Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:27][CH2:28][CH3:29])=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:30](Cl)([Cl:32])=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:30]([Cl:32])=[O:31])[C:10]([C:20]3[C:21]([O:27][CH2:28][CH3:29])=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H27N6O3Cl2 [(M+H)+] 553.1516, observed 553.1515.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([C:18]2([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([C:18]2([CH:24]=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: OCC1(c2cccc(F)c2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1(c2cccc(F)c2)CCCCC1
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a solution of oxalyl chloride (0.851 mL, 9.72 mmol) in 15 ml of CH2Cl2 at −20° C. was added DMSO (0.690 mL, 9.72 mmol) dropwise, and the mixture was stirred for mins. Then a solution of (1-(3-fluorophenyl)cyclohexyl)methanol (675 mg, 3.24 mmol) in 5 mL of CH2Cl2 was added dropwise and the mixture was stirred for 30 mins at −20° C. Next, triethylamine was added (1.807 mL, 12.96 mmol) dropwise, and the resulting suspension was stirred for 1 hr at a temperature in the range of from −20° C. to 20° C. and then for 1.5 hrs at room temperature. It was diluted with Et2O and washed with water and brine. The combined washings were back-extracted with Et2O once and washed with brine. The combined extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 5:95 followed by 2:8 EtOAc-hexane to give 1-(3-fluorophenyl)cyclohexanecarbaldehyde (470 mg, 70.3% yield) as an oil. 1H NMR (400 MHz, CCl3D) δ ppm 9.37 (1H, s), 7.33 (1H, td, J=8.02, 6.15 Hz), 7.07-7.11 (1H, m), 7.04 (1H, dt, J=10.77, 2.20 Hz), 6.94-7.00 (1H, m), 2.28 (2H, dd, J=13.51, 4.94 Hz), 1.83 (2H, ddd, J=13.62, 10.55, 3.30 Hz), 1.29-1.72 (6H, m).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[K+]>CO>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:27])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Yield: 93.1 %

