Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCc1nnc(Br)s1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCc1nnc(-c2ccc(F)cc2)s1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (1.2 g, 6.153 mmol) in toluene (40 mL) and ethanol (40 mL) was added 4-fluorophenyl boronic acid (1.026 g, 7.384 mmol) and 2 M solution of aqueous Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.354 g, 0.355 mmol) was added, the reaction mixture again degassed with argon for 10 min, and the mixture heated to 100° C. for 2 h. The reaction mixture was evaporated under vacuum to remove the ethanol, diluted with water (50 mL), extracted with ethyl acetate (200 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (using 30% ethyl acetate and hexane) to give (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol as pale yellow solid (0.85 g, 65% yield); LC-MS m/z calculated for [M+H]+ 211.03. found 211.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)[N:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2nc(Cn3ccc(N)n3)cs2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1nc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-4-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.0 min; [M+H]+=394.25.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:37])[S:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:34]=[CH:33][C:22]3=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:26]=[C:21]3[C:20](=[O:35])[C:19]=2[CH:36]=1)(=[O:13])=[O:12].C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:33]1[C:22]2=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:26]=[C:21]2[C:20](=[O:35])[C:19]2[CH:36]=[C:15]([NH:14][S:11]([N:10]([CH3:37])[CH3:9])(=[O:13])=[O:12])[CH:16]=[CH:17][C:18]=2[CH:34]=1
Reactant: CN(C)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)Nc1ccc2cc(Cl)c3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
N-Chlorosuccinimide (30.6 mg, 0.229 mmol) was added to N,N-dimethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide (Compound 118) (75 mg, 0.183 mmol) suspended in acetonitrile (18.3 ml) at room temperature. The resulting suspension was heated to 100° C. in a sealed vial for 24 h. After standing at room temperature for an additional 2 days, the reaction was basified with aqueous sodium hydrogen carbonate (saturated, 75 mL) and extracted with dichloromethane (2×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA, to afford the title compound as a yellow/orange solid. 1H NMR (600 MHz, CDCl3) δ 9.10 (d, 1H, J=1.8 Hz); 8.45 (d, 1H, J=2.4 Hz); 7.94 (d, 1H, J=0.6 Hz); 7.83 (s, 1H); 7.79 (d, 1H, J=2.4 Hz); 7.68 (s, 1H); 7.55 (dd, 1H, J=8.4, 2.4 Hz); 7.50 (d, 1H, J=9.0 Hz); 7.03 (s, 1H); 4.00 (s, 3H); 2.91 (s, 6H). LCMS (APCI) exact mass calc'd for [M+H]+ (C20H18ClN5O3S) requires m/z 444.1 found 444.1.
Reaction SMILES: OS(O)(=O)=O.O[C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15](=[O:17])[CH3:16].[CH2:18](Cl)Cl.O1C=CCC1=O>C1COCC1>[CH3:16][C:15]1[O:17][C:7]2[CH2:12][CH2:11][C:10](=[CH2:18])[C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: ClCCl
Reactant: CC(=O)CC1=C(O)CCCC1=O
Agent: O=C1CC=CO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C=C1CCc2oc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of conc. H2SO4 (300 ml) cooled in an ice-bath was added a solution of 3-hydroxy-2-(2-oxopropyl)-2-cyclohexen-1-one (190 g in 300 ml CH2Cl2). Upon completion of addition, the mixture was stirred at ambient temperature for about 1 hour. The mixture was then slowly poured into 3 liters ice water, and then about 1 liter of CH2Cl2 was added. The layers are separated and the aqueous layer extracted thrice with CH2Cl2 and the combined CH2Cl2 layers again extracted thrice with water. The CH2Cl2 layer was washed thrice with dilute aqueous NaHCo3, then once with water and dried (MgSO4). Concentration in vacuo afforded an orange oil. Step B. To a solution of the furanone of Step A (164.5 g, 1.10 mole) in about 400 ml THF was added, in four separate portions, N-methylanilinium trifluoroacetate (TAMA) (243 g) and trioxymethylene (99 g) over 3-1/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and partitioned between Et2O and water, the layers separated and the aqueous layer was extracted twice with Et2O. The combined Et2O layers were washed exhaustively with water, with NaHCO3 and then with brine, dried over MgSO4 and conc. in vacuo to yield an amber oil. This oil was flash chromatographed on silica gel using CH2Cl2 as solvent in several runs of 10-20 g per run. Fractions containing the fast moving material were combined, concentrated in vacuo to obtain the desired product as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.072 g, 0.12 mol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% methanol in dichloromethane) to give the title compound as a white solid (0.012, 0.024 mol, 20%). 