Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:23])=[O:9])=[C:6]([F:11])[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)c(C(=O)O)c2F)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCCC1CCC(c2ccc(Br)c(C(=O)OC)c2F)CC1
Yield: 101.6 %

Procedure:
17.1 g (46.0 mmol) of trans-6-bromo-2-fluoro-3-(4-pentylcyclohexyl)-benzoic acid were dissolved in 70 ml of acetone, 7.66 g (55.4 mmol) of potassium carbonate and 3.14 ml (50.6 mmol) of methyl iodide were added, and the mixture was refluxed overnight. The batch was filtered, and the solvent was distilled off, giving 18 g (100%) of methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate as a colourless oil, which was reacted further without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[S:29]1(=[O:36])(=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1>>[O:35]=[S:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 81.6 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (271 mg) described in Preparation Example 254 and [1,2]thiazinane 1,1-dioxide (102 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (247 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C[O:18][C:19](=[O:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][C:23]=1[CH3:29]>>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([OH:30])=[O:18])=[C:23]([CH3:29])[CH:24]=2)=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2ccc(OCc3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1-chloromethyl-4-benzyloxy-benzene and 2C. MS m/z 409 (M+1).
Reaction SMILES: C([N:14]1[C:17](=[O:18])[C@H:16]([N:19]=[N+:20]=[N-:21])[C@@H:15]1[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])(C1C=CC=CC=1)C1C=CC=CC=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O.O.O.O.O.O.O.O.O.O.O.O.P(O)([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[N:19]([C@H:16]1[C:17](=[O:18])[NH:14][C@H:15]1[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[N+:20]=[N-:21]
Reactant: CCCCOC(=O)[C@H]1[C@@H](N=[N+]=[N-])C(=O)N1C(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-]
Yield: 175.5 %

Procedure:
A mixture of 200 mg (0.529 mmole) of butyl cis-1-benzhydryl-3-azido-4-oxo-2-azetidine carboxylate, 473 mg (1.75 mmole) of potassium persulfate, 307 mg (0.858 mmole) of disodium phosphate dodecahydrate, 9.2 ml of water and 8.4 ml of acetonitrile was thoroughly degassed with argon and then heated to 80°-85° C. under argon for three hours. The reaction mixture was cooled and the acetonitrile removed on the rotary evaporator. The aqueous residue was saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic extractions were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 197 mg of crude material. This material was chromatographed on ten grams of 70-230 mesh silica gel and 31 mg (28%) of the desired product, a light yellow foam was eluted with 20% EtOAc in benzene. tlc: silica gel GF; 20% ethylacetate benzene, R.f.=0.15.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39]>CN(C=O)C.O>[F:31][C:29]1[CH:28]=[C:27]([F:32])[CH:26]=[C:25]2[C:30]=1[C:21]([O:13][C:9]1[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=[N:11][CH:10]=1)=[C:22]([CH3:39])[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[N:24]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Oc1cncc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Oc1cncc(N2CCOCC2)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a vial containing 5-morpholinopyridin-3-ol (67.3 mg, 0.37 mmol) in DMF (3 mL) was added cesium carbonate (0.26 g, 0.8 mmol) in portions. The mixture was stirred at 23° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (90.7 mg, 0.31 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 18 h, the reaction mixture was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford light yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)pyridin-3-yl)morpholine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 8.12 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.68 (1H, dd, J=9.4, 1.3 Hz), 7.59 (1H, d, J=2.2 Hz), 7.43 (1H, sxt, J=4.4 Hz), 7.02 (1H, ddd, J=11.4, 8.9, 2.4 Hz), 6.87 (1H, s), 3.93 (4H, m), 3.29 (4H, m), 2.41 (3H, s). Mass Spectrum (pos.) m/e: 435.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([Cl:17])=[O:14])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc2c1OCCO2
Product: O=C(Cl)c1cc(Cl)cc2c1OCCO2
Yield: 100 %

