Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18](Br)([CH3:20])[CH3:19].C(=O)(O)[O-]>ClCCl>[C:18]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:10][CH:11]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)Br
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.1 %

Procedure:
5-Nitro-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.92 mmol) was taken up in dry dichloromethane (9 mL) and was chilled to 0° C. Aluminum chloride (613 mg, 4.60 mmol, 5 eq.) was then added, and the mixture was allowed to stir at 0° C. for 15 minutes. 2-Methyl-2-bromopropane (107 μL, 0.919 mmol) was then added, and the mixture was allowed to gradually warm to room temperature over a 16 hour period. The mixture was then poured into cold saturated bicarbonate solution and extracted with dichloromethane (2×). The extracts were dried over sodium sulfate and concentrated. Prep plate purification (2×1.0 mm plates, 3:1 hexane:ethyl acetate) afforded 3-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.3 mg, 4%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 9.07-9.09 (m, 1H), 8.84-8.86 (m, 1H), 7.48 (s, 1H), 1.42 (s, 9H); m/z (APCI-neg) M−1=218.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:19][CH2:18][CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCC1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (6.5 g, 29.5 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (4.25 g, 36.9 mmol) and potassium carbonate (16.33 g, 118 mmol) in N,N-dimethylformamide (130 mL) was heated at 80° C. for 1 hour. After cooling, the mixture was diluted with 400 mL ethyl acetate. The mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH:11]=O.[C:16]([Br:20])(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.[Cl:45]CCl>>[Br:17][C:16]([Br:20])=[CH:11][C:10]([CH3:14])([CH3:13])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][C:6]([Cl:45])=[CH:7][CH:2]=1)=[O:15]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C=O)C(=O)Nc1ccccc1Cl
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C=C(Br)Br)C(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Using the procedure described by Corey and Fuchs, Tetrahedron Letters, p 3769, 1972, N-(chlorophenyl)-2,2-dimethyl-3-oxopropanamide (1 g), which was prepared as described in Example 9, and carbon tetrabromide (3 g) were dissolved in 75 mL of dichloromethane, the solution was cooled, and triphenylphosphine (4.6 g) in 20 mL of dichloromethane was added dropwise over 30 minutes. After the solution was stirred one hour, an additional 1 g of triphenylphosphine was added. Ether (100 mL) was then added, and the solution was filtered through a silica gel column to remove triphenylphosphine oxide (eluting with ether). The filtrate fractions which contained the product were concentrated to give the title compound, a solid, m.p. 104° C.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C(Cl)[Cl:48]>>[ClH:48].[ClH:48].[OH:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(C)(=O)=O)c4ccccc24)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)n1cc(/C=C2\Oc3c(ccc(O)c3CN3CCNCC3)C2=O)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of tert-butyl (Z)-4-[(6-hydroxy-2-{[1-(methylsulfonyl)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0500 g, 0.0903 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (4 mL) was added with a 5% solution of hydrogen chloride in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain the objective (Z)-6-hydroxy-2-{[1-(methylsulfonyl)-1H-indol-3-yl]methylene}-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0421 g, 88%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[K+]>>[CH2:4]([OH:5])[CH:3]=[CH2:2].[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:8])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [K+]
Product: C=CCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 135 °C

Procedure:
A 15-gallon stainless steel reactor was charged with 15.49 kg of propoxylated allyl alcohol (available from Arco Chemical Company of New Town Square, Pa.) and 9.88 kg of maleic anhydride (available from Huntsman Specialty Chemical). For stability, 2.53 g (100 ppm) of HQ was added to the reactor. The mixture was heated under a nitrogen atmosphere at 250-300° F. (121-149° C.) for four hours. The reaction endpoint was when the acid value reached a level of 263.4 Meq KOH/g of alkyd and no more maleic anhydride was observed by infrared spectroscopy. The viscosity of this product ranges from 100-130 cps at a temperature of 200° F. (93° C.) as measured by an ICI cone-and-plate viscometer. This material may be used directly as a film former.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:20]N(C)C=O.CI>C(N(CC)CC)C>[CH3:19][CH:13]1[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([S:1][CH3:20])=[N:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)=[N:17][NH:16][C:15](=[O:18])[CH2:14]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(S)ncnc2c1
