Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:20]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([O:18][CH3:20])([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of sodium hydride suspension in mineral oil (60% wt) (3.86 g, 96 mmol) in dry THF (60 mL) were added (R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (7.5 g, 32.2 mmol) in THF (50 mL) at 0° C. slowly. After stirring for 1 h at room temperature, iodomethane (4.31 ml, 38.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quenched with water, the reaction mixture was extracted by ether. The aqueous layers was acidify to pH=3 by adding 6 N HCl, then extracted by EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered though Buchner funnel, and concentrated to yield crude (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (7 g, 28.3 mmol, 88%), which was used in next step reaction without purification. LC/MS (uplc): MH+ 160.1, 0.68 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[S:20][C:21]([N+:24]([O-])=O)=[N:22][N:23]=2)[CH:3]=1>CCO.O.Cl>[NH2:24][C:21]1[S:20][C:19]([O:18][C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=3[CH:5]=2)=[N:23][N:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(Cl)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(Cl)c21
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)acetate (430 mg, 1.08 mmol) in EtOH (15 mL) and H2O (5 mL) was added 2 drops of conc. HCl and the mixture was heated to reflex for 2 h. Upon cooling, the reaction mixture was filtered and the EtOH was removed under the reduced pressure and the residue was extracted with EtOAc (3×10 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil (330 mg). MS (ESI) m/z=370 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Nc1nnc(SCc2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-benzylthio-1,3,4-thiadiazole (1.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.9 g) and carbonyldiimidazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 0.7 g of the aimed compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20]Cl)[C:12]=2[NH2:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([CH2:20][CH2:19][O:18][C:13]1[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12]=1[NH2:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cc(F)cc(CS(=O)(=O)c2ccccc2)c1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-4-fluorophenylamine (1.67 g, 4.87 mmoles) and sodium azide (0.38 g, 5.84 mmoles) in DMSO (20 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.44 g, 4.14 mmoles).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([Mg]Br)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: Clc1cccc2c1CC(c1ccccc1)=C2
Product: C1=C(c2ccccc2)Cc2c1cccc2-c1cccc2ccccc12

Procedure:
2-phenyl-7-napthylindene is prepared in like manner from 2-phenyl-7-chloroindene (see Example I(a)) and naphthyl magnesium bromide.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:11]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=[C:12]=[O:13]>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[CH:24][C:14]([NH:11][C:12]2[O:13][CH2:2][C:3](=[O:10])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(Nc2ccc(C(=O)OCC)cc2)OCC1=O
Reaction time: 1 h

Procedure:
Triethylamine (9.87 ml) was added dropwise, over a period of 1 hour to a cooled (ice bath) solution of ethyl 4-chloroacetoacetate (9.87 g, 60 mmol) and ethyl p-isocyanatobenzoate (14.34 g, 75 mmol) in 60 ml of petroleum ether-ethyl acetate (10:1 by volume), under nitrogen atmosphere. The reaction mixture was stirred at 0°-5° C. for 1 hour. The resulting ethyl 2-[[4-(ethoxycarbonyl)phenyl]-amino]-4,5-dihydro-4-oxo-3-furancarboxylate was filtered and then washed sequentially with petroleum ether, 1 N hydrochloric acid and water. Yield 13.0 g Mp 152°-153° C. (isopropanol).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([O:10][CH3:11])[CH2:8][S:9][C@H:4]12.[C:27]([O:31][C:32]([CH2:34][O:35][N:36]=[C:37]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:38](O)=[O:39])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([CH2:34][O:35][N:36]=[C:37]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:38]([NH:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:7]([O:10][CH3:11])[CH2:8][S:9][C@H:4]12)=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 100.4 %

Procedure:
4-Nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride (4.02 g) and 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 3.62 g) were treated in a similar manner to to that of Example 1 to give 4-nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 6.8 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][NH:30]4)[N:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17].[OH-].[Na+].O.CN([CH:43]=[O:44])C>>[F:36][C:7]([F:6])([F:35])[C:8]1[CH:9]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH:43]=[O:44])=[CH:29][NH:30]4)[N:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(Oc1ccc(-c2nc(-c3cccc4[nH]cc(C=O)c34)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (158.4 μl) was added dropwise to a DMF solution (4 ml) at 0° C. After warming to room temperature, it was stirred for 0.5 hour. Then, a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (500.0 mg) in DMF (1 ml) was added thereto at 0° C., followed by stirring at room temperature for 15 hours. After cooling to 0° C., to the reaction solution was added a 1M aqueous NaOH solution for adjustment of its pH to 9 to 10. This solution was stirred at 100° C. for 1 hour. After being left to be cooled, to the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane, EtOAc=90:10 to 70:30) to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carboaldehyde (456.7 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[C:20]1([N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:28])[O:1][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(c2ccccc2)c2ccccc2)nc(C(Cl)(Cl)Cl)n1
Yield: 88 %