Procedure:
32.2 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid and 64 ml of thionyl chloride were introduced into a balloon flask provided with an agitator, a thermometer and a condenser. The mixture was heated under reflux and then the thionyl chloride in excess was distilled off under vacuum. 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 140° C.; yield: 100%).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:58]1[CH2:61][CH2:60][CH2:59]1>CN(C)C=O>[N:58]1([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:61][CH2:60][CH2:59]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) were added triethylamine (0.130 ml) and azetidine hydrochloride (60 mg) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and residue was dried under reduced pressure to provide the titled compound as white powder (41.7 mg, 69%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(N)cc1
Yield: 69.3 %

Procedure:
A solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene (1.0 g, 3.3 mmol) (obtained from preparation 20) in 1,4-dioxane (20 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (100 mg) at 30 psi for 16 h. The mixture was filtered through a bed of celite and washed with dioxane and evaporated to dryness under reduced pressure to yield the title compound (625 mg, 70%).
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]/[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([O:23]CC=C)=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31].[Cl-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]/[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31]
Reactant: C=CCOC(=O)C1(C)CCC(NC(=O)/C=C/c2ccc(O)c(OC)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)NC2CCC(C)(C(=O)O)CC2)ccc1O
Yield: 67.8 %

Procedure:
0.5 of bis(triphenylphosphine)palladium dichloride and 7.5 g of ammonium formate were added to a solution of 2.81 g of allyl trans-4-(4-hydroxy-3-methoxycinnamamido)-1-methyl-1-cyclohexanecarboxylate (Example 24) in 100 ml of THF. The solution was reacted for 18 hours under an argon stream, while it was refluxed. After reaction, 150 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution, was then dried over magnesium sulfate. Then, the solvent was removed in vacuo. The oil substance thus obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:2, the solvent was removed in vacuo, yielding 1.7 g of trans-4-(4-hydroxy-3-methoxycinnamamido)-1-methyl-1-cyclohexanecarboxylic acid (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11](=[O:27])[CH:10]([N:28]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1.O.NN>O1CCCC1>[NH2:28][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]1=[O:27]
Reactant: Cc1cccnc1CN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc21
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A solution of (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-3-phtalimido-1H-1,4-benzodiazepin-2-one (1.24 g) in tetrahydrofuran (30 ml) was treated with a solution of hydrazine monohydrate (0.129 g) in tetrahydrofuran (5 ml) under stirring for 3 hours at room temperature and followed at 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. The resultant precipitates were filtered off by suction and the filtrate was concentrated in vacuo. The residue was taken up with ethyl acetate and extracted with 1N aqueous hydrochloric acid. The aqueous layer was alkalined with sodium bicarbonate and extracted with chloroform twice. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methylpyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.87 g), which was used in a following reaction step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=2[N:18]=1)[CH3:13].C(N(CC)CC)C>ClCCl.O>[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=2[N:18]=1)(=[O:11])[CH3:13]
Reactant: COc1cccc2oc(C(C)O)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2oc(C(C)=O)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
A solution of oxalyl chloride (0.25 ml) in dichloromethane (6.5 ml) was cooled to −55° C. under nitrogen. A solution of dimethylsulphoxide (0.44 ml) in dichloromethane (1.3 ml) was added dropwise, and the mixture stirred for 5 minutes at −55° C. before addition of a solution of 2-(1-hydroxyethyl)-4-methoxybenzoxazole (0.5 g) in dichloromethane (2.5 ml). Stirring was continued for 15 minutes at −55° C., then triethylamine (1.8 ml) was added. The mixture was stirred at −55° C. for 5 minutes and was then allowed to warm to room temperature. It was poured into water (25 ml) and the layers separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as a white solid (350 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][NH:9][C:10](=O)[C:11]=2[CH:12]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2ncc(C(F)(F)F)cc12
Solvent: CC#N
Product: FC(F)(F)c1cnc2ccnc(Cl)c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-(trifluoromethyl)-1,6-naphthyridin-5(6H)-one (as prepared in the previous step, 1 g, 4.67 mmol, 1.00 equiv) in acetonitrile (10 mL) and phosphoryl trichloride (10 mL). The reaction mixture was stirred for 2 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20). The title compound was obtained as a yellow solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:35])[CH2:21][N:22]3[C:30]4[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=4[N:24]=[CH:23]3)[S:17][CH:18]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].[P:36]([O:48][CH2:49]I)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].[H-].[Na+]>CN(C=O)C>[P:36]([O:48][CH2:49][N:15]1[C:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)=[CH:18][S:17][C:16]1=[N:19][C:20](=[O:35])[CH2:21][N:22]1[C:30]2[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=2[N:24]=[CH:23]1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:37]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)Nc2nc(-c3ccc(Cl)c(Cl)c3)cs2)n(C)c1=O
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CC(=O)N=c2scc(-c3ccc(Cl)c(Cl)c3)n2COP(=O)(OC(C)(C)C)OC(C)(C)C)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling N-[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetamide (150 mg, 0.322 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (395.16 mg, 1.129 mmol) in the presence of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.483 mmol) in dry DMF (2 ml) with to yield 135 mg of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.48 (br s, 18H), 3.35 (s, 3H), 3.47 (s, 2H), 3.62 (s, 3H), 5.71 (s, 2H), 6.36 (br s, 2H), 7.42-7.50 (m, 1H), 7.60-7.72 (m, 1H), 8.02 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10]2)(=O)C.C(O)CC.Cl>O>[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])=[CH:10]2
Reactant: CC(=O)Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 74.4 %

