Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:18][OH:19])[O:4][C@H:5]2[N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11].[CH3:20][O:21][C:22]1[CH:43]=[CH:42][C:25]([C:26](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([O:19][CH2:18][C@@:3]23[C@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:4]3)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:25]2[CH:42]=[CH:43][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@H]3O)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cc(C)c(=O)[nH]c4=O)O2)[C@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 50 %

Procedure:
To a stirred solution of nucleoside 9 (0.500 g, 1.85 mmol) in anhydrous pyridine (10 cm3) was added 4,4′-dimethoxytrityl chloride (0.941 g, 2.78 mmol) and the mixture was stirred for 25 h at room temperature for 25 h after which additional 4,4′-dimethoxytrityl chloride (0.062 g, 0.18 mmol) was added and stirring at room temperature was continued for another 21 h. A saturated aqueous solution of sodium hydrogen carbonate (50 cm3) was added and extraction was performed using dichloromethane (3×25 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (3×20 cm3) and brine (3×25 cm3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (1–4% methanol, 0.5% pyridine, v/v/v) as eluent to give nucleoside 10 (0.53 g, 50%) as a white solid material after evaporation of the solvents under reduced pressure (0.307 g, 28.9%).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (333 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (275 mg, 88%) as a white solid.
Reaction SMILES: O[NH:2][C:3](=[NH:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([O:19][CH3:20])(=[O:18])[C:16]#[CH:17]>CCO>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]2[NH:14][CH:17]=[C:16]([C:15]([O:19][CH3:20])=[O:18])[N:2]=2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: C#CC(=O)OC
Reactant: N=C(Cc1ccc([N+](=O)[O-])cc1)NO
Solvent: CCO
Product: COC(=O)c1c[nH]c(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A 250-mL round bottomed flask was charged with N-hydroxy-2-(4-nitrophenyl)acetamidine (1 g, 5 mmol, 1 eq.), methyl propiolate (500 mg, 6 mmol, 1.2 eq.) and EtOH (24 ml). The resulting mixture was stirred under reflux for 7 hrs. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was added phenyl ether (200 ml). The mixture was stirred at 190° C. for 30 minutes. After cooling to room temperature, the mixture was poured into hexane (1 L). Solid was collected and washed with hexane. The crude product thus obtained (964 mg) was purified by chromatography on silica gel using 10˜20% acetone in dichloromethane as eluent to afford the title compound as a gray solid (220 mg, 17% yield over two steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]([NH2:24])=[O:23]>>[C:9]1([C@H:21]2[C@H:21]([C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[Cl:13])[C:22](=[O:23])[NH:24][C:22]2=[O:23])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccc(Cl)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Cl)cc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2,4-dichlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2,4-dichlorophenylacetamide. Yield 20.9 mg, 5.2%. 1H NMR (DMSO-d6) 400 MHz δ: 11.65 (s, 1H), 7.69 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.34 (s, 1H), 7.12 (m, 1H), 6.87 (m, 2H), 4.65 (d, 1H, J=7.6 Hz), 4.55 (d, 1H, J=7.6 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0), 2.12 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+]>CO>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:10][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=3[N:9]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3ccc(OC)cc3[nH]2)cc1
Yield: 66.2 %

Procedure:
4-Methoxybenzene-1,2-diamine (1.96 g, 14.2 mmol), 4-formylbenzoic acid methyl ester (2.33 g, 14.2 mmol) and sodium bisulphite (1.55 g, 14.9 mmol) were refluxed in methanol (50 mL) for 3 h, then evaporated to dryness. The solid residue was partitioned between dichloromethane and water. The organic layer was dried, evaporated and purified by column chromatography, eluting with. The title compound (2.65 g, 9.40 mmol, 66%) was obtained as a dark solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[C:4]=2[CH:3]=1.CN1CCOCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:17])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: Nc1ccncc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Nc1ccncc1
Yield: 15.3 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (0.5 g, 1.5 mmol) in 20 mL of CH2Cl2 was converted to its mixed anhydride with NMM (0.16 mL, 1.5 mmol) and IBCF (0.2 mL, 1.5 mmol). This intermediate was condensed with 4-aminopyridine (0.21 g, 2.25 mmol) to produce the title compound (94 mg).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[C:6]([NH2:9])=[N:7][OH:8])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1>[C:1]([O:4][CH:5]([CH2:10][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)[C:6]([NH2:9])=[N:7][O:8][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)C(N)=NO
Solvent: C1CCOC1
Product: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)C(N)=NOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A solution of 2-acetoxy-5-(1-benzylpiperidin-4-yl)-1-hydroxyiminopentylamine (0.59 g) in tetrahydrofuran (5 ml) was added dropwise to a solution of 4-nitrobenzoyl chloride (0.29 g) in tetrahydrofuran (5 ml) and the mixture was stirred overnight at ambient temperature and extracted with ethyl acetate. The extract was washed with a sodium hydrogencarbonate aqueous solution and water, dried over magnesium sulfate and evaporated in vacuo to give 2-acetoxy-5-(1-benzylpiperidin-4-yl)-1-(4-nitrobenzoyloxyimino)pentylamine (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[CH:22]=[CH:23][CH2:24]Br)#[N:19].CC(C)=O>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:24][CH:23]=[CH:22][C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[C:18]#[N:19])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: N#Cc1ccccc1C=CCBr
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 31 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-cyano-cinnamyl bromide (melting point: 69°-71° C.) in anhydrous dimethylformamide for 15 hours at 20° C. Yield: 31% of theory, Melting point: 140°-144° C. (acetone).
Reaction SMILES: CC(C)(S([NH:6][CH2:7][C:8]1[N:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[C:17]([O:19][CH3:20])=[O:18])=O)C.Cl.C(OCC)C.C([O-])(O)=O.[Na+]>ClCCl>[NH2:6][CH2:7][C:8]1[N:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc2n(c1CNS(=O)C(C)(C)C)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc2n(c1CN)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 238b (3.5 g, 11.2 mmol), saturated HCl/diethyl ether solution (15 mL), and dichloromethane (15 mL). The mixture was stirred at room temperature for 4 h. After the reaction was completed, saturated aqueous NaHCO3 solution (50 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was evaporated under reduced pressure to afford 238c (2.2 g, 94%), which was directly used in the next step without further purification. MS: [M-NH2]+ 192.1. 1H NMR (500 MHz, MeOD) δ 6.28 (s, 1H), 4.38 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.84 (s, 3H), 2.78 (t, J=6.5 Hz, 2H), 2.06-2.02 (m, 2H), 1.87-1.82 (m, 2H).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:15]=[C:2]=[O:3])=[O:14])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1cccc(C(N)=O)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: CC(=O)Oc1cccc(C(=O)N=C=O)c1OC(C)=O

