Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(=O)CNC(=O)OC(C)(C)C)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of N-tert-butoxy carbonyl-glycine (1.05 g, 6 mmol) in DMF (15 mL) was added HATU (2.85 g, 7.5 mmol), ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.74 g, 5 mmol) and DIEA (1.73 mL). The mixture was stirred at room overnight. The mixture was concentrated to afford the target molecule.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), the above-mentioned 3-ethoxybenzyl chloride (636 mg) and potassium carbonate (515 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to remove the solvent, and the residue was subjected to purification using silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (308 mg) as a yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-4-fluorobenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:10][C:11]([CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][N:16]=1)=O.C(N(CC)CC)C>C(Cl)Cl>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:11]([CH2:13][O:14][C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][N:16]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(O)COc1cc(-c2ccccc2)[nH]n1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1cc(-c2ccccc2)[nH]n1)NCCN1CCOCC1
Reaction time: 3 h

Procedure:
1.33 ml N-(2-aminoethyl)-morpholine, 2.2 g 3-hydroxycarbonylmethoxy-5-phenylpyrazole and 4.3 ml triethylamine were added in this order to 3.06 g 1-methyl-2-chloropyridinum iodide in methylene chloride. The reaction mixture was then heated to boiling for 3 hours under reflux. After cooling and washing with aqueous sodium hydroxide solution, the organic phase was evaporated, and the crude product obtained was purified chromatographically. 2.3 g 3-(2-morpholinoethylaminocarbonylmethoxy)-5-phenyl-pyrazole were obtained as an oily base. IR-spectrum (as film): 3205 cm-1, 1660 cm-1.
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([O:26][CH2:27][CH3:28])C.C(O[K])(C)(C)C.[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=2C=O)=[CH:38][CH:37]=1>C1COCC1.O>[Br:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([C:46]2[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][C:51]=2[CH:28]=[CH:27][O:26][CH3:24])=[CH:38][CH:37]=1
Reactant: CCOCC
Reactant: O=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Agent: CC(C)(C)O[K]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cc(Cl)ccc1-c1ccc(Br)c2ccccc12
Yield: 99 %

Procedure:
Subsequently, 9.67 g (28.2 mmol) of (methoxymethyl)triphenylphosphonium chloride and 48 mL of dry diethyl ether were charged into a 300-mL recovery flask filled with nitrogen at room temperature. The mixture was stirred. Then 28.2 mL (28.2 mmol) of 1 M tert-butoxypotassium solution in THF was added thereto. The resulting mixture was stirred for 1 hour. Subsequently, a solution of 3.90 g (11.3 mmol) of 1-bromo-4-(4-chloro-2-formylphenyl)naphthalene dissolved in 93 mL of a THF solvent was added to the reaction mixture. After the resulting mixture was stirred for another 4 hours at room temperature, water was added thereto, terminating the reaction. The separation of two phases was performed to recover the aqueous phase. Extraction of the aqueous phase was performed three times with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give a crude product. The crude product was then purified by silica gel column chromatography (eluent: heptane/chloroform=20/1) to give 4.17 g (yield: 99%) of 1-bromo-4-(4-chloro-2-methoxyethenylphenyl)naphthalene.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([N:10]1[C:14](=[O:15])[C:13](Cl)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:24])=[O:23])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([N:10]1[C:14](=[O:15])[C:13]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:24])=[O:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)N
Product: CC(C)(C)NC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Yield: 17 %

Procedure:
The title compound was prepared as described for Example 24 from tert-butylamine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide at 140° C. for 1.5 h. The residue was purified by silica gel column chromatography (Horizons Biotage) using 0-5% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.029 g, 17%) as a solid. 1H NMR (500 MHz CDCl3): δ 0.54-7.50 (m, 2H), 7.48-7.44 (m, 3H), 5.53 (s, 1H), 1.74 (s, 9H), 1.08 (s, 9H); 13C NMR (125 MHz CDCl3): 160.9, 133.8, 133.5, 130.3, 129.1, 126.8, 106.6, 61.8, 52.2, 30.1, 27.8; Mass Spectrum: M+H+ 337.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To 300 g of polyphosphoric acid (117% phosphoric acid) heated to 90° C. was added 68.2 g of 2,5-dianilinoterephthalic acid. The reaction mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 95° C., the acid strength was adjusted to 112% by the dropwise addition of phosphoric acid. The resultant melt was stirred for 15 minutes and then slowly poured into 453 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 55° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 7.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to greater than 9.0-9.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for two hours in a closed system (e.g., a pressure reactor), cooled, acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake was dried in an oven at 60° C. to give approximately 54 g of quinacridone as a violet pigment. The quinacridone thus obtained was blended with 0.5 g of N-[3-(N,N-dimethylaminopropyl)] copper phthalocyanine sulfonamide to give a violet pigment.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].N12CCCN=C1CCCCC2.Br[CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1.[Cu](Br)Br>[CH2:26]([O:25][C:23]([C:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:1][C:2]1([CH3:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: C=C(C)c1ccccc1
Agent: Br[Cu]Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CC1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 45.2 %