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1 H), 7.56 (d, J=8.4 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.18-7.09 (m, 2 H), 6.80 (d, J=7.6 Hz, 1 H), 6.60 (s, 1 H), 6.09 (q, J=6.8 Hz, 1 H), 4.82-4.78 (m, 2 H), 4.64-4.60 (m, 1 H), 4.12-4.07 (m, 2 H), 3.76-3.58 (m, 4 H), 3.43-3.38 (m, 2 H), 2.90-2.76 (m, 2 H), 2.48-2.36 (m, 1 H), 2.13-2.20 (m, 3 H), 1.98 (d, J=6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O2 [M+H]+ 502.2, found 502.4.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[Br-:13].[CH2:1]([N+:8]1[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(CCCBr)cc1
Reactant: CCCCCCCn1ccnc1
Product: CCCCCCC[n+]1ccn(CCCc2ccc(OC)cc2)c1
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.5 g (0.015 mole) of 1-heptyl-1H-imidazole and 3.45 g (0.015 mole) of 1-(3-bromopropyl)-4-methoxybenzene is heated at 140° C. for about 1.5 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol: 1M sodium chloride, 95:5). At the completion of the reaction, the cooled reaction product is triturated thoroughly with ether and on drying, provides the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:13][CH2:14][C@@H:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21](N=N[N:25]=2)[CH:22]=1)[OH:16])([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[Cl:26][Sn]Cl>CO>[ClH:26].[ClH:26].[NH2:25][C:20]1[N:21]=[CH:22][C:17]([C@H:15]([CH2:14][NH:13][C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[OH:16])=[CH:18][CH:19]=1
Reactant: CC(C)(CCc1ccccc1O)NC[C@H](O)c1ccc2nnnn2c1
Reactant: Cl[Sn]Cl
Solvent: CO
Product: CC(C)(CCc1ccccc1O)NC[C@H](O)c1ccc(N)nc1
Product: Cl

Procedure:
A solution of 127 mg (0.37 mmol) of (R)-a-[[(1,1-dimethyl-3-(2-hydroxyphenyl)propyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol and 170 mg (0.75 mmol) of SnCl2 ·2H2O in 15 ml of methanol is heated at reflux for 20 hours. The reaction mixture is cooled in ice and H2S is bubbled through the solution. The precipitate is collected by filtration and the filtrate concentrated. The residue is chromatographed on silica gel to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Br:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Br:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Br)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(Br)nc3n2)cc1
Temperature: 4 °C
Yield: 46.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.8 g) and 2-amino-7-bromo-1,8-naphthyridine (11.2 g). The product produced by precipitation in water (9.8 g; m.p. 220° C.) is dissolved in boiling acetonitrile (1000 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-bromo-1,8-naphthyridin-2-yl)-4-methoxybenzamide (8.3 g) is produced, m.p. 221° C.
Reaction SMILES: [Br-].[CH2:2]([O:4]C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[CH3:3].[O-:27][CH2:28][CH3:29].[Na+].[C:31]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)(=O)[CH3:32]>C(O)C>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34](/[C:31](/[CH3:32])=[CH:29]\[C:28]([O:4][CH2:2][CH3:3])=[O:27])[CH:35]=1
Reactant: CC[O-]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cccnc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C=C(/C)c1cccnc1
Reaction time: 336 h
Yield: 111.3 %

Procedure:
Ethoxycarbonylmethyltriphenylphosphonium bromide (100 g) in ethanol (500 ml) was added with stirring under nitrogen to a solution of sodium ethoxide (from 4.28 g sodium) in ethanol (100 ml). 3-Acetylpyridine (18.8 g) in ethanol (300 ml) was added dropwise over 0.5 hour. The mixture was allowed to stand for 14 days and was evaporated to dryness. The residue was taken up in water, the pH adjusted to 8.5 and the mixture was extracted with benzene. The extract was dried, evaporated and the residue was distilled at reduced pressure to give ethyl 3-(3-pyridyl)-crotonate (13.39 g) b.p. 78°/0.1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(C(C)(C)C)cc3)CC2)CS1

Procedure:
Compound 202 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=188-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d, J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73 (m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25 (s, 9H). LCMS: 538 [M+H].
