Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22]C1C2C(=CC=CC=2)CN1.[CH2:32]1[CH2:42][CH2:41][N:40]2C(=N[CH2:37][CH2:38][CH2:39]2)[CH2:34][CH2:33]1>CN(C=O)C>[F:22][C:32]1[CH:33]=[CH:34][CH:37]=[C:38]2[C:42]=1[CH2:41][N:40]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:39]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: FC1NCc2ccccc21
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(F)c4C3)c(F)c(F)c2c1=O

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 106 mg of 40 fluoroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 35 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 78.8 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.12 mmol, 1.00 equiv), 2-cyanoacetic acid (14 mg, 0.18 mmol, 1.50 equiv), HATU (52 mg, 0.18 mmol, 1.5 equiv) and TEA (42 mg, 0.40 mmol, 5.00 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at 25° C. It was quenched with water (50 mL), which was extracted with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtrated and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 48 mg (83%) of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:17][C:18]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)[CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(-c3ccc(CN4CCOCC4)c(F)c3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (250 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.03 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 80% EtOAc in hexanes to afford 100 mg (yield: 35.71%) of the title compound as pale yellow solid.
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Na+:9].[Na+].C(O)(=O)CCC(O)=O.[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].C(O)C.C([O-])(=O)CCC([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[S:19]([O-:23])([O-:22])(=[O:21])=[O:20].[Na+:9].[Na+:9]
Reactant: O=S(=O)(O)O
Reactant: O=C([O-])CCC(=O)[O-]
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)([O-])[O-]
Temperature: 30 °C

Procedure:
A mixture of 10.02 g of 200 proof ethanol and 0.502 g of 98% sodium succinate was prepared and heated to 30° C. These quantities allowed for a final solution of 10 wt % succinic acid in ethanol to be obtained upon acidification. The solubility of succinic acid in ethanol at 30° C. is about 12 wt %. Sulfuric acid (H2SO4) (0.338 g, 98%) was added to the ethanol/sodium succinate slurry with stirring to produce free succinic acid and sodium sulfate.
Reaction SMILES: [OH:1][C:2]1([CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]2=[O:26])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[Cl-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[OH:1][C:2]1([CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]2=[O:26])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: COc1ccc2ncc(=O)n(CCC3(O)CCC4(CC3)OCCO4)c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2ncc(=O)n(CCC3(O)CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
To 8 mL of a dioxane suspension containing 0.25 g of 1-(2-(8-hydroxy-1,4-dioxaspiro(4.5)decan-8-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was dividedly added at room temperature, and the mixture was stirred for 5 hours and 15 minutes. An aqueous saturated sodium hydrogen carbonate solution was added with the reaction mixture, and then added with ethyl acetate and sodium chloride. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 1:3] to obtain 0.10 g of a colorless oily substance, 1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxyquinoxalin-2(1H)-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl.[F:9][C:10]([F:29])([S:25]([O-:28])(=[O:27])=[O:26])[CH:11]([O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([F:15])([F:14])[F:13].[Na+].ClCCl>O.C(OCC)C>[F:29][C:10]([F:9])([S:25]([O-:28])(=[O:26])=[O:27])[CH:11]([O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([F:13])([F:15])[F:14].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC[NH+](CC)CC

Procedure:
Triethylamine was dissolved in cold water, and hydrochloric acid was added thereto to adjust the pH of the reaction liquid to fall within a range of 1 to 3. Then sodium 1,1,3,3,3-pentafluoro-2-(benzoyloxy)propanesulfonate and dichloromethane were added thereto and stirred. The separated organic layer was washed with water, and dichloromethane was removed under reduced pressure from the washed organic layer. To the residue thus obtained, diethyl ether was added for recrystallization. The resultant was filtrated and dried to obtain a desired product at a yield of 75%.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:40][C:41]1[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=[C:45]([Br:47])[CH:46]=1>C(Cl)Cl>[Br:47][C:45]1[CH:46]=[C:41]([NH:40][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(Br)cc(NC(=O)C2CC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
To a mixture of cyclopropanecarboxylic acid (180 mg, 2.0 mmol), HATU (570 mg, 1.5 mmol) and DIPEA (390 mg, 3.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (230 mg, 1.12 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column chromatography eluting with 20:1 DCM/methanol to afford the 102a (220 mg, 72%). MS-ESI: [M+H]+ 270.1
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1)#[N:15].[NH2:31][C:32]1[S:33][CH:34]=[C:35]([CH3:37])[N:36]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:31][C:32]3[S:33][CH:34]=[C:35]([CH3:37])[N:36]=3)[N:3]=[CH:4][C:5]=2[C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[N:17][CH:18]=2)[N:10]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3ccc(C#N)nc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=359.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-cyanopyridine-5-boronic acid pinacol ester and 2-amino-4-methylthiazole.
Reaction SMILES: [N+]([O-])([O-])=O.[Nd+3:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[O:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CO>[Nd:5].[O:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Nd+3]
Agent: O=C(O)COc1ccccc1
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: [Nd]
Temperature: 25 °C

Procedure:
The compound was synthesized by the same method as that for Synthesis Example 1-2 above, that is, after forming a triethylamine salt of phenoxyacetic acid in anhydrous methanol, a methanol solution of neodymium nitrate was added while stirring. Specifically, a reactor similar to that of 1-1 was used to stir a solution obtained by adding 100 ml of an anhydrous methanol to 45.65 g (0.3 mol) of phenoxyacetic acid, while dripping 30.4 g (0.3 mol) of triethylamine while maintaining at 25° C. by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a transparent synthesis solution of phenoxyacetic acid-triethylamine salts. Next, this synthesis solution was maintained at about 30° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 100 ml of methanol was dripped in while stirring. Upon completion of the dripping of the neodymium nitrate solution, it began to cloud, and the clouding increased with time. 30 minutes after completion of dripping, the solution was heated to 40° C. for 30 minutes, to produce a slurry solution of a neodymium salt of phenoxyacetic acid. Crystals obtained by filtering this slurry solution were added to 200 ml of methanol, stirred and washed, then refiltered, and 200 ml of methanol were once again added to the crystals, stirred and washed, then filtered. The resulting crystals were dried under reduced pressure at 50° C., to obtain 38.8 g of a neodymium salt of phenoxyacetic acid (yield 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:25]=[CH:26]/[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1/[CH:25]=[CH:26]/[CH3:27])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 111.1 %

Procedure:
The mixture 5-fluoro-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (153) (260 mg, 0.68 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (0.2 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 2.5 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The filtered compound is purified by HPLC to give a pure product (154) as white solid (267 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19]Cl)[C:13]=1[OH:21].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[C:7]([CH:8]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=2[OH:9])[C:13]=1[OH:21])#[N:2]
Reactant: Oