Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxy-phenyl-acetic acid (2.26 g, 10 mmol) and dichloromethane (50 mL). Cool to -5° C. using a ice-salt bath. Add 2 drops of dimethylformamide followed by dropwise addition of oxalyl chloride (1.74 mL, 20 mmol). after 1 hour, warm the reaction mixture to ambient temperature. After 2 hours, evaporate the reaction mixture in vacuo to give the title compound as a liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])(=O)C.[NH4+].[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)c(C)c(C)nc12
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc2cc(C)c(C)nc12
Yield: 127.1 %

Procedure:
1.23 g of 2,3-dimethyl-4-chloro-8-methoxy-quinoline, 1 g of ammonium acetate, 20 ml of acetic acid and 1.2 g of palladium-on-charcoal (5%) are introduced into a Parr flask. The mixture is subjected to a hydrogen pressure of 50 psi for 4 h. The reaction medium is filtered and neutralized with 75 ml of 1 N sodium hydroxide. This mixture is extracted with ethyl acetate (2×75 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. 1.32 g (yield: 77%) of 2,3-dimethyl-8-methoxyquinoline are obtained—m.p.: 138-139° C.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[NH:22])[CH:11]=1)[CH3:8].CN(C[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:34]SCCNC(N)=N)[CH:29]=1)C.[CH:42]([CH:44]([CH2:50]CC1C=NC(C)=CC=1)[C:45](OCC)=O)=[O:43].[O-]CC.[Na+]>C(O)C>[CH3:8][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:21]2[NH:23][C:42](=[O:43])[C:44]([CH2:50][C:33]3[CH:32]=[N:31][C:30]([CH3:34])=[CH:29][CH:28]=3)=[CH:45][N:22]=2)[CH:11]=1)[CH3:6]
Reactant: CCOC(=O)C(C=O)CCc1ccc(C)nc1
Reactant: CN(C)Cc1ccnc(CSCCNC(=N)N)c1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1

Procedure:
Reaction of N-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethyl]guanidine hemisulphate with ethyl 2-formyl-3-(6-methyl-3-pyridylmethyl)propionate and sodium ethoxide in ethanol gives 2-[2-(4-dimethylaminomethyl-2-pyridyl-methylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:55])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([O:32][Si](C(C)(C)C)(C)C)[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][C:18]=1[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51]>>[CH3:8][O:9][C:10](=[O:55])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([OH:32])[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([OH:40])[CH2:19][C:18]=1[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)C(C)(C)C)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)C(C)(C)C)C[C@H]1O
Yield: 54.6 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.7 ml) and methyl(11R,12S,13E,15S,17R)-9-pivaloyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (564 mg), the same procedure was performed as in Example 2 was performed to obtain methyl(11R,13E,15S,17R)-9-pivaloyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (211 mg, 55%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)nn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A mixture of 153c (170 mg, 0.29 mmol) and NaBH4(20 mg, 0.50 mmol) in methanol (5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was then quenched with water (7 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford the 153 as a pale yellow solid (35 mg, 21%). MS-ESI: [M+H]+ 586.3. 1H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.0 Hz 1H), 7.93 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.77 (dd, J=1.5, 12.5 Hz, 1H), 7.60-7.59 (m, 1H), 6.03 (s, 1H), 4.82-4.81 (m, 1H), 4.51-4.45 (m, 2H), 4.01-3.98 (m, 2H), 3.77 (s, 3H), 3.62-3.60 (m, 2H), 2.90-2.86 (m, 2H), 2.42-2.40 (m, 3H), 1.34 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[NH:37])[NH:35]O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[N:37]=[C:3]([CH2:2][OH:1])[O:5][N:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2noc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of hydroxy-acetic acid (1.67 g, 22 mmol), NEt3 (4.4 g, 44 mmol) in toluene (150 mL) was added isobutylchloroformate (6 g, 44 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (5.35 g, 22 mmol) was added to the mixture. The mixture was heated under reflux overnight, and then cooled to room temperature; the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was dissolved in THF (20 mL), and aqueous NaOH (10 mL, 10 mmol) was added. The mixture was stirred at room temperature for 2 hours and diluted with EtOAc (50 mL). The organic layer was washed with brine, after drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14].C(O)C.[OH-].[Na+]>O>[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13]1[CH:14]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: COC(OC)C(C)=O
Reactant: Nc1ncccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)c1ccc2cccnc2n1
Temperature: 7.5 °C