Reactant: CN(C)C=O
Solvent: CI
Solvent: CCN(CC)CC
Product: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To 0.36 g of Compound 56 obtained in Example 18 were added 10 ml of dimethylformamide, 0.2 ml of triethylamine and 0.1 ml of methyl iodide. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.3 g (79%) of 4,5-dihydro-5-methyl-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (Compound 57).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]O.C(O)(=O)CC>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O
Solvent: CCC(=O)O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 100 parts of 3,3-dimethylacrolein, 200 parts of prenol and 150 parts of propionic acid is heated for three hours at 130° C., the water formed being distilled out azeotropically. The reaction product is worked up. 24 parts of citral is obtained. This is equivalent to yield of 51% of theory at a conversion of 26% (based on 3,3-dimethylacrolein).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:14]=[C:15](N4C=NN=C4)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.[CH3:35][CH2:36][O-:37].[Na+].CCO>C1COCC1.CN(C=O)C>[CH2:36]([O:37][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[N:14]=1)[CH3:35]
Reactant: CC[O-]
Reactant: NS(=O)(=O)c1ccc(CNc2nc(-n3cnnc3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1nc(NCc2ccc(S(N)(=O)=O)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-{[6-(4-fluoro-phenyl)-4-[1,2,4]triazol-4-yl-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (638 mg, 1.34 mmol) in 10 ml THF was added to a solution of 21% (w/w) NaOEt in EtOH (1.50 ml, 4.03 mmol) in 20 ml of dry THF over 5 min. The triazole flask was rinsed once with 5 ml THF and the rinse was added to the reaction flask. The reaction was stirred at room temperature for 15 min. Analysis by reversed phase HPLC/MS indicated the reaction was complete. The pH was adjusted to 7 with 10% acetic acid/EtOAc and then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous layer was extracted twice with EtOAc. The combined organics were washed twice with water and once with brine, dried over MgSO4, filtered and concentrated. The solid was absorbed onto SiO2, and purified by eluting onto a 30 g SiO2 column with CH2Cl2/MeOH. The fractions containing the desired compound as determined by LC/MS were combined and concentrated. The solid thus obtained was dissolved in DMF and re-purified by reverse phase HPLC using acetonitrile/H2O in 4 runs. The pure fractions from each run were combined and the acetonitrile was removed in vacuo. The resulting aqueous suspension was neutralized with excess saturated aqueous NaHCO3, and extracted three times with EtOAc. The organics were dried over MgSO4, filtered and concentrated. The material was solidified by addition of MeOH. The solid was dried at high vacuum for 24 hrs, giving 110 mg of 4-{[4-ethoxy-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (Example 109) as a white powder. MS (m/z) 454 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>O>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:15])[CH:10]=[CH:11][C:12]2=[O:13])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(N2C(=O)C=CC2=O)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a three-neck 1 liter reaction vessel equipped with a condenser, a teflon stirring rod and a thermometer, 97 g (0.49 moles) of N-(4-hydroxyphenyl)maleamic acid, 27.7 g (0.38 moles) of sodium acetate and 400 g of acetic anhydride are added and then heated by using silicone oil. When the reaction solution reaches 70° C. for 2 hours with stirring, the solution is poured into a large amount of distilled water and a great amount of precipitates are formed. The precipitate is taken by filtration and washed several times with distilled water to remove acetic acid, followed by recrystallization from ethanol to give the titled compound. Yield 53%. B.P. 155°-158° C.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:36])([F:35])[CH2:5][C:6]([CH3:34])([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:19]=[C:18]([CH3:33])[CH:17]=2)=[CH:12][N:11]=1)[C:7]#N.CS(C)=[O:39]>CN(C=O)C>[F:3][C:4]([F:36])([F:35])[CH2:5][C@@:6]([C:7]([OH:39])=[O:1])([CH3:34])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:19]=[C:18]([CH3:33])[CH:17]=2)=[CH:12][N:11]=1