Procedure:
To a solution of α-methylstyrene (570 mL, 4.4 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (240 mL, 1.6 mol) and copper (II) bromide (9.8 g, 44 mmol) in toluene (700 mL) was added diethyl bromomalonate (210 g, 0.88 mol) at 0° C., and the mixture was stirred for 22 hours at room temperature. The obtained solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Then, the solution was filtrated and the solvent was evaporated. The obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give the title compound (110 g, yield 45%) as a colorless oil.
Reaction SMILES: N(OC(C)(C)C)=O.ON1C(=O)C2=CC=CC=C2C1=O.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([CH:25]=[N:26]O)=[CH:23][CH:22]=1.CC1C=CC(C=O)=CC=1>C(O)(=O)C.CC1C=CC(C)=CC=1>[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C=NO)cc1
Agent: CC(C)(C)ON=O
Agent: Cc1ccc(C=O)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a flask p-xylene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed and were stirred at 60° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that p-methylbenzaldehyde oxime, p-methylbenzaldehyde, and p-methylbenzonitrile were formed in yields of 68%, 3%, and 5%, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:28])=[O:27]>CN(C)C=O>[O:27]=[S:26]1(=[O:28])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35](=[O:36])[N:25]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: NCC1CCc2ccccc2O1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCNCC1CCc2ccccc2O1
Temperature: 60 °C

Procedure:
The mixture of 5.4 g (0.033 mol) (-)-2-aminomethylchroman (example 92f; αD =-122.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl) saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-(N-[4-(1,1-Dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl)chroman.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:24]C(=O)C(F)(F)F)[C:5]2=1.[C:31]([O-])([O-])=O.[K+].[K+].O>CO>[NH2:24][C:6]1[C:5]2[C:4]3[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][C:18]=4[CH3:31])[CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncccc1C(=O)Nc1cc(Cl)cc2c1[nH]c1cncc(N)c12
Temperature: 60 °C
Yield: 55.6 %

Procedure:
N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide (41 mg, 0.092 mmol, 1 equiv.) was suspended in 5 ml of MeOH and a 2 ml aqueous solution of K2CO3 (127 mg, 0.92 mmol, 10 equiv.) was added thereto. The resulting clear solution was heated at 60° C. for 16 hr and then allowed to cool to RT. Additional water was added producing fine solids that were captured by filtration, washed once with 10 ml of 5% MeOH in Et2O, and dried under high vacuum to give 18 mg of N-(4-amino-6-chloro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as powdery yellow solids (56% yield). 1H-NMR (300 MHz, DMSO-d6): δ 11.18 (s, 1H), 10.41 (s, 1H), 8.62 (d, J=3.6, 1H),), 8.32 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=7.5, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.43 (m, 1H), 5.91 (br, 2H), 2.66 (s, 3H). Formic acid standard conditions. DAD RT=1.63 min. M+H=352.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>O1CCCC1>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH:31][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: COC(CN)OC
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(CNC(=O)C(CSC(C)=O)CC(C)C)OC
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of 2-[(acetylthio)methyl]-4-methylpentanoic acid (2.0 g) and triethyl amine (1.0 g) in 50 ml of tetrahydrofuran (THF) is cooled to -5° C. Ethyl chloroformate (1.1 g) in 5 ml of THF is added dropwise and the reaction mixture is stirred at -5° C. for 30 minutes. Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml of THF is added dropwise to the mixed anhydride solution at -5° C. After addition, it is stirred at 10°-20° C. for 2 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. Silica gel (5 g) is added and ether is evaporated off. This is placed on top of 40 g of dry silica gel and washed through with pentane, 1:1 pentane:ether and finally ether. Product elutes with ether to yield 1.3 g of product which solidifies to give a low melting waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2)SC(/C=C\c2ccc(Cl)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDC13) δ 4.60 (2H, s), 6.70 (1H, d, JH,H=11.78), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2]C(C)C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC#[N:35]>>[CH:17]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:1][C:2]#[N:35])=[O:18]
Reactant: N#CCBr
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Agent: O=Cc1c(O)ccc2ccccc12
Product: N#CCOc1ccc2ccccc2c1C=O