Procedure:
Oxalyl chloride (5.3 g) was added to a solution of 2,3-diacetoxybenzamide (4.0 g) in 1,2-dichloroethane (40 ml) with stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 10 hours. Then, the solvent and excess oxalyl chloride were distilled off under reduced pressure to give 2,3-diacetoxybenzoyl isocyanate, which was dissolved in anhydrous dichloromethane (40 ml) for the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]3[C:22]([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:41])NC(C)(C)CO)[CH:31]=[CH:30][C:29]=4[F:42])=[O:26])=[CH:23][N:24]=[C:18]3[CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].[OH-:43].[Na+].Cl>COCCOC.O>[F:42][C:29]1[CH:30]=[CH:31][C:32]([C:34]([OH:43])=[O:41])=[CH:33][C:28]=1[NH:27][C:25]([C:22]1[N:19]2[CH:20]=[CH:21][C:16]([C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[C:2]([F:1])[CH:3]=3)=[CH:17][C:18]2=[N:24][CH:23]=1)=[O:26]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NC(C)(C)CO)c(F)c4)ccn23)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(CO)NC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)O)ccc4F)cnc3c2)cc1F
Temperature: 60 °C

Procedure:
7-(3-Fluoro-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)phenyl)-N-(2-fluoro-5-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1) (590 mg, 1.129 mmol) in 1,2-dimethoxyethane (10 ml) and water (10.00 ml) was treated with sodium hydroxide (181 mg, 4.52 mmol) and warmed to 60° C. for 1 hr. After cooling to RT, the pH of the mixture was adjusted to pH5 using 2M HCl (2.2 ml). The solvent was removed in vacuo and the resulting crude product was triturated with water to afford the title compound;
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:22](=[O:23])[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 24 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
4-(Trifluoromethyl)benzoic acid hydrazide (commercially available from Maybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250 ml)/triethylamine (2.7 ml, 26 mmol) under N2 and 1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution was stirred for 18 h at 24° C., concentrated, and the residue was taken up in ethyl acetate, washed with 1N HCl solution, sat'd NaHCO3 solution, and brine prior to drying (MgSO4). Concentration gave 5 g (89%) of the title compound from which a sample was recrystallized from diethyl ether/hexanes: mp 214-216° C. MS m/z: 231 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:26][C:27]1([C:32]2([CH:35]=O)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29][O:28]1>>[CH:35]([C:32]1([C:27]2([CH3:26])[O:28][CH2:29][CH2:30][O:31]2)[CH2:33][CH2:34]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: [Br-]
Product: CCCCC=CC1(C2(C)OCCO2)CC1

