Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CC[C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([OH:17])=[C:15]([OH:18])[CH:14]=[C:13]([CH2:19][CH:20]=[CH2:21])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH3:22][CH2:23][CH2:24]CCC>CO.C(OC(=O)C)C.[Pd](Cl)Cl>[CH:22](/[C:5]1[CH:4]=[CH:9][C:8]([O:10][C:11]2[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH3:21])[CH:14]=[C:15]([OH:18])[C:16]=2[OH:17])=[CH:7][CH:6]=1)=[CH:23]\[CH3:24]
Reactant: C=CCc1cccc(Oc2cc(CC=C)cc(O)c2O)c1
Reactant: CCCCCC
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C/C=C/c1ccc(Oc2cc(/C=C/C)cc(O)c2O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of obovatol (1 g) in methanol was added palladium chloride (PdCl2) (10 mg), followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer containing the active material was collected and concentrated in a vacuum. The concentrate (1.1 g) was dissolved in methylene chloride (30 ml) and loaded onto a silica gel (Merck, Art No. 9385) so as to adsorb the active material thereonto. Purification through silica gel column chromatography eluting with a gradient of a mixture of ethylacetate and hexane from 10:90 to 20:80 afforded colorless 3-(4-((E)-prop-1-enyl)phenoxy)-5-((E)-prop-1-enyl)benzene-1,2-diol (0.91 g, yield 90%)
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-:23].[Na+].II.C(Cl)Cl>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:23][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: [OH-]
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCOCCOCCOCCCCCCCCCCCSSCCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
To a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (145 mg, 0.43 mmol) in 5 mL of THF was added 1 mL of a NaOH solution (0.1 M), followed by iodine (5 crystals). The solution was stirred at room temperature for 24 h and added to 20 mL of CH2Cl2. After the solution was rinsed with H2O (2×5 mL), the organics were dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography (CH2Cl2/MeOH, 20:1, v/v) to afford 78 mg (54%) of 2. 1H NMR 400 MHz (CDCl3) d 3.72-3.52 (br, 24H), 3.44 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.0 Hz, 2H), 2.41 (br s, 2H), 1.65 (m, 4H), 1.57 (m, 4H), 1.41-1.20 (br, 28H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([CH2:10][N+:11]([O-])=O)=[CH:8][C:7]([Br:14])=[CH:6][C:5]=1[F:15].C([O-])=O.[NH4+].N>CO.C(Cl)Cl.[Zn]>[Br:14][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([F:15])[CH:6]=1)[C:3](=[O:2])[NH:11][CH2:10]2
Reactant: COC(=O)c1c(F)cc(Br)cc1C[N+](=O)[O-]
Agent: N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCc2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
Crude 4-bromo-2-fluoro-6-(nitromethyl)benzoic acid methyl ester from the previous step is dissolved in MeOH (100 mL). To this clear orange solution is added Zinc dust (3.35 g, 51.3 mmol, 3 equiv.) followed by ammonium formate (3.23 g, 51.3 mmol, 3 equiv.) which results in an exothermic reaction. After 0.3 h, 7M NH3 in MeOH (50 mL) is added and the mixture is stirred overnight at room temperature. The resulting mixture is filtered through celite, and the yellow filtrate is adsorbed on silica and roughly cleaned by LC using 94/6 DCM/MeOH 7M NH3. Removal of the solvent affords a tan solid that is redissolved in DCM, washed with 10% NaOH, and concentrated under reduced pressure to leave a white solid, which is triturated further with small amounts of DCM to afford the title compound. LCMS: Rt 0.96 min (100%) m/z 230/232 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([CH3:18])[C:12]([C:19]([OH:21])=O)=[CH:11]3)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:44][N:45]([CH2:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.C(N(CC)CC)C>[CH3:44][N:45]([CH2:52][C:53]1[CH:54]=[CH:55][C:56]([NH:57][C:19]([C:12]2[C:13]([CH3:18])=[N:14][C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:17][CH:16]=3)=[O:21])=[CH:58][CH:59]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: Cc1ccc(-c2ccc3nc(C)c(C(=O)O)cc3c2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3nc(C)c(C(=O)Nc4ccc(CN(C)C5CCOCC5)cc4)cc3c2)cc1
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of 6—(4-methylphenyl)-2-methylquinoline-3-carboxylic acid (120 mg) and 1-hydroxybenzotriazole (88 mg) in DMF (5 ml) was added 1-ethyl-3—(3′-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) at room temperature, and the mixture was stirred for 2 hours. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (105 mg) and triethylamine (0.2 ml) in DMF (5 ml), and the mixture was stirred for 18 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2), and recrystallized from ethyl acetate-hexane to give N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-6—(4-methylphenyl)-2-methylquinoline-3-carboxamide (Compound 216) (82 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24]Cl)[CH3:21].[OH-].[K+].Cl>CC(C)=O.CO.C(OCC)(=O)C.C(OCC)(=O)C.O.COC(C)(C)C>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CCN(CC)CCN(C(C)=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Combine N-acetyl-4-aminobenzophenone (250 g, 1.05 mol), 2-diethylaminoethyl chloride hydrochloride (207.5 g, 1.20 mol), and 85% potassium hydroxide (140 g, 2.12 mol) in acetone (3 L). Heat to reflux. After 2 hours, cool and filter. Evaporate the filtrate in vacuo to give a residue. Combine the residue and t-butyl methyl ether (1 L) and water (2 L). Add aqueous 1M hydrochloric acid solution until the pH is about 2.5. Separate the aqueous layer and extract several times with t-butyl methyl ether. Adjust the pH of the aqueous layer to 10 using aqueous 50% sodium hydroxide solution. Extract the aqueous layer twice with dichloromethane. Dry the combined dichlormethane layers over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 5/95 methanol/ethyl acetate, 10/90 methanol/ethyl acetate to give the title compound: Rf =0.36 (silica gel, 2/8/0.1 methanol/ethyl acetate/triethylamine).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:47][C:48]([F:55])([F:54])[CH2:49][CH2:50][C:51](O)=[O:52].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[F:47][C:48]([F:55])([F:54])[CH2:49][CH2:50][C:51]([NH:12][C@@H:11]([CH3:13])[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14])=[O:52]
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)CCC(F)(F)F)C(=O)OCc1ccccc1
Reaction time: 20 h
Yield: 93.5 %