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)=[O:21])=[N:4][N:3]=[N:2]1.[CH3:33][N:34]([CH3:39])[C:35](=[O:38])[CH2:36]O.C(O)(=O)C>CN(C)C=O.O>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([O:30][CH2:36][C:35](=[O:38])[N:34]([CH3:39])[CH3:33])=[O:29])=[CH:31][CH:32]=2)=[O:21])=[N:1][N:2]=[N:3]1
Reactant: CN(C)C(=O)CO
Reactant: O=C(O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Yield: 38.5 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 1.2 g of 4-[2-[2-(1H-tetrazol-5-yl)phenylthio]phenylcarbamoyl]p-henoxyacetic acid (prepared in Example 6), followed by addition of 0.44 g of N,N'-carbonyldiimidazole with ice-cooling and stirring. The mixture was stirred with ice-cooling for 20 minutes, then 0.42 g of N,N-dimethylglycolamide was added, and the mixture was stirred at room temperature overnight. This reaction mixture was acidified with acetic acid and diluted with water and the crystals separated out therefrom were collected by filtration and recrystallized from N,N-dimethylformamide-ethyl acetate to give 0.55 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC1CCCCC1)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=1.C(Br)C=C>O1CCCC1.C(OCC)C>[CH2:3]([CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[C:25]#[N:26])[CH:2]=[CH2:1]
Reactant: COc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: CC(C)NC1CCCCC1
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCC(C#N)c1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
n-Butyl lithium (0.16 mole of 1.6 M in hexane) was added under a nitrogen atmosphere to dry tetrahydrofuran (100 ml.) which was cooled in a CO2 -acetone bath. This was followed by the successive dropwise additions during 10 minutes of solutions in tetrahydrofuran (10 ml. each) of N-isopropylcyclohexylamine (22.6 g., 0.160 mole) and p-methoxyphenylacetonitrile (21.2 g., 0.144 mole). The mixture was stirred in the cold for 10 minutes when allyl bromide (24.2 g., 0.20 mole) was added dropwise during 10 minutes. Stirring was continued in the cold for 15 minutes and then at ambient temperature for 1.5 hours. The solution was diluted with diethyl ether and washed successively with 4% hydrochloric acid (2 × 100 ml.) H2O and brine. The ethereal solution was dried (Na2SO4), concentrated, and the residue distilled to give 24.2 g. (89% yield) of the nitrile, b.p. 99°-114° (0.1 mm.).
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.O1CCN([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)CC1.C(N(CC)CC)C>ClCCl>[O:15]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:2]([C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)=[N:14]1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: C1=C(N2CCOCC2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@@H](c2noc3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.20 g, 5.13 mmol) and 1-morpholinocyclohexene (1.72 g, 10.3 mmol) in dichloromethane (50 ml) was added triethylamine (0.72 ml, 5.1 mmol) at 0-5° C. The cooling bath was removed 30 minutes after completed addition. After stirring for 4 h the solvent was evaporated. The residue was redissolved in 6 M aqueous hydrochloric acid solution (50 ml), and the mixture was and heated at reflux for 1 h. After cooling to room temperature the reaction mixture was partitioned between crushed ice (100 g) and ethyl acetate (50 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave cis-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.40 g, 31%) as white solid (MS m/e: 248 ([M−H]−)) and trans-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.09 g, 7%) as white solid (MS m/e: 248 ([M−H]−)).