Procedure:
2.07 g of pentyltriphenylphosphonium bromide and 600 mg of aldehyde 7 are reacted analogously to 193., and 567 g of title substance 200 is obtained as a colorless oil (8:1 E,Z-mixture that cannot be separated).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>C1COCC1>[CH3:50][O:49][N:48]([CH3:47])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) in THF (50 mL) was added EDCl (2.10 g, 10.93 mmol), HOBt (1.48 g, 10.93 mmol), and N,N-diisopropylethylamine (5.19 mL, 29.82 mmol). The mixture was stirred at rt for 15 min. N,O-dimethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol), was added and stirring continued for 64 h. The crude reaction was purified via ISCO® chromatography using 3:1 ethyl/hexanes to afford 2.4 g (99%) of the desired product, which was used without further characterization.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:27](Cl)([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:27](=[O:28])[O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc([N+](=O)[O-])c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a stirring suspension of 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-amine hydrochloride (0.500 g, 1.685 mmol, 1.00 eq) and pyridine (0.412 ml, 5.05 mmol, 3.00 eq) in CH2Cl2 (17 ml) at 22° C. was added Troc-Cl (0.244 ml, 1.769 mmol, 1.05 eq). The reaction was stirred overnight at RT. The completed reaction was diluted with CH2Cl2 and washed with 3M HCl (2×). The combined aqueous were extracted with CH2Cl2 (1×). The combined organics were washed with H2O (2×), brine (1×), dried (Na2SO4), filtered ad evaporated. The crude product was purified by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) to afford 2,2,2-trichloroethyl 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-ylcarbamate (0.67 g, 91% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[N+:8]([O-])([OH:10])=[O:9]>>[Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([Cl:7])[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1csc(Cl)n1
Product: O=[N+]([O-])c1sc(Cl)nc1Cl
Temperature: 0 °C
Yield: 95.5 %

Procedure:
400 g (2.6 mols) of 2,4-dichloro-thiazole are introduced in portions, in the course of one hour at between 15° and 20° C., into 2 liters of 98% strength nitric acid (density=1.51; about 47 mols), while stirring and cooling. Thereafter, the mixture is discharged in portions onto about 20 kg of ice/water, while stirring thoroughly and the precipitate formed is filtered off under suction while still cold, washed neutral with water and dried between clay plates. 494 g (95.5% of theory) of 2,4-dichloro-5-nitro-thiazole are obtained in this manner. Melting point of a sample recrystallized from low-boiling petroleum ether: 38°-39° C.
Reaction SMILES: [N:1]1([C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]1[CH:6]=[CH:5][C:4]2[CH2:3][CH2:2][N:1]3[C:9]=2[C:8]=1[C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=13
Reactant: O=C1C=C(N2CCc3ccccc32)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc3c1n2CC3
Yield: 14.5 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-l-yl)-2-cyclohexen-1-one (2.515 g), cupric acetate (4.71 g) and palladium (II) acetate (0.20 g) in dry dimethylformamide (40 ml) was heated at 135° under nitrogen for 4 h. The solvent was then removed under reduced pressure and the residue was suspended in methanol and then filtered. The filtrate was evaporated under reduced pressure and the resultant residue was purified by FCC eluting with ethyl acetate to give the title compound (0.36 g) as a solid. A sample (20 mg) was recrystallised from ethyl acetate to give the title compound (15 mg), m.p. 208°-210°.
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([Zn]I)[CH:10]=1>CN(P(N(C)C)(N(C)C)=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH2:1][CH3:2])[CH:10]=1
Reactant: CCI
Reactant: Fc1ccc(Br)cc1[Zn]I
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1cc(Br)ccc1F
Temperature: 100 °C
Yield: 109.4 %

Procedure:
Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of (5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml, 2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C. for 48 hrs. After which time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes:ethyl acetate, to afford the title compound as a yellow oil (0.4 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>ClCCl>[CH2:29]([N:31]([CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:32][CH3:33])[CH3:30]
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reaction time: 14 h
Yield: 67.4 %

Procedure:
A mixture of ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g), diethylamine (1.04 g) and dichloromethane (35 ml) was stirred for 14 hours under reflux. The reaction mixture was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform, ethyl 6-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.1 g, 68%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[C:27]([Cl:33])=[N:28][S:29][C:30]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[S:29][N:28]=[C:27]([Cl:33])[C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: O=Cc1snc(Cl)c1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2snc(Cl)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 4-benzenesulfonyl-3-chloroisothiazole-5-carbaldehyde.
Reaction SMILES: [Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[CH3:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[CH:31]=[C:30]2[C:40]([OH:42])=O.[NH2:43][C:44]1[O:45][C:46]([C:49]2[O:50][CH:51]=[CH:52][CH:53]=2)=[N:47][N:48]=1>N1C=CC=CC=1>[O:50]1[CH:51]=[CH:52][CH:53]=[C:49]1[C:46]1[O:45][C:44]([NH:43][C:40]([C:30]2[C:29]3[C:34](=[C:25]([CH3:24])[CH:26]=[CH:27][CH:28]=3)[N:33]=[C:32]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=2)=[O:42])=[N:48][N:47]=1
Reactant: Cc1cccc2c(C(=O)O)cc(-c3cccs3)nc12
Reactant: Nc1nnc(-c2ccco2)o1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc2c(C(=O)Nc3nnc(-c4ccco4)o3)cc(-c3cccs3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
Triphenylphosphine bromide (352 mg, 0.80 mmol) was added to a methylene chloride (1 mL) solution of commercially available 8-methyl-2-(2-thienyl)-4-quinolinecarboxylic acid (108 mg, 0.40 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a pyridine (3 mL) solution of 2-amino-5-(2-furyl)-1,3,4-oxadiazole (90.7 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 hours and then heated with stirring overnight at 60° C. The reaction solution was concentrated. After that, to the residue, water was added, and the deposited solid was collected by filtration, washed with water, dried, and then purified by preparative HPLC to obtain the title compound (22 mg, 0.05 mmol).