Procedure:
To a mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.6 g (0.025 mole) triethylamine, and 100 ml acetonitrile was added 5.8 g (0.025 mole) diphenylcarbamoyl chloride. The reaction mixture was refluxed 4 hours. A precipitate was filtered out and ether was added to the filtrate yielding more precipitate. Rotary evaporation gave 9.3 g residue which was recrystallized from ligroin to give 6.15 g (58% yield) of product. An analytical sample was recrystallized a second time from ligroin and had mp 132°-134° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A solution of 4-bromoaniline (1.76 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol) in dichloroethane (15 mL) was treated with NaBH(OAc)3 (2.32 g, 11 mmol) and glacial acetic acid (1 mL), stirred overnight at room temperature, quenched with 1N NaOH, and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water and brine, dried, (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide 2.21 g (84%) of the desired product. MS (ESI) m/e 261.9 (M+H)+, 263.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:10]=1)=[O:9]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
The starting material is prepared as follows: The mixture of 68 g of 5-chloro-2-methylbenzoic acid and 170 ml of thionyl chloride is refluxed for 1 hour, evaporated under reduced pressure and the residual acid chloride dried in a high vacuum. It is taken up in 500 ml of benzene and the solution added dropwise to the suspension of 100 g of anhydrous aluminum chloride and 600 ml of benzene while stirring and cooling with an ice bath. Thereupon the bath is removed and the mixture stirred at room temperature for 16 hours. It is combined with some ice, followed by 340 ml of 2N hydrochloric acid and the mixture stirred for a half hour. It is diluted with diethyl ether, the organic layer separated and washed with 5% sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated under reduced pressure, to yield the 5-chloro-2-methylbenzophenone showing in the I.R. spectrum a strong band at 1660 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH:41]=O)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH2:41][NH:17][CH2:16][CH2:15][N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[CH2:14][CH2:13]4)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 89.1 %

Procedure:
Compound 47 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-(4-cyclohexylphenyl)-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16][CH2:17]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccc(Br)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
1-Bromo-4-(1-chloroethyl)benzene (3.46 g, 15.8 mmol), 1-methanesulfonylpiperazine (5.19 g, 31.6 mmol) and diisopropylethylamine (11.8 mL, 79 mmol) were stirred in acetonitrile (125 mL) and heated to 65° C. for 3 d. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with sat. NaHCO3 (aq.). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 100% isohexanes to 100% EtOAc to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: Oc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution, cooled to 10° C., of 2-chlorophenol (100 g, 0.778 mol) in 250 ml of dichloromethane is slowly admixed with triethylamine (120.7 ml). A solution of 60.7 ml of propionyl chloride in 60 ml of dichloromethane is added slowly dropwise to this mixture over the course of an hour. Following the addition of the propionyl chloride, the mixture is allowed to come slowly to room temperature and is stirred at room temperature for a total of five hours. Following removal of the triethylammonium chloride by filtration, the filtrate is diluted with 100 ml of dichloromethane and washed with 0.1 N hydrochloric acid (500 ml), 0.1 M aqueous sodium hydroxide solution (500 ml) and water (500 ml). The organic phase is dried over sodium sulphate (100 g) for three hours. After the drying agent has been removed by filtration, the solvent is removed on a rotary evaporator. Distillation of the oily yellow residue under reduced pressure gives 129.2 g (90% yield) of 2-chlorophenyl propionate as a colourless liquid (bp 90-93° C./0.3 mm).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]([NH2:16])=[N:14][C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:6]=1)(=O)=O.[OH-:31].[Na+]>CN(C=O)C>[NH2:16][C:15]1[N:11]([C:9]2[CH:8]=[C:7]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:6][C:5](=[O:31])[N:10]=2)[N:12]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1
Reactant: CS(=O)(=O)c1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccccc2)nn1-c1cc(Nc2ccccc2)[nH]c(=O)n1
Yield: 90 %