Procedure:
Add successively L-alanine benzyl ester hydrochloride (7.00 g, 32.5 mmol), diisopropylethylamine (28.30 mL, 162.3 mmol), 1-hydroxybenzotriazole hydrate (7.46 g, 48.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.33 g 48.7 mmol) to a solution of 4,4,4-trifluorobutyric acid (7.131 g, 48.7 mmol) in dichloromethane (162 mL) at ambient temperature under nitrogen and stir for 20 hours. Add a 20% aqueous solution of citric acid (150 mL, 162 mmol), stir mixture for 5 minutes and separate layers. Extract from aqueous with dichloromethane (100 mL). Wash combined organics with saturated aqueous solution of sodium bicarbonate (150 mL), dry over magnesium sulfate and concentrate. Purify the residue by flash chromatography, eluting with hexane:ethyl acetate (4:1 to 2:1) to give the title compound as a white solid (9.22 g, 30.4 mmol, 94%). MS (m/z): 304 (M+1); [α]N825=−44.6° (c=5.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](Cl)=[O:6].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(#N)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([O:19][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([Cl:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.8 g of 2,6-dichloroisonicotinic acid chloride, dissolved in 10 ml of acetonitrile, are added dropwise to a solution, maintained at 15°-20° C. by cooling, of 5.4 g of benzyl alcohol, 0.5 g of 4-dimethylaminopyridine and 3.0 g of pyridine in 50 ml of acetonitrile. After stirring overnight at room temperature the batch is poured onto ice-water, taken up in methylene chloride, washed with water, dried and concentrated by evaporation. The oil that remains crystallises from pentane in the form of white crystals having a melting point of 39°-41° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:43][CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49](Cl)=[N:50][OH:51])=[CH:47][CH:46]=1>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]2[O:51][N:50]=[C:49]([C:48]3[CH:53]=[CH:54][C:45]([CH2:44][Cl:43])=[CH:46][CH:47]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.8 %

