.[NH2:38][CH2:39][C:40]1[CH:41]=[C:42]([C:46]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:47]=2[CH2:48][CH2:49][CH2:50][N:51]3[C:56](=[O:69])[CH2:57][CH2:58][CH2:59][O:60][C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([CH3:67])[C:62]=2[CH3:68])[CH:43]=[CH:44][CH:45]=1.[NH2:70][CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74].N1(CCS(O)(=O)=O)CCNCC1>>[CH3:68][C:62]1[C:63]([CH3:67])=[CH:64][CH:65]=[CH:66][C:61]=1[O:60][CH2:59][CH2:58][CH2:57][C:56]([N:51]1[C:52]2[C:47](=[C:46]([C:42]3[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=3)[CH2:39][NH:38][C:21]([N:16]3[CH2:17][CH2:12][N:70]([CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74])[CH2:14][CH2:15]3)=[O:34])[CH:55]=[CH:54][CH:53]=2)[CH2:48][CH2:49][CH2:50]1)=[O:69]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn(Cc5cccc(N)c5)n4)cccc32)c1C
Reactant: NCCS(=O)(=O)O
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Agent: O=S(=O)(O)CCN1CCNCC1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)N5CCN(CCS(=O)(=O)O)CC5)c4)cccc32)c1C

Procedure:
Example 118 was prepared using a procedure analogous to Example 115 except that 1-(5-(2-(3-aminobenzyl)-2H-tetrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one was replaced with 1-(5-(3-(aminomethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one and taurine was replaced with 2-(piperazin-1-yl)ethanesulfonic acid. LCMS, [M+H]+=649.3. 1H NMR (400 MHz, MeOD) δ 7.48-7.30 (m, 4H), 7.28-7.17 (m, 2H), 7.13-7.00 (m, 2H), 6.79 (d, J=7.5 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 4.48 (s, 2H), 4.28 (br. s, 2H), 3.99 (t, J=5.2 Hz, 2H), 3.83 (t, J=7.0 Hz, 2H), 3.72 (br. s, 2H), 3.62 (t, J=6.9 Hz, 2H), 3.43-3.38 (m, 2H), 3.29 (t, J=6.9 Hz, 2H), 3.20 (br. s, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.49 (t, J=6.1 Hz, 2H), 2.31-2.15 (m, 5H), 1.94 (s, 3H), 1.90-1.80 (m, 2H). HPLC-1: Rt=10.5 min, purity=99.3%; HPLC-2: Rt=10.4 min, purity=100%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12)#[N:2].Cl.[NH2:20][OH:21].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([C:1](=[N:20][OH:21])[NH2:2])=[C:7]2[CH2:8]1
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccccc2C1=O

Procedure:
A mixture of 0.0125 mole 3-cyano-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine, 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of a 20% potassium carbonate solution in water was refluxed for 22 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 100 ml of water and the crystalline solid was filtered off and was washed with water.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.Br[CH:18]([CH:20](Br)[CH3:21])[CH3:19]>C1COCC1>[F:3][C:4]([F:15])([F:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:21][CH2:20][CH2:18][CH2:19]2)=[CH:10][CH:11]=1
Reactant: CC(Br)C(C)Br
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
To sodium hydride (600 mg, 15 mmol) in anhydrous THF (5 mL) at 0° C., was added dropwise 2-(4-(trifluoromethoxy)phenyl)acetonitrile (1006 mg, 5 mmol) and then the reaction mixture was stirred for 5 mins, followed by dibromobutane (1075 mg, 5 mmol) dropwise. The reaction mixture was heated to reflux for 16 h, then cooled to 0° C., quenched with MeOH (1 mL), diluted with EtOAC (50 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile as a yellow oil (905 mg, 71%) (1H NMR (400 MHz, CDCl3) 7.50 (dd, J=2.1, 6.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.10-1.97 (m, 6H)
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][C:9](=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:23](Br)[CH:24]1[O:28][CH2:27][CH2:26][CH2:25]1.O>CN(C)C=O>[CH2:23]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:20])[CH:24]1[O:28][CH2:27][CH2:26][CH2:25]1.[CH2:23]([O:20][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10]=1)[CH:24]1[O:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(OCC3CCCO3)nc(-c3ccccc3)c2c1
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CCCO1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 3.2 g of 4-phenyl-6-nitro-2(1H)-quinazolinone in 50 ml of dimethylformamide was added 0.7 g of 50% sodium hydride, and the mixture was stirred at 50° C. for 1 hour. Then, 3.96 g of tetrahydrofurfuryl bromide was added thereto and the resultant mixture was stirred at 100° C. for 7 hours. After cooling, the reaction mixture was poured into 300 ml of water and the resultant mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give red oily residue. The residue was chromatographed on silica gel using chloroform as eluting solvent to obtain 1.9 g of 1-tetrahydrofurfuryl-4-phenyl-6-nitro-2(1H)-quinazolinone and 0.6 g of 2-tetrahydrofurfuryloxy-4-phenyl-6-nitroquinazoline. Each of them was recrystallized from ethanol, and the former gave pale yellow prisms, m.p. 151°-153° C. and the latter gave pale yellow scales, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>O1CCOCC1.O>[CH3:24][O:23][C:19](=[O:22])[CH2:20][S:21][C:4]1[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COC(=O)CS
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CSc1nc(N)nc(Cl)c1C=O
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a mixture of 2-amino-4,6-dichloro-5-pyrimidinecarbaldehyde (Apin, 2.00 g, 10.4 mmol) in dioxane (20 mL) was added triethylamine (1.60 mL, 11.5 mmol) and methyl thioglycolate (1.90 mL, 21.2 mmol). After about 3 hours, the reaction mixture was diluted with water (30 mL) and then filtered, washed with additional water to give (2-amino-6-chloro-5-formyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester (1.801 g, 66%) as a yellow solid; RP-HPLC (Table 1, Method a) Rt 1.85 min, m/z (ESI+) 262.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:15][S:14][CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(CCCCSC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Yield: 106 %

