Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]4[CH2:27][O:26][C:25](=[O:28])[C:14]=4[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[CH:17]4)=[CH:11][C:6]=2[O:5][CH2:4]1>CO>[Na+:2].[O:23]1[C:19]2[CH:18]=[CH:17][C:16]([C:15]3[C:14]([CH2:25][OH:28])=[C:13]([C:27]([O-:1])=[O:26])[CH:12]=[C:10]4[C:11]=3[C:6]3[O:5][CH2:4][O:3][C:7]=3[CH:8]=[CH:9]4)=[CH:24][C:20]=2[O:21][CH2:22]1
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 70 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1 N aqueous NaOH solution (2.9 mL) was added to the solution of 2 (100 mg, 0.29 mmol) in MeOH (10 mL). The mixture was stirred at 70° C. for 1 h. The solvent was evaporated to give a crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1, v/v) to afford 3 (110 mg, 98%) as a white powder. mp 128-130° C.;
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][N:5]=1.[C:21](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([O:16][CH3:21])=[O:15])[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1Oc1ccnc(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(Oc2ccnc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 1.6 ml methyl iodide are added to a mixture of 6.21 g 3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoic acid, 4.88 g potassium carbonate to and 30 ml N,N-dimethylformamide. The mixture is stirred overnight at ambient temperature. Then the mixture is added to ice-cold water, and the precipitate is filtered off and dried at 45° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[Br:14][C:7]1[N:6]=[C:5]([N:4]([CH2:20][C:19]2[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:18]=2[Cl:17])[C:1](=[O:3])[CH3:2])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccc(C#N)cc1Cl)c1nc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-(Acetamido)-6-bromo-3-nitropyridine (3.21 g) was dissolved in dry N,N-dimethylformamide (16 ml), and sodium hydride (60% in oil, 326 mg) was added under ice-cooling. The mixture was stirred for 30 min. A solution of 2-chloro-4-cyanobenzyl bromide (2.34 g) in dry N,N-dimethylformamide (4 ml) was dropwise added at the same temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the objective compound (4.17 g) as a pale-yellow powder.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[CH:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35].C(=O)(O)[O-].[Na+]>C(O)C>[NH:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:34][NH2:35])=[O:2])=[CH:9][CH:8]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: NN
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 80 °C
Yield: 63.2 %

Procedure:
To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoic acid methyl ester (AMD9711) (140 mg, 0.33 mmol) in dry ethanol (3 mL) was added hydrazine monohydrate (0.5 mL, 10.3 mmol) and the resulting mixture was heated at 80° C. for 24 h. Saturated aqueous sodium bicarbonate (5 mL) was added, the phases separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 75:1:1 CH2Cl2—MeOH—NH4OH) afforded the title compound (89 mg, 61%) as a white solid. 1H NMR (CDCl3) δ 1.64–1.68 (m, 1H), 1.94–2.04 (m, 2H), 2.20–2.24 (m, 1H), 2.66–2.72 (m, 1H), 2.78–2.83 (m; 1H), 3.73 (s, 2H), 3.93 (d, 1H, J=16 Hz), 4.00–4.12 (m, 3H), 4.15 (d, 1H, J=16 Hz), 7.14–7.18 (m, 3H), 7.40 (d, 2H, J=8 Hz), 7.50 (br d, 1H, J=7 Hz), 7.58 (d, 2H, J=8 Hz), 7.62 (br d, 1H, J=7 Hz), 8.06 (s, 1H), 8.66 (dd, 1H, J=5, 1Hz); 13C NMR (CDCl3) δ 21.2, 23.6, 29.0, 48.7, 53.7, 60.4, 111.4, 118.4, 121.5, 122.3, 126.9, 128.6, 131.5, 134.7, 137.3, 143.5, 146.8, 155.8, 157.1, 168.4. ES-MS m/z 427 (M+H). Anal. Calcd. for C25H26N6O.0.5CH2Cl2: C, 65.31; H, 5.80; N, 17.92. Found: C, 65.22; H, 5.77; N, 17.97.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2cccc(Br)n2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=Cc1ccc(-c2cccc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 75.2 %

Procedure:
4-(6-Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol), 4-trifluoromethoxyphenyl boronic acid (0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2M potassium carbonate (0.31 mL) and dioxane (2 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (80 mg) as an off-white solid: mp 109-112° C.; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 343 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:20]1([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]1=[O:28].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(#N)C>[CH2:32]([O:31][CH2:30][CH2:29][C:20]1([O:1][C:2]2[CH:18]=[CH:17][C:5]([O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)[C:21](=[O:28])[NH:22][C:23](=[O:27])[NH:24][C:25]1=[O:26])[CH3:33]
Reactant: CNC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(C(=O)NC)cc3)cc2)C(=O)NC(=O)NC1=O
Yield: 15.6 %