Procedure:
Triethylamine (899.0 mg, 1.238 mL, 8.884 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 8 (4.05 g, 8.074 mmol) and 4-(chloromethyl)-N-hydroxy-benzimidoyl chloride (2.063 g, 8.494 mmol) in DCM (12 mL). The mixture was stirred at RT for 22 h then partitioned between DCM and an ice/water solution. The combined organic extract was dried over MgSO4 and concentrated under reduced pressure then purified by chromatography on silica gel (eluent 30-50% EtAc/petrol) yielding tert-butyl N-tert-butoxycarbonyl-N-[3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate as colourless crystals (4.53 g, 79%). 1H NMR (400 MHz, CDCl3) δ 1.41 (18H, s), 4.66 (2H, s), 7.37 (1H, s), 7.54 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.66 (1H, s)
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[P:6]([O:15]C(C)C)([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH:8]([O:7][P:6]([CH2:2][CH:3]1[CH2:5][CH2:4]1)(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: BrCC1CC1
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(CC1CC1)OC(C)C
Temperature: 144 °C
Yield: 94.3 %

Procedure:
Bromomethyl-cyclopropane (26.00 g, 0.193 mol) was added to triisopropyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was stirred and heated at reflux (144° C. bath temperature) overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation and then under high vacuum to yield 39.96 g of cyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H); 1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H); 0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): (M+1)+ found, 221; (M+23)+ found, 243.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Cl)nc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(Cl)nc2)CC1
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a stirred mixture of the (6-chloropyridin-3-yl)acetonitrile (8.00 g, 0.0524 mol), benzyltriethylammonium chloride (0.8 g, 0.004 mol), and 1-bromo-2-chloro-ethane (8.69 mL, 0.105 mol) was added dropwise sodium hydroxide, 50% aqueous solution (16.1 mL, 0.419 mol) at 50° C. After stirring for 2 h, the reaction mixture was diluted with water and the resulting layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 1N HCl and brine successively, dried with magnesium sulfate, filtered, and concentrated in-vacuo. The crude product was purified by combiflash to obtain 2.5 g of pure product as a white solid.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2)(=[O:4])[CH3:3].Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2c(c1)CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 26.3 %

Procedure:
Using 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (76 mg, 0.41 mmol), triethylamine (0.23 ml, 1.6 mmol), and ethanol (6 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (34 mg, 0.10 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:12]([C:14](=[O:29])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:28])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]2)[N:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[N:50]([CH:24]1[CH2:23][CH2:22][CH:21]([C:20]2[N:19]([CH3:28])[N:18]=[CH:17][C:16]=2[NH:15][C:14]([C:12]2[N:13]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[S:10][C:11]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:29])[CH2:26][CH2:25]1)=[N+:51]=[N-:52]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.3 %

Procedure:
tert-Butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (58 mg, 0.11 mmol) was dissolved in methylene chloride (3 mL) and THF (1.5 mL). Triethylamine (33 mg, 0.33 mmol) and methanesulfonyl chloride (19 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for 2.5 h. The reaction was diluted with ethyl acetate (50 mL), washed with sat. sodium bicarbonate and brine and concentrated in vacuo (65 mg). The residue was dissolved in NMP (3.0 mL) and sodium azide (21.4 mg, 0.33 mmol) was added. The mixture was stirred at 85° C. overnight. After cooling to room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified via flash chromatography, eluted with 0 to 100% ethyl acetate in heptane to give tert-butyl 4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (18 mg, 30%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[CH2:25]([N:27](CC)CC)C.C(OCC)(=O)C.O1CCCC1>CN1CCCC1=O>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:23][CH3:24])[N:3]=[C:2]([NH:27][CH3:25])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCN(CC)CC
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Temperature: 130 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
2.50 g of 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline obtained in Production Example 1,4.89 g methylamine hydrochloride and 11.0 g triethylamine were suspended in 25 ml 1-methyl-2-pyrrolidinone and stirred at 130° C. for 18 hours in a sealed tube. Ethyl acetate and tetrahydrofuran were added thereto, and the reaction solution was washed with water 5 times and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:2). The product was recrystallized from tetrahydrofuran-ethyl acetate to give 1.89 g of the title compound as yellow crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:12][C:13]2[CH:36]=[C:35]([O:37]C)[CH:34]=[CH:33][C:14]=2[C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1)=[O:17].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].CO>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:12][C:13]2[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:14]=2[C:15]=1[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4ccccc4c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc3ccccc3c2)sc2cc(O)ccc12
Yield: 98.1 %