Procedure:
5-Acetylamino-N-benzylnaphthalene-2-sulfonamide (compound No. 5-1; 175 mg, 0.494 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (128 mg, 74.4%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C>CN(C=O)C.O>[F:20][C:21]([F:36])([F:37])[C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[CH2:32][C:33]([N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1)=[O:34]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (420 mg) in DMF (10 mL) were added [2,4-bis(trifluoromethyl)phenyl]acetic acid (426 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (1.17 mL) and N-[(dimethylamino) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (595 mg). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (498 mg).
Reaction SMILES: C(=O)=O.C(O)C.Cl[C:8]([F:12])=[C:9]([F:11])[F:10].Cl[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].C([Li])CCC>C1COCC1>[CH2:15]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:8]([F:12])=[C:9]([F:11])[F:10])[CH3:16]
Reactant: CC[Si](Cl)(CC)CC
Reactant: FC(F)=C(F)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Product: CC[Si](CC)(CC)C(F)=C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A reactor flushed with argon gas was cooled with a dry ice-ethanol cooling medium, and 2.03 g (0.0174 mol) of chlorotrifluoroethylene was introduced into the reactor. To this reactor, 17 ml of THF was introduced to bring the chlorotrifluoroethylene concentration to 1 mmol/ml, and then 2.35 g (0.016 mol) of chlorotriethylsilane was added. The reactor was cooled to -78° C., and 12 ml (0.018 mol) of butyllithium (1.47M hexane solution) was added in 1 hour. The mixture was stirred at 78° C. for 4 hours and at room temperature for about 1 hour. Workup was conducted in the same manner as in Example 1, whereby 2.64 g (86.2%) of triethyltrifluorovinylsilane was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of 3-isopropyl-4-methoxy-benzaldehyde (1.5 g, 8.42 mmol) in anhydrous THF (17 mL) cooled to -78° C. with a dry ice-acetone bath was added diisobutylaluminum hydride (34 mL, 1.0 M solution in THF, 34 mmol). After 1.5 h of cooling, 1N HCl (30 mL) was slowly added to the mixture. After the addition, the cooling bath was removed and the mixture left to stir at RT (ca. 15 min). The product was extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give 1.405 g of colorless oil as crude product. The crude product was purified by chromatography using the ISCO Combiflash SQ16X system (35 g Redisep silica gel column, 0 to 40% EtOAc in hexane for 30 min at 30 mL/min) to afford 1.272 g (84%) of compound 55 as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:6][C:5]([C:21]([NH2:23])=O)=[N:4]1)[CH3:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[CH:6][C:5]([C:21]#[N:23])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxamide (8.5 g, 27.2 mmol) and thionyl chloride (20 mL) in toluene (40 mL) was heated at reflux for five hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in chloroform and made basic with the addition of 2 M sodium carbonate. The aqueous layer was separated at extracted with chloroform (4×), and the combined organic fractions were washed with brine. The brine was extracted with chloroform (4×). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product (8.08 g) was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with chloroform/CMA in a gradient from 100:0 to 80:20) to provide 7.73 g of 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile as a white solid.