Reactant: [OH-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C#N)CC(F)(F)F)nc2)c1
Reactant: CS(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(N[C@](C)(CC(F)(F)F)C(=O)O)nc2)c1
Temperature: 25 °C

Procedure:
Sodium hydroxide (5 M, 33.3 μL, 0.167 mmol) was added to a mixture of 4,4,4-trifluoro-2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}butanenitrile (40.0 mg, 0.083 mmol) in DMSO (167 μL) and the reaction mixture was stirred at room temperature. Upon the reaction completion (monitored by LCMS) was diluted with DMF and filtered. The residue was directly purified by reverse phase chromatography and then by silica gel chromatography (0-100% ethyl acetate in hexanes) to yield 4,4,4-trifluoro-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]isovaline. MS APCI calc'd for C22H20F6N5O2 [M+H]+ 500. found 500. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.7 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J=11.2 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.10 (d, J=5.4 Hz, 1H), 6.90 (s, 1H), 6.72 (d, J=9.8 Hz, 1H), 3.04 (s, 1H), 2.59-2.24 (m, 4H), 1.98-1.81 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].[C:28]1([C:34]2[CH:35]=[CH:36][C:37]3[O:41][C:40]([CH2:42][OH:43])=[CH:39][C:38]=3[CH:44]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:24]([O:43][CH2:42][C:40]1[O:41][C:37]2[CH:36]=[CH:35][C:34]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:44][C:38]=2[CH:39]=1)=[O:25])=[O:5]
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(-c2ccccc2)ccc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 90 °C

Procedure:
To a solution of methyl 2-amino-5-phenylbenzoate (1.2 g, 5.28 mmol) in toluene (17.5 mL) and pyridine (0.75 mL, 9.24 mmol) was added 20% phosgene in toluene (3.97 mL, 7.65 mmol) under nitrogen. The mixture was heated at 90° C. for 1 h, cooled to 25° C. and filtered. The filtrate was taken to dryness. Toluene (30 mL), (5-phenyl-benzofuran-2-yl)-methanol (1.19 g, 5.28 mmol) and 4-dimethyl-aminopyridine (0.064 g, 0.53 mmol) were added to the residue under a nitrogen atmosphere. The mixture was heated at 50° C. for 24 h, then concentrated to dryness. Purification by chromatography followed by crystallization gave 1.04 g of 4-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccccc1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (6.37 g, 24.5 mmol) was dissolved in dichloromethane (100 mL) at -78° C. and treated with 4-methylmorpholine (5.5 mL, 50 mmol, 2.0 eq.) and benzoyl chloride (3.0 mL, 25.8 mmol, 1.05 eq. ). The solution was allowed to warm to 0° C. and stir for 2 hours. The reaction mixture was washed with 1N HCl and 5% NaHCO3, and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 6.32 g (71%) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([OH:25])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22]O)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:28](Cl)(OC1C=CC=CC=1)([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:26])([CH3:27])[C@@H:14]([OH:25])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22][PH:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C[PH](=O)Oc1ccccc1

Procedure:
Following the general procedure for phosphorylation of Description 23, (2-hydroxyacetyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (45) (40 mg, 0.10 mmol) dissolved in 2 mL of anhydrous dichloromethane (DCM) was reacted with 60 L (78 mg, 0.29 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of pyridine (15.6 μL, 15.3 mg, 0.19 mmol) and triethylamine (TEA) (13.5 μL, 9.8 mg, 0.10 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude title compound (53a) was obtained and used in the next step without purification. MS (ESI) m/z 646.05 (M+H)+, 668.02 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:34][C:35]([NH2:37])=[NH:36])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:43](OC(=O)[C@H](CC1C=CC=CC=1)NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:46])([CH3:45])[CH3:44]>CS(C)=O>[C:43]([O:32][C:31](=[O:33])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:34][C:35]([NH2:37])=[NH:36])=[CH:17][CH:16]=1)(=[O:20])=[O:21])([CH3:46])([CH3:45])[CH3:44]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine trifluoroacetate ##STR37## NaH (22 mg, 80% dispersion by wt in mineral oil, 0.73 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (76.7 mg, 0.80 mmol) in DMSO (5.0 mL) and the mixture was heated at 60° C. under N2 for 20 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (103 mg, 0.21 mmol) was added and the mixture heated at 95° C. for 17 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 80:20:2) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (34.7 mg, 0.069 mmol) as a yellow resin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([CH3:32])[C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
390 mg (1 mmol) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester were solubilized in 5 mL of DMF under nitrogen before adding 61 mg (1.5 mmol) of sodium hydride in mineral oil 60%. The reaction mixture was agitated for 5 minutes before the addition of 70 μL (1.1 mmol) of iodomethane. After 2 hours of agitation at room temperature, the reaction mixture was quenched with 20 mL of water and then extracted with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtrated and evaporated in vacuo to give quantitatively (404 mg) 3-(4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Br:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:12]([CH3:13])=[N:1][C:2]=2[CH:10]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2cc(Br)ccc2c(=O)o1
Temperature: 130 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
2-amino-4-bromobenzoic acid (825 mg, 3.82 mmol) was taken up in acetic anhydride (5.2 mL, 55.01 mmol) and mixture was heated at 130° C. After 4 hours, reaction mixture was cooled to rt and left there for two hours. The solid that precipitated was filtered and washed with cold ether, and dried in-vacuo to yield 7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one 7.25 (451 mg), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8](=S)[NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)=[O:6].[F:22][C:23]([F:31])([F:30])[C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1.CN(C)CCCN=C=NCC>COC(C)(C)C.CCOC(C)=O.O>[CH3:23][C:24]([CH3:25])=[O:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([N:7]=[C:8]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)[NH:29][C:26]1[CH:25]=[C:24]([C:23]([F:31])([F:30])[F:22])[NH:28][N:27]=1)=[O:6]
Reactant: O=C(NC(=S)Nc1cc(F)cc(Cl)c1)c1cccc(Cl)c1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)=O
Product: O=C(N=C(Nc1cc(F)cc(Cl)c1)Nc1cc(C(F)(F)F)[nH]n1)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A suspension of 3-chloro-N-((3-chloro-5-fluorophenyl)carbamothioyl)benzamide (75 g, 219 mmol) in tert-butyl methyl ether (TBME) (1.1 L) was heated to 50° C. Next, 5-(trifluoromethyl)-1H-pyrazol-3-amine (39.6 g, 262 mmol, 1.20 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (64.2 g, 328 mmol, 1.50 equiv) were added. The resulting reaction mixture was stirred at 50° C. for 1 hour and diluted with EtOAc (1.0 L) and water (1.0 L). The organic extract was washed with a saturated, aqueous sodium chloride solution (0.5 L), dried (Na2SO4), filtered, and concentrated. The resulting residue was diluted with EtOAc (300 mL) and this mixture was warmed to 50° C., then filtered through Celite. Next, the filtrate was concentrated to approximately 75 mL and slowly diluted with hexanes (750 mL). The resulting mixture was stirred at room temperature for 1 hour and filtered. The resulting solid was heated in acetone (100 mL), filtered, diluted with hexanes (100 mL), and the resulting mixture was heated until a clear solution developed. Next, the mixture was further diluted with hexanes (300 mL) and stirred at room temperature overnight. The resulting solids were collected by filtration, rinsed with hexanes (100 mL) and dried in vacuo at room temperature to afford (25.1 g, 25% yield) of crystalline 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide acetone solvate. 1H NMR analysis indicates that the molar ratio of 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide to acetone is 3 to 2. 1H NMR (DMSO-d6) of the title compound: δ 13.3 (s, 1H), 10.7 (s, 1H), 10.0 (s, 1H), 7.90 (s, 1H), 7.82 (d, 1H, J=7.6), 7.69 (d, 1H, J=8.4), 7.58 (m, 2H), 7.07 (d, 1H, J=8.4), 6.03 (s, 1H), 2.05 (s, 4H, Acetone). HPLC: 97.6% purity at 26.08 min.