Procedure:
3-(2′,4′,5′-Trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (2.9 g, 7.79 mmol) and 2N KOH (15.6 mL, 31.2 mmol) in 140 mL MeOH were reacted as above to yield 2.6 g (93.2%) of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid. LC-MS (ES) calculated for C20H13F3O3, 358.32; found m/z 357.1 [M−H]−.
Reaction SMILES: C(O)C.COS([O-])(=O)=O.[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]1[C:23]([CH2:24][N+](C)(C)C)=[C:22]([CH3:29])[N:21]=[C:16]12.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CS(C)=O>[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]1[C:23]([CH2:24][C:31]3[NH:30][CH:34]=[CH:33][N:32]=3)=[C:22]([CH3:29])[N:21]=[C:16]12
Reactant: c1c[nH]cn1
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C[N+](C)(C)C
Agent: COS(=O)(=O)[O-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1Cc1ncc[nH]1
Temperature: 100 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
Ethanol (50 ml) was added to a mixture of 7-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (2.3 g) and imidazole (0.95 g) in dimethyl sulfoxide (20 ml) and heated at 100° C. with stirring for 5 hours. After the removal of ethanol by distillation, the residue was poured into water. The resulting precipitates were collected by filtration, dried and recrystallized from ethyl acetate. The obtained crystals were chromatographed on silica gel (16 g) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates were evaporated in vacuo and the residual solid was recrystallized from ethyl acetate to give 7-chloro-3-(1-imidazolylmethyl)-2-methylimidazo[2,1-a]isoquinoline (0.7 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](=[N-])(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][S:23]2(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=S(=O)=O
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Then, 590 mg of 1-benzyl-4-[N-(o-aminobenzyl)amino]-piperidine, 600 mg of sulfurylamide and 12 ml of pyridine are mixed and refluxed with heating for 2 hours. The reaction mixture is cooled to room temperature and poured into 50 ml of ice water. The white crystals deposited are separated by filtration, washed with 10 ml of water and dried to obtain 520 mg of the desired product as crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Cl)c(Cl)c1
Yield: 23 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 10.0 g (0.06 mole of KI and 49.0 g (0.25 mole) of 3,4-Dichlorobenzyl chloride. The reaction mixture was heated at 100° for 3 hours and poured into 1.8 1 of H2O. The aqueous mixture was extracted with 1.3 1 of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness to give 14 g (23%) of a light yellow semisolid. The crude product was crystallized using 20 ml of acetonitrile, filtered, washed with ether, air dried and dried at 60° for 2 hrs to give 10.5 g (17%) of a white solid, m.p. 129°-130°. An analytical sample, m.p. 129°- 130°, was a portion of the above crystallized product.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]([CH2:51][CH3:52])[CH2:49][CH3:50]>>[CH2:47]([N:48]([CH2:51][CH3:52])[CH2:49][CH2:50][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1)[CH3:46]
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using (2-chloroethyl)-diethylamine hydrochloride. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 374.0 [M+H]+; single peak at tR=3.04 min (System 2).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH: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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cnc(Br)cn1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cnc(Br)cn2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of 2,5-dibromopyrazine (100 mg, 0.4 mmol) in toluene (6 mL) and ethanol (3 mL) was added (4-fluorophenyl)boronic acid (29 mg, 0.2 mmol) and 2M sodium carbonate solution (2.84 mL). The solution was purged with argon for 15 min, Pd(PPh3)4 (4 mg, 0.004 mmol) was added, and the reaction mixture was purged with argon for 15 min. The resulting mixture was heated to 40° C. and stirred for 1 h. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (10 mL), and dried over Na2SO4 and concentration in vacuo. The crude product was purified by flash chromatography (60-120μ, 5% ethyl acetate in hexane) to afford 2-bromo-5-(4-fluorophenyl)pyrazine as off-white solid (60 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.88 (s, 1H), 8.18-8.15 (m, 2H), 7.37 (dd, 2H); LC-MS m/z calculated for [M+H]+ 252.97. found 253.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:15][CH2:13][CH3:14])(=[O:11])=[O:10])#[N:2]
Reactant: CCN
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccccc1C#N
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (10 mL), a 2M THF solution of ethylamine (5.0 mL, 10.0 mmol) was added. After stirring for 30 min, the reaction was concentrated then purified via preparative HPLC eluting with MeOH/H2O/TFA to provide 2-cyano-N-ethylbenzenesulfonamide (105 mg). The product was dissolved in MeOH (8 mL), conc. HCl (70 mg) was added, and the whole was hydrogenated at 30 psi for 3 h. The reaction was filtered and dried (Na2SO4) to provide 201A (123 mg, 49%). LC-MS: 215.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-succinic acid 1-benzyl ester (2.62 g, 8.10 mmol) under an atmosphere of nitrogen was dissolved in THF (40 mL) and cooled to 0° C. A 1.0 M borane-THF complex in THF (15 mL) was added dropwise and the reaction mixture was stirred for 3 h, quenched carefully with MeOH (20 mL) and stirred for 20 min. The reaction mixture was treated with MeOH (2×15 mL) and concentrated to dryness. The residue was dissolved in EtOAc and washed with 1N HCl (10 mL), saturated sodium bicarbonate (10 mL), and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and purified on SiO2 to give the intermediate (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester as a clear colorless oil (1.2 g), which was used in the procedure of Preparation 14 to prepare the title compound.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:18]([C:31](OCC)=[O:32])=[CH:17]2.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH:12][C:31]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)=[O:32])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 0 °C

Procedure:
23.8 ml (47.57 mmol) of a 2M solution of trimethylaluminum in toluene are added to a solution, stirred at 20° C. under an argon atmosphere, of 4.48 g (34.89 mmol) of 6-chloro-3-aminopyridine in 317 ml of toluene. The solution is then brought to 120° C. and 10 g (31.71 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate are added in several steps (WO 2006/024776). The reaction mixture is refluxed for 4 hours and is then cooled to 0° C. 15 ml of water are added to the reaction medium, which is then extracted with twice 200 ml of ethyl acetate. The organic phases are combined and washed twice with 50 ml of water and once with 50 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is triturated in 100 ml of ethyl ether, the product is filtered, and 10 g of expected product are recovered in the form of a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:2]=1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([Cl:16])=[O:12])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCc1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 247 mg (1.49 mmol) of 4-pyridin-3-yl-butyric acid in 10 mL CH2Cl2 was added one drop DMF and 2.3 mL (4.56 mmol) oxalyl chloride and the mixture stirred at rt for 4 h. The volatiles were evaporated under reduced pressure and the material used crude in the following procedure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.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>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:5]3[CH:10]=[CH:9][C:1]([O:2][CH2:3][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:7][CH:6]=3)=[CH:22][C:20]=2[N:21]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: COC(=O)c1ccc(B(O)O)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: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 36 %

Procedure:
(1E,4E)-2-Amino-8-(4-(benzyloxy)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (36%) was prepared as follows, substituting 4-(benzyloxy)phenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. m/z (APCI-pos) M+1=468.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3](=O)[CH3:4].O.NN.[OH-].[Na+].Cl>O.C(O)COCCO>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCC(C)C(C)=O
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCC(C)CC
Temperature: 200 °C
Yield: 52.7 %