Procedure:
To a solution of 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL)and the mixture was heated to 50-55° C. for 15 h. TLC analysis of the reaction mixture did not detect the presence of starting ester and the reaction was cooled to room temperature,. The volatiles were removed under reduced pressure and the residue was diluted with water (100 mL) and was extracted with diethyl ether (2×50 mL) to remove any neutral impurities. Then the separated aqueous layer was acidified with 1 N hydrochloric acid and the mixture was extracted with ethyl acetate (2×75 mL). The combined ethyl acetate extracts were washed with brine, dried (MgSO4), filtered, then concentrated in vacuo and the residue was dried under high vacuum to afford 4.31 g (92%) of 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid as a low melting colorless solid. HR MS: Obs. mass, 216.1181. Calcd. mass, 216.1184, M+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:31]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([NH:41][CH2:40][C:39]([O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:42])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanoic acid (55.0 g), glycine benzyl ester tosylate (69.7 g), and diphenylphosphoryl azide (46.7 ml) in N,N-dimethylformamide (550 ml) was added dropwise N,N-diisopropylethylamine (75.6 ml) at 4° C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (700 ml). The mixture was extracted twice with ethyl acetate (total 1.3 L) and washed successively with water (400 ml×2), saturated aqueous ammonium chloride solution (200 ml), aqueous sodium hydrogencarbonate solution (300 ml×2), and brine (40 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (77.4 g) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:14].O.II.C1[CH2:22][O:21]CC1>>[Cl:1][C:2]1[C:11]([C:12]#[N:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: C1CCOC1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: II
Solvent: O
Product: COc1ccc2nc(Cl)c(C#N)cc2c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a mixture of 2-chloroquinoline-3-carboxaldehyde (1.00 g, 4.50 mmol) in THF (30 mL) was added NH3.H2O (30 mL, 25%) and I2 (1.26 g, 4.90 mmol), the mixture was stirred at 20° C. for 8 hours. Aqueous workup with EtOAc extraction gave the crude product. Purification by silica gel column (PE/EtOAc=10/1 to 2/1) gave the product (370 mg, yield 38%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].N[NH:24][C:25]([NH2:27])=[S:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]2[S:26][C:25]([NH2:27])=[N:24][N:13]=2)=[CH:14][CH:15]=1
Reactant: COCCCCOc1ccc(C#N)cc1
Reactant: NNC(N)=S
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COCCCCOc1ccc(-c2nnc(N)s2)cc1

Procedure:
To a solution of 4-(4-methoxybutoxy)benzonitrile (21.8 g) and trifluoroacetic acid (109 ml) in toluene (218 ml) was added thiosemicarbazide (11.62 g). The solution was stirred for 31 hours at 60° C., during which period additional thiosemicarbazide (2.90 g) and trifluoroacetic acid was added to the mixture. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration and dried to give 5-[4-(4-methoxybutoxy)phenyl][1,3,4]thiadiazol-2-ylamine trifluoroacetic acid salt (15.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC(O)(C)C.CC(C)([O-])C.[K+].Cl>CC(OC)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)(C)O
Product: O=C1COCC(CO)(c2cccc(Br)c2)N1

Procedure:
A suspension of N-[1-(3-bromo-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (3.24 g, 10.04 mmol) and 35 ml of t-BuOH was treated with potassium tert-butoxide (1.127 g, 10.04 mmol). The mixture was heated at reflux for 1 h and neutralized with 10 ml of 1N HCl. Water and TBME were added, and the precipitate was filtered off. The organic phase of the filtrate was separated, dried with sodium sulfate and chromatographed on silica gel (EtOAc/MeOH 1-2%) to give the title compound in the form of a colourless solid. TLC (EtOAc/MeOH 1%): Rf=0.23; HPLC: RtH2=2.839 min; 1H-NMR (400 MHz, CD3OD): 7.70 (s, 1H), 7.53-7.47 (m, 2H), 7.35 (t, 1H), 4.17 (s, 2H), 4.08 (d, 1H), 3.98 (d, 1H), 3.91 (d, 1H), 3.87 (d, 1H); MS: 287, 289 [(M+H)+].