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and bromoacetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:23]>>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([C:30]3[CH:31]=[C:26]([NH:25][S:22]([CH3:21])(=[O:23])=[O:24])[CH:27]=[CH:28][CH:29]=3)=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CCCC1=NNC(=O)/C1=C1/C=C(c2cccc(NS(C)(=O)=O)c2)c2ccccc2N1

Procedure:
The tile compound was synthesized from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 3-(methylsulfonamido)phenylboronic acid using Suzuki coupling conditions. The final compound was purified by LC-MS. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.33 Hz, 3H) 1.71 (td, J=14.53, 6.82 Hz, 2H) 2.94 (t, J=7.33 Hz, 2H) 3.09 (s, 3H) 7.33 (d, J=7.83 Hz, 1H) 7.41 (d, J=1.77 Hz, 2H) 7.50-7.61 (m, 2H) 7.69 (s, 1H) 7.77-7.83 (m, 2H) 7.99 (d, J=8.34 Hz, 1H) 10.04 (s, 1H); ESI-MS: m/z calc'd for C22H22N4O3S 422.5. found 423.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:26][O:27][C:28](=[O:37])[CH2:29][N:30]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[N:31]1.[Na+].[I-]>CN(C=O)C>[CH3:26][O:27][C:28](=[O:37])[CH2:29][N:30]1[CH:34]=[C:33]([CH2:35][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=[N:31]1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: COC(=O)Cn1cc(CCl)cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (93 mg, obtained in Example 93, step 6) in DMF (2 mL) was added to a suspension of NaH (60% in mineral oil, 24 mg) in DMF (1 mL) over 10 minutes. Stirring was continued for 30 minutes at r.t. The mixture was cooled to 0° C. and (4-chloromethyl-pyrazol-1-yl)-acetic acid methyl ester (61 mg, obtained in Example 103, step 4) dissolved in DMF (2 mL) was added dropwise over a period of 5 minutes. Stirring was continued for 2 hours at r.t. followed by the addition of NaI (3 mg). The mixture was heated to 50° C. overnight. The reaction mixture was cooled, poured into ice and extracted two times with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow gum (13 mg, 10%). MS (m/e)=498.2 [MH−].
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]1C[CH2:18][CH2:17][CH2:16][CH:15]1CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6][CH2:7][CH:8]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:13])=[O:5]
Reactant: CN1CCCCC1CO
Reactant: CCOC(=O)C1CCCCN1C
Agent: CCCC[Sn](=O)CCCC
Product: CN1CCCCC1COC(=O)C1CCCCN1C
Temperature: 130 °C

Procedure:
A mixture of 85.6 g (0.5 mole) of ethyl 1-methylpipecolinate, 64.6 g (0.5 mole) of 1-methyl-2piperidinemethanol and 1.1 g dibutyltin oxide was heated at 130° C. for three hours and then gradually heated to 200° C. When the amount of ethanol collected indicated the reaction was essentially complete the liquid product, N-methyl-(2-piperidyl)methyl N-methylpipecolinate, was distilled at 0.25 mm Hg pressure at about 130° C. The nuclear magnetic resonance and infrared spectra of the product were consistent with the structural assignment.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:27]=2[CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:24][C:25]1[CH:41]=[CH:40][C:28]2[CH2:29][O:30][C:31](=[O:39])[N:32]([CH:33]3[CH2:34][CH2:35][N:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([C:10]5[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=5[C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=4[N+:20]([O-:22])=[O:21])[CH2:37][CH2:38]3)[C:27]=2[CH:26]=1
Reactant: O=C1OCc2ccc(Cl)cc2N1C1CCNCC1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccc(Cl)cc43)CC2)c([N+](=O)[O-])c1

Procedure:
Methyl 2-[(4-chloro-3-nitrophenyl)carbonyl]benzoate (0.5 g), the product from step (ii) (0.47 g) and triethylamine (0.5 ml) in N,N-dimethylformamide (2.5 ml) were heated at 60° C. overnight. The mixture was evaporated under reduced pressure and the residue purified by chromatography eluting with 25% ethyl acetate/toluene. Yield 0.7 g of a solid.