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.OO.[NH2:14][C:15]([NH2:17])=O.N[C:19]1[C:24]([Cl:25])=CN=[CH:21][C:20]=1[Cl:26].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.CO>[NH2:14][C:15]1[C:24]([Cl:25])=[CH:19][C:20]([Cl:26])=[CH:21][N+:17]=1[O-:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(N)=O
Reactant: Nc1c(Cl)cncc1Cl
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Nc1c(Cl)cc(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of phthalic anhydride (22.7 g, 2.5 eq) and urea hydrogen peroxide (17.3 g, 3.0 eq) in 80 mL 3:1 acetonitrile/methanol was heated at 35–40° C. until all solids dissolved. After cooling to room temperature, solid 4-amino-3,5-dichloropyridine (10 g, 61 mmol, available from Aldrich Chemical Company, Milwaukee, Wis.) was added portion-wise. The reaction temperature was maintained at 20–25° C. during addition. This mixture was stirred at room temperature for 18 h and quenched with 150 mL chilled aqueous sodium sulfite solution (10.4 g Na2SO3, 1.4 eq). The resulting slurry was filtered and washed with water. The wet phthalate salt of the N-oxide was reslurried in 20 mL water and free based with aqueous K2CO3. After stirring for 6 h at room temperature, the slurry was filtered and washed with water. The wet cake was air-dried at 75° C. The residual water was removed by reslurrying the dry cake in refluxing methanol for 2 h. It was filtered at 10-20° C. and washed with methanol. The cake was vacuum dried at 75° C. until the methanol content was less than 0.1%. The product, 4 amino-3,5-dichloropyridine-N-oxide (the compound of formula X) was obtained (9.5 g, 98% purity, 85% yield).
Reaction SMILES: C1[C:6](CCCC(O)=O)=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])C=1.[OH:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.[O:51]1CCCC1>C(#N)C.CN(C)C1C=CN=CC=1>[Cl:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][Cl:16])[CH2:3][CH2:4][CH2:5][C:6]([O:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:25])=[O:51]
Reactant: C1CCOC1
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(NCCO)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(CCCN(CCCl)CCCl)OCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Chlorambucil (20 g, 0.0657 mol) was dissolved in 800 mL of dry acetonitrile, then 13.1 g (0.079 mol) of N-(2-hydroxyethyl)-3-pyridinecarboxamide were added. Acetonitrile was added until the solution was clear. The total volume of acetonitrile used at this stage was 850 mL. To the stirred solution, maintained over argon, there were added 1.492 g (0.0723 mol) of dicyclohexylcarbodiimide and 0.802 g (0.0066 mol) of 4-(dimethylamino)pyridine (DMAP). The reaction mixture was stirred overnight at room temperature under dry conditions, and the progress of the reaction was followed by thin layer chromatography. At the end of the reaction period, the solid which formed was removed and washed with 50 mL of cold acetonitrile. The filtrate was evaporated in vacuo at 30° C., and the yellow solid thus obtained was dissolved in a minimum amount (15 mL) of 8:2 chloroform/tetrahydrofuran and applied to a column packed with 900 g of silica gel. The column was eluted with 8:2 chloroform/tetrahydrofuran. The adduct and chlorambucil were eluted within the first 500 mL, and the desired ester was then collected upon evaporation of the eluent under vacuum. The title compound was obtained in 82.7% yield as a yellow solid melting at 73°-75° C. It had the formula ##STR110##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Solvent: O
Product: NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 10.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine, 6.6 g. of hydrazine hydrate and 150 ml. of butanol is heated at reflux overnight. The reaction mixture is cooled and the precipitate is collected by filtration, washed with butanol and water and then dried yielding 6-(p-chlorophenyl)-3-hydrazinopyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[CH:7]=O.[CH3:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[C:7]1[NH:18][C:12]2[CH:11]=[C:10]([CH3:9])[C:15]([CH3:16])=[CH:14][C:13]=2[N:17]=1
Reactant: O=Cc1[nH]ncc1Br
Reactant: Cc1cc(N)c(N)cc1C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]ncc3Br)[nH]c2cc1C

Procedure:
Starting with 100 mg of commercial 4-bromo-2H-pyrazole-3-carboxaldehyde, 77.8 mg of 4,5-dimethyl-1,2-phenylenediamine, and 108.6 mg of sodium metabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica, 143.2 mg of 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole are obtained in the form of a yellow foam.