Procedure:
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 20 l 4-necked round-bottom flask was placed 2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 l), and water (2 l). This was followed by the addition of a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise with stirring at 0-15° C. The solution was stirred for 3 h at 0-20° C. and then concentrated under vacuum. The resulting solution was extracted with 3×1200 ml of ethyl acetate and the organic layers were combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was washed with 3×300 ml of hexane and the solid was collected by filtration. This resulted in the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 (s, 1H), 3.41 (s, 6H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17])[CH2:7][CH3:8].[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([CH2:35][CH2:36]I)[CH2:31][CH2:30]2)[CH2:23][CH2:22]1)[CH2:19][CH3:20].CC1N(C(N(C)C)=O)C1>CCCCCC.O1CCCC1>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:36][CH2:35][C@H:32]2[CH2:33][CH2:34][C@H:29]([CH2:28][CH2:27][C@H:24]3[CH2:23][CH2:22][C@H:21]([CH2:18][CH2:19][CH3:20])[CH2:26][CH2:25]3)[CH2:30][CH2:31]2)=[C:12]([F:16])[C:11]=1[F:17])[CH2:7][CH3:8]
Reactant: CCCOc1cccc(F)c1F
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCI)CC2)CC1
Agent: CC1CN1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOc1ccc(CC[C@H]2CC[C@H](CC[C@H]3CC[C@H](CCC)CC3)CC2)c(F)c1F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
65 ml of a solution of 0.1 mol of n-butyllithium in hexane is added at -100° C. to a mixture of 0.1 mol of 4- propoxy-2,3-difluorobenzene, 0.09 mol of potassium tert.butylate and 250 ml of tetrahydrofuran. After stirring for 10 minutes a mixture of 0.1 mole of trans-4-(trans-4-propylcyclohexylethyl)-cyclohexylethyl iodide, 0.1 mol of N,N-dimethylpropyleneurea and 100 ml of tetrahydrofuran is added to the mixture. Stirring for 1 hour at -85° C., warming up to -40° C. and working up in the customary manner gives trans-4-(2-(4-propoxy-2,3-difluorophenyl)-ethyl)-1-(2-(trans-4-propylcyclohexyl)ethyl)-cyclohexane.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:43][O:44][C:45]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[C:46]=1[NH2:47].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:23])([CH3:22])[C:19]([NH:47][C:46]2[C:48]([O:54][CH3:55])=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:45]=2[O:44][CH3:43])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)O)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-α,α-dimethyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCON)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) were added tert-butyl 4-[2-(aminooxy)ethoxy]piperidine-1-carboxylate 71 (0.240 g, 0.543 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 72 (0.276 g, 98%) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[CH:46]=[N:45][N:44]=[C:43]1[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:43]4[S:42][CH:46]=[N:45][N:44]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1nncs1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 68.6 mg, 0.112 mmol), 1,3,4-thiadiazol-2-amine (12.51 mg, 0.124 mmol), and cesium carbonate (110 mg, 0.337 mmol). The vial was flushed with Ar (g), then acetonitrile (562 μl) was added. After stirring overnight, the mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM). Some fractions were discarded, and the remainder containing product were combined and concentrated to 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (35.19 mg, 0.067 mmol, 59.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.80 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.87-7.79 (m, 1H), 7.62-7.53 (m, 2H), 7.49-7.41 (m, 2H), 7.32 (dt, J=3.0, 8.5 Hz, 1H), 7.27 (s, 1H), 3.71 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25]COC(C)=O>>[CH2:17]([O:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[C:3]=1[CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: CCOC(C)=O
Product: CCCCCCCCC1(C)SC(=O)C(C)=C1OCc1ccccc1
Yield: 75 %