Procedure:
1-(2-Methanesulfonyl-6-phenylamino-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine (12 mg, 0.028 mMol) was stirred at ambient temperature in 500 uL of DMF with 200 uL of 1N NaOH for 2 hrs. The reaction was quenched with water and a precipitate allowed come out of solution. The filtrate was decanted off and the solid was resuspended with water, allowed to settle, and again decanted. The solid was transferred to a round bottom flask with acetonitrile and the solvents removed under reduced pressure. The resultant material, a beige yellow solid, resulted in 90% yield.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:29]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:33]([O:32][C:30]1[CH:29]=[C:18]([CH:17]=[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:24][N:23]=1)=[O:20])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
A solution of tert-butyl isocyanate (51 mg) in THF (5 ml) was treated with 2-[(3,5-dibenzyloxybenzoyl)amino]-5-aminopyridine (212 mg), and stirred at ambient temperature for 24 hours. More tert-butyl isocyanate (0.34 ml) added, and stirring continued at ambient temperature for a further 4 days. Volatile material was removed by evaporation and the residue was triturated under methanol to give the title compound (159 mg) as a solid, 1H NMR δ (d6-DMSO): 1.30 (s, 9H), 5.18 (s, 4H), 6.09 (s, 1H), 6.85 (s, 1H), 7.32 to 7.50 (m, 12H), 7.78 (dd, 1H), 8.04 (d, 1H), 8.38 (s, 1H), 8.44 (s, 1H), 10.65 (s, 1H). MS ES+ 525.61 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Br>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
2-Pyridin-2-yl-lH-benzoimidazole (1.95 g, 0.01 mol) was dissolved in DMF (50 mL) under an atmosphere of nitrogen. Sodium hydride (60% dispersion in oil, 0.48 g, 0.012 mol) was then added. The reaction mixture was stirred at ambient temperature for 0.5 hour. 3,4-Dichlorobenzyl bromide (2.4 g, 0.01 mol) was then added. The mixture was stirred at 80° C. for a period of 4 hours. The mixture was cooled and diluted with water. The mixture was then extracted with ethyl acetate. The organic extract was washed with water twice then evaporated. The residue was triturated with a small amount of ethyl acetate/hexane. The solid was collected and crystallized from ethanolic hydrogen chloride. The solid was collected to give the title compound (1.3 g, 36.7% yield) as a mono-hydrochloride, light brown solid, m.p. 227°-229° C. Anal. Calcd. for Cl9Hl3Cl2N3-HCl: C, 58.41; H, 3.61; N, 10.76.. Found: C, 58.21; H, 3.54; N, 10.80. Mass spectrum (+FAB; [M+H]+) 354/356/358. 1H-NMR (DMSO-d6 ; 400 MHz) 8 8.78 (d, 1H), 8.52 (d, 1H), 8.15 (t, 1H), 7.9 (d, 1H), 7.77 (d, 1H), 7.65 (d, 2H), 7.54 (d, 1H), 7.48-7.52 (m, 2H), 7.23 (d, 1H), and 6.22 ppm (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C:8]3=[CH:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17])([O-:3])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH:8]3[CH2:7][C:6]=2[C:5]=1[C:16]([O:18][CH3:19])=[O:17])([O-:3])=[O:2]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2c1cc1n2CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c([N+](=O)[O-])ccc2c1CC1CCCN21
Temperature: 25 °C
Yield: 164.7 %

Procedure:
Methyl 7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 19, 1.00 g) was dissolved in TFA (100 ml) and sodium triacetoxyborohydride (8.11 g) was added. The reaction mixture was stirred at room temperature, then diluted with toluene and concentrated in vacuo. The residue was dissolved in aqueous potassium carbonate solution and extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-2% to give methyl 7-nitro-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (1.66 g) as a yellow gum.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=3[CH3:27])=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[CH3:27])=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)OC)cc3C)cc2C(=O)N(C)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(C(=O)O)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 84.1 %

Procedure:
A solution of methyl 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoate (471 mg, 1.05 mmol) and aqueous 1 N NaOH solution (5.0 mL, 5.0 mmol) in MeOH (10 mL) and THF (5 mL) was heated to 50° C. for 5 h. Aqueous 1 N HCl solution (6 mL) was added to the cooled reaction mixture. The resulting suspension was filtered and the solid was washed with water and dried to give the title compound (382 mg, 83% yield) as a white solid.