Procedure:
2 g (7.46 mmol) of 3-methyl-heptadecan-2-one (Compound No. 3 of Table 1) are introduced into 10 ml of diethylene glycol, and the mixture is treated with 1.11 g (22.4 mmol) of hydrazine hydrate and 1.2 g (29.85 mmol) of sodium hydroxide. The mixture is stirred for twenty hours at 200° C. When the mixture has cooled to room temperature, it is treated with 100 ml of water, acidified with hydrochloric acid, with cooling, and extracted three times using cyclohexane. The combined organic extracts are washed twice with a little water, dried over sodium sulphate and concentrated. Separation by column chromatography using cyclohexane as the eluent gave 1.0 g (53% of theory) of 3-methylheptadecane.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2CNC(=O)[C@H]2Cc2ccccc2)cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CNC[C@H]2Cc2ccccc2)cc1OC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
10 ml of 1M borane/THF complex was added to 10 ml of a solution of 0.81 g (2.6 mmol) of trans-3-benzyl-4-(3,4-dimethoxyphenyl)-2-pyrrolidone in THF, and the mixture was heated under reflux for 6 hr. After the completion of the cooling, 10 ml of a 6N hydrochloric acid solution was dropwise added at room temperature carefully, and the mixture was stirred at 60° C. for 30 min. THF was distilled off in vacuo, and the residue was basified with a 10% aqueous sodium hydroxide solution and extracted twice with methylene chloride. The resultant organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo to prepare a crude product. The crude product was adsorbed on silica gel to elute impurities (methylene:methanol=95:5), and elution was again conducted to prepare 0.37 g (yield: 48%) of an intended product.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[K+].Cl>CO>[C:10]([C:8]1[CH:9]=[C:4]2[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH:15]=[CH:16][CH:17]=3)=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)#[N:11]
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 132 mg, 0.923 mmol), propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (22, 151 mg, 0.616 mmol) and potassium hydroxide (104 mg, 1.85 mmol) were combined in a round bottom flask with 1.2 mL of methanol. The reaction was stirred for 2 hours at room temperature. The reaction solution was neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and dichloromethane to provide the desired compound (23, 79 mg). MS(ESI) [M−H+]31 =387.5.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:10]=[CH:11][CH:12]=[CH2:13]>>[CH2:8]=[C:7]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:9]
Reactant: C=CC=C
Reactant: C=CCCCC=CCO
Product: C=C(CC=CC)CCCC=CCO

Procedure:
Additional examples of reactions according to the invention are of 2,7-octadiene-1-ol with 1,3-butadiene to yield 7-methylene-2,9-undecadiene-1-ol and the reaction of 1-methoxy-2,7-octadiene with 1,3-butadiene to yield 1-methoxy-7-methylene-2,9-undecadiene. Additional examples of suitable compounds of Formula (II) are 1-acetoxy-2,6-dimethyl-2,7-octadiene, 1-methoxy-2,6-dimethyl-2,7-octadiene, 2-acetoxy-3,8-decadiene, 2-methoxy-3,8-decadiene and 3,8-decadiene-2-ol. Additional examples of suitable compounds of Formula (III) are isoprene and piperylene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Product: Cn1c(-c2cncc(CNS(C)(=O)=O)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine and methanesulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 3.03 (s, 3H), 3.80 (s, 3H), 4.45 (s, 2H), 6.71 (s, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 7.54 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.09 (t, J=2.2 Hz, 1H), 8.63 (d, J=2. Hz, 1H), 8.71 (d, J=2. Hz, 1H). HRMS (ESI) m/z 350.0728 [(M+H)+ Calcd for C16H17ClN3O2S: 350.0730].
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].N1CCCC1>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:14])[O:13][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:3](=[O:4])[CH2:2]1
Reactant: CC(C)=O
Reactant: O=C(CO)c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2ccccc2O1
Yield: 21.6 %

Procedure:
Twenty five grams (25 g) of 2-hydroxyacetophenon, 10.7 g of acetone, and 5.5 g of pyrrolidine were added to 50 ml of toluene, and heated and refluxed. Twenty hours later, the temperature was returned to ambient temperature and the solvent was distilled off under reduced pressure, to which was added 100 ml of 1N hydrogen chloride. The extraction was carried out with 50 ml×3 of chloroform, followed by washing in water, drying over anhydrous magnesium sulfate, filtering off and condensation of the filtered solution. The residue was purified on a silica gel column the fraction containing the purified product were mixed together and the solvent therein was distilled off under reduced pressure to obtain 7 g of 3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-4-one.