Procedure:
To 32 (50 mg, 0.21 mmol) and benzyl bromide (37 mL, 0.31 mmol) following General Procedure H, was obtained 76 (49 mg, 75%) after flash chromatography (15% EtOAc/Hex). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=6.9 Hz, 3H), 1.24 (m, 11H), 1.41-1.48 (m, 1H), 1.66 (s, 3H), 1.79-1.86 (m, 2H), 4.98 (s, 2 H), 5.39 (s, 1H), 7.31-7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.6, 25.0, 26.4, 29.1, 29.3, 29.4, 31.8, 38.8, 59.7, 74.0, 102.2, 127.6, 128.8, 128.8, 134.3, 185.8, 194.1. IR (NaCl) 2928, 1681, 1610 cm−1.
Reaction SMILES: Cl[CH:2]([O:12][CH2:13][CH:14]([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[C:3]([N:9]([F:11])[F:10])([N:6]([F:8])[F:7])[CH2:4][F:5].[N-:21]=[N+:22]=[N-:23].[Na+].CC(C)=O>O>[N:21]([CH:2]([O:12][CH2:13][CH:14]([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[C:3]([N:9]([F:11])[F:10])([N:6]([F:8])[F:7])[CH2:4][F:5])=[N+:22]=[N-:23]
Reactant: O=[N+]([O-])C(COC(Cl)C(CF)(N(F)F)N(F)F)[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(OCC([N+](=O)[O-])[N+](=O)[O-])C(CF)(N(F)F)N(F)F

Procedure:
A mixture of 1.7 g of 1-chloro-2,2-bis(difluoramino)-3-fluorodinitroethoxypropane, 0.7 g of sodium azide, 10 ml of acetone, and 5 ml of water was refluxed for 72 hours. The mixture was extracted with methylene chloride, washed with water, and concentrated to give 1.3 g of light yellow liquid. I.R. showed an absorption for azide at 4.7μ.
Reaction SMILES: [Cl:1][C:2]([CH3:15])([CH:4]([N:13]=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[NH3:16]>CO>[ClH:1].[NH2:16][C:2]([CH3:15])([CH3:3])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(C)(Cl)C(COc1ccccc1)N=O
Solvent: CO
Product: CC(C)(N)C(COc1ccccc1)=NO
Product: Cl
Yield: 66 %

Procedure:
A suspension of 2-chloro-4-(p-methyl)phenoxy-2-methyl-3-nitrosobutane (V) in dry methanol (120 ml) was heated to reflux and ammonia gas was passed through until all the solid dissolved (2 hours). Filtration and evaporation of solvent gave a brown solid, which was largely freed of impurities by washing with benzene. Recrystallisation from isopropanol (a small inorganic residue remained) gave the ketoxime hydrochloride (IV) (5.27 g, yield 66%) as colourless crystals, m.p. 217°-8° (decomp.).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][CH:22]([CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=1)=[O:24]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:36]1[CH2:37][CH2:38][CH:33]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:39])[CH:31]=[CH:30][C:29]=2[CH3:32])[CH2:34][CH2:35]1)(=[O:20])[CH3:19]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cc(NC(=O)C(C)C)ccc3C)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure G and Scheme AI using 1-(3-{[(1S)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 513.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.Cl[C:31]1C=CC(C2N=C3C=CC=CN3C=2CN2CC(OC)=CC2=O)=CC=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:23]3[CH2:31][CH2:28][N:26]([CH3:27])[CH2:25][CH2:24]3)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: CN1CCNCC1
Product: CN1CCN(C2=CC(=O)N(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)C2)CC1