Procedure:
By the method described in Example 2, the product of Example 3 (1.35 g, 2.59 mmol), ethanethiol (0.56 mL, 7.69 mmol), and aluminum chloride (2.07 g, 15.52 mmol) were reacted in anhydrous methylene chloride (50 mL) to give, after chromatography (silica gel, 5% methanol in methylene chloride) 1.29 g (98%) of the title product as a yellow foam; 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.66 (M, 4H), 2.58 (m, 4H), 2.77 (t, J=5.5 Hz, 2H), 4.04 (t, J=5.5 Hz, 2H), 6.54 (d, J=8.9 Hz, 2H), 6.75 (dd, J=2.2 Hz, 8.8 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.39-7.46 (m, 4H) 7.64 (d, J=8.6 Hz, 1H), 7.69-7.76 (m, 4H), 7.86 (d, J=1.5 Hz, 1H); 13C NMR (75 MHz, DMSO--d6) δ23.3, 24.9, 53.7, 56.4, 65.3, 106.7, 114.0, 115.0, 123.2, 125.4, 126.3, 126.3, 126.9, 127.0, 127.5, 127.9, 129.1, 130.0, 131.1, 131.2, 131.7, 131.8, 132.1, 138.9, 139.4, 155.4, 162.4, 191.9; MS (FD) m/e 508 (MH+), 507 (M+); Anal. calc'd. for C32H29NO3S: C, 75.71; H, 5.76; N, 2.76. Found: C, 75.86; H, 5.82; N, 2.75.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].[CH3:14][O:15]C(Cl)Cl>ClCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH:7]=2)[CH:14]=[O:15])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CC2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Solvent: ClCCl
Product: COc1ccc(C2(C#N)CC2)cc1C=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a stirred solution of Compound 1 (2.0 g, 11.6 mmol) in dry CH2 Cl2 (50 ml) was added TiCl4 (5.7 ml, 52.0 mmol) with cooling (-10° C.). After 15 min., to this was added a solution of dichloromethyl methyl ether (2.0 g, 17.3 mmol) in dry CH2Cl2 (5 ml) dropwise. The reaction mixture was stirred at same temperature for 10 min. and then at room temperature for 1 h. The mixture was poured into ice-water and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product (2.36 g) as a yellow solid. The crude product was recrystallized from hexane-ethyl acetate to give Compound 2 (2.04 g, 88%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Br)=[CH:7]2.BrC1C=C2C(=CC=1)C(F)=C(N)C=C2.F[B-](F)(F)F.[H+].FC1C=C2C(=CC=1)C=C(Br)C=C2.[CH2:45]([CH:50]1[CH2:55][CH2:54][C:53](=O)[CH2:52][CH2:51]1)[CH2:46][CH2:47][CH2:48][CH3:49]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@H:53]1[CH2:52][CH2:51][C@H:50]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:55][CH2:54]1)=[CH:7]2
Reactant: Fc1ccc2cc(Br)ccc2c1F
Reactant: CCCCCC1CCC(=O)CC1
Agent: F[B-](F)(F)F
Agent: Fc1ccc2cc(Br)ccc2c1
Agent: Nc1ccc2cc(Br)ccc2c1F
Product: CCCCC[C@H]1CC[C@H](c2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
The procedure of Example 14 was followed except that 5,6-difluoro-2-bromonaphthalene (synthesized by converting 6-bromo-1-fluoro-2-naphthylamine to a diazonium salt of tetrafluoroboric acid, and then subjecting the diazonium salt to thermal decomposition) was used instead of 6-fluoro-2-bromonaphthalene and 4-pentylcyclohexanone was used instead of 4-propylcyclohexanone to obtain 5,6-difluoro-2-(trans-4-pentylcyclohexyl)naphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10]\[CH:11]=O)=[CH:5][CH:4]=1.[C:18]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH3:21])=[O:19]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])/[CH:22]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C/C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Yield: 52.7 %

Procedure:
As described in Example 99, (Z)-3-(4-methoxyphenyl)-2-octenal (5.5 g) was treated with (carbomethoxymethylene)triphenylphosphorane (8.7 g) in carbon tetrachloride (55 mL) for 4 days at room temperature. The mixture was isolated in the usual way and purified by HPLC (ether-hexane; 3:17) to afford 3.6 g of (2E,4E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester as an oil.