Procedure:
Following the procedure outlined for the preparation of Example 1 4-(4-hydroxy-phenoxy)-N-methyl-benzamide (0.14 g, 0.58 mmol) was reacted with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.16 g, 0.58 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.40 g) and 2.0 mL of acetonitrile, affording 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N-methyl-benzamide (0.040 g) as a colorless solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([N+:18]([O-])=O)[CH:17]=2)[NH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]3)[CH2:4][CH2:3]1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][CH:31]([NH:18][C:16]2[CH:17]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:27])(=[O:1])[CH2:3][CH2:4]3)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]3)[CH2:30][CH2:29]1
Reactant: O=C1CCOCC1
Reactant: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2cc(-c3ccccc3)[nH]c12
Product: O=S1(=O)CCN(Cc2cc(NC3CCOCC3)c3[nH]c(-c4ccccc4)cc3c2)CC1

Procedure:
5-(1,1-Dioxo-thiomorpholin-4-yl)methyl-2-phenyl-7-nitro-1H-indole prepared in Step B and tetrahydropyran-4-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[N:15][NH2:16])[CH3:6]
Reactant: CON=C(C(C)=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CON=C(C(C)=NN)c1ccccc1
Yield: 56 %

Procedure:
2.5 g (0.014 mol) of 1-phenylpropane-1,2-dione 1-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 1.45 g (0.029 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with diethyl ether and the crystals are filtered off. 1.5 g (55.6% of theory) of 2-hydrazono-1-phenylpropan-1-one O-methyl oxime of melting point 132° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([CH3:21])=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([CH3:21])=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1nc(C)c(Cl)c(Sc2sc(C(=O)O)cc2[N+](=O)[O-])c1Cl
Reactant: CN1CCC(N)CC1
Agent: Cl
Product: Cc1nc(C)c(Cl)c(Sc2sc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])c1Cl

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloro-2,6-dimethylpyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid from the above (200 mg, 0.53 mmol) and 1-methylpiperidin-4-amine hydrogen chloride salt (72.0 mg, 0.63 mmol). The title compound was obtained as a solid (180.0 mg, 72% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (1H, m), 8.49 (1H, s), 3.58 (1H, m), 2.75 (2H, m), 2.65 (6H, s), 2.14 (3H, s), 1.92 (2H, m), 1.72 (2H, m), 1.49 (2H, m). MS m/z: 475.18, 477.17 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][O:10][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(C)=O)s1
Yield: 60.3 %

Procedure:
A solution of 5-acetyl-thiophene-2-carboxylic acid (1 g, 5.88 mmol) in DMF (24 mL) is treated with potassium carbonate (813 mg, 5.88 mmol), then iodomethane (0.368 mL, 5.88 mmol), and stirred for 60 h at rt. The reaction mixture is acidified and extracted into ethyl acetate twice. The combined organic layers are washed with brine, dried, filtered, and concentrated, then taken up in ethyl acetate, washed with saturated aqueous potassium carbonate, dried, filtered and concentrated to give 5-acetyl-thiophene-2-carboxylic acid methyl ester (653 mg).
Reaction SMILES: C([C@H]1CSC(=O)N1[C:14]([C@@H:16]([C@@H:29]([OH:45])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)=[O:15])C1C=CC=CC=1.[OH:46]O.O.[OH-].[Li+]>O1CCCC1.O.O>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C@@H:29]([OH:45])[C@H:16]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=[N:19]3)[C:14]([OH:15])=[O:46])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1
Reactant: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound obtained from step f above (0.18 g) in tetrahydrofuran:water (3:1, 10 mL), aqueous hydrogen peroxide solution (30%, 0.15 mL) was added at 0° C., followed by the addition of lithium hydroxide monohydrate (17.6 mg) in water (2 mL). The reaction mixture was stirred at 0° C. until the completion of the hydrolysis. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate. The combined layers were washed with water and brine, and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure and the crude residue was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.075 g).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO.CO[CH:10](OC)[CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)C.[ClH:21]>>[ClH:21].[CH2:13]([C:12]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[CH:10][CH:11]=1)[CH3:14]
Reactant: CCC(=O)CC(OC)OC
Reactant: NC(=O)NO
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCc1cc[n+]([O-])c(O)n1
Temperature: -6.5 °C
Reaction time: 1 h