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and 1-methylpiperazine. (56 mg, 47%) m/e+=422 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.47 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H, D, J=9.1 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85 (t, 1H, D, J=6.4 Hz), 5.09 (s, 2H), 4.74 (s, 1H), 3.57 (s, 2H), 3.03 (m, 4H), 2.36 (m, 4H), 2.27 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]([C:22]([O:24]CC)=[O:23])[C:17]([O:19]CC)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]([C:22]([OH:24])=[O:23])[C:17]([OH:19])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1c2ccccc2CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(C(=O)O)C1c2ccccc2CCc2ccccc21
Reaction time: 8 h

Procedure:
A solution of 305 g of crude diethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonate and 138 g of potassium hydroxide in 1.5 l of ethanol and 400 ml of water is heated to boiling under reflux for 1.5 hours while stirring and subsequently evaporated in vacuo. The residue obtained is partitioned between 1 l of ether and 1 l of ice-water. The aqueous, alkaline phase is extracted further with 500 ml of ether, made acid with about 220 ml of concentrated hydrochloric acid while cooling with ice and extracted with 2 l of ether. The ethereal phase is washed three times with 500 ml of water each time and the aqueous washings are back-extracted with 1 l of ether. The combined ether extracts are washed for an additional three to four times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a volume of about 400 ml. After dilution with 300 ml of petroleum ether, the clear solution obtained is cooled in an ice-bath and left to stand at 4° overnight. The crystallized-out material is removed by filtration under suction while back-washing with petroleum ether and dried at 50° in a vacuum drying oven. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonic acid of melting point 183° (with decarboxylation).
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([O-:28])=[CH:26][CH:25]=1.[Na+].CC1C=CC(O)=CC=1>C1COCC1>[C:24]1([CH3:23])[CH:30]=[CH:29][C:27]([O:28][C:2]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc([O-])cc1
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Agent: Cc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(OC(=CC(=O)c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di(4-bromobenzoyl) ethane (11.1 g, 0.02 mole) in 35 ml of THF was added a suspension of sodium 4-methyl phenoxide [prepared from 0.92 g (0.04 mole) Na and 4.32 g (0.04 mole) 4-methylphenol in 30 ml THF by refluxing for 4-5 hr]. The yellow mixture was refluxed for 2-3 hr (TLC followed) after which the THF was removed under reduced pressure. The residue was treated with water, and the solid was filtered, washed with water, dried (Na2SO4), and dissolved in chloroform. The chloroform solution was passed through a silica column (elution with 2-5% ether in hexane). The result was an off white crystalline solid, 4.95 g (50%), mp 137°-8° C. IR (KBr) 3087, 3035, 2868, 1687, 1646, 1587, 1572, 1557, 1502, 1399, 1364, 1194, 1068, 1009, 971, 876, 815, 772, 526. 1H NMR (CDCl3 /35° C.) 7.92 (d, 2H, J=8.8), 7.65 (d, 2H, J=8.8), 7.55 (d, 2H, J=8.8), 7.48 (d, 2H, J=8.8), 7.27 (d, 2H, J=8.3), 7.11 (d, 2H, J=8.3), 6.32 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3 /35° C.) 189.4, 187.6, 168.4, 150.9, 136.6, 136.0, 133.4, 132.3, 131.8, 130.9, 130.3, 129.6, 129.2, 128.2, 120.6, 101.8, 20.95. MS m/e 500 (M+).
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.C(O)=O.OS(O)(=O)=O>[Pd].CN(C=O)C>[CH3:3][CH2:2][CH2:1][CH2:5][CH2:3][CH2:2][CH2:1][CH2:5][CH2:3][CH2:2][CH2:1][CH3:5]
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCCCCCCCCCCC
Yield: 83 %

Procedure:
HMF, THF, formic acid (4 equiv.), H2SO4 (3 mol %, relative to HMF) and Pd/C (8 mol %) were stirred at 100° C. to yield DMF in 83% yield by gas chromatography relative to a dodecane standard.