Procedure:
0.388 mol (25.9 g) hydroxy urea were dissolved in 195 ml 2 M HCl, 80 ml of methanol were added and 0.388 mol (56.7 g) of 1,1-dimethoxypentane-3-on (62% content in product mixture) were added dropwise under cooling with the internal temperature being maintained at −6 to −7° C. The solution was thawed to room temperature in an ice bath and stirred for 1 h, then evaporated until dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to below 0° C. in an ice/ethanol bath, the solid filtered off and washed with little ice-cold acetone. After drying 32.6 g crude product were obtained. The crude product was heated until boiling with 200 ml ethanol, hot filtered and slowly cooled to −18° C. The precipitated solid was filtered off, washed with a little amount of ethanol and dried. 11.7 g of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH3:22]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:22])[CH3:20])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.5 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were dissolved, with heating, in 10 ml. dimethyl formamide and gaseous dimethylamine passed in at 60° C. over the course of 15 minutes. The resultant suspension was then diluted with 6 ml. water, filtered with suction, first washed with aqueous dimethyl formamide, then with water and finally with methanol. There was thus obtained 0.4 g. (78 percent of theory) of the desired 3-(1-methyl-2-nitro-5-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]pyridazine in the form of yellow crystals which melt, with decomposition, at 261° - 263° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1)(0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0)(16 mg), then heated under reflux for 4 hours. The mixture was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)(=O)C.O>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: NN
Reactant: CCC(=O)CC(=O)CC
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CC)[nH]n1
Yield: 91.7 %

Procedure:
A solution of 3,5-heptanedione (2.4 g, 18.8 mmol) and hydrazine hydrate (1.0 g, 19.0 mmol) and acetic acid (1 drop) in water (10 mL) was heated to reflux for 1 h. The reaction mixture was then cooled in an ice bath to form a white precipitate. The precipitate was then filtered, dissolved in chloroform and dried over MgSO4. The resulting reaction was concentrated under reduced pressure to provide 2.14 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)[CH:12]=1.O.CN([CH:28]=[O:29])C>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[C:21]=2[CH:28]=[O:29])[CH:12]=1
Reactant: COc1ccc(Br)cc1-c1cn2ccccc2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Br)cc1-c1nc2ccccn2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
POCl3 (0.39 g, 2.5 mmol) was added to DMF (0.43 g, 6 mmol) by dropwise at 0° C. Then 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine (0.1 g, 0.33 mmol) in DMF (3 mL) was added. Then warmed to 25° C. and heated to 120° C. and stirred for 30 minutes and at 80° C. for 2 hours and then cooled to 25° C. H2O (20 mL) was added and extracted with EtOAc (3*50 mL), washed by aq NaHCO3 (3*50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 9.60 (s, 1H), 7.77˜7.81 (m, 2H), 7.54˜7.58 (m, 2H), 7.12˜7.15 (m, 1H), 6.92˜6.94 (m, 1H), 3.82 (s, 3H). MS (M+H)+: 331/333.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:45](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:20]=[N:19][N:18]([CH3:45])[N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 0.5 g, 0.85 mmol), methyl iodide (0.3 g, 2.1 mmol) and potassium carbonate (0.29 g, 2.1 mmol) were stirred at 50° C. in acetonitrile (20 ml) for 2 hours. Concentrated in vacuo then partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 20, 50 and 75% ethyl acetate/iso-hexanes to afford the title compounds: isomer A (0.25 g, 49%) and isomer B (0.17 g, 33%).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C-:11]#[N:12].[Na+]>CO.O>[CH:1]([CH:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC(C#N)c1ccccc1
Yield: 71 %

Procedure:
12.2 g of commercially available vinylbenzyl chloride (a mixture of 60% of a meta-isomer and 40% of a para-isomer) were reacted with 5 g of NaCN in a mixed solvent of methanol/water=12.2 g/5 g at 64° C. for 12 hours. A reaction product solution was filtered, and the solvent was then distilled off, followed by distillation under reduced pressure, thereby obtaining 8.1 g of vinylbenzyl cyanide (yield 71%).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)C>[CH3:9][CH2:8][O:7][C:5]([C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=1)=[O:10])=[O:6]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1
Yield: 60 %

Procedure:
Diethyloxalate (133 g) and p-fluoroaniline (100 g) were refluxed together for 2 hours, during which time the temperature dropped from 160° to 100°. The dark coloured mixture (with suspended crystalline solid) so produced was allowed to cool to 90°, and then diluted with ethanol (100 ml). After cooling overnight, the crystalline product was filtered off and washed thoroughly with cyclohexane. The white solid so obtained, was thoroughly dried to give ethyl 4'-fluorooxanilate (114 g; 60% yield), m.p. 117°-119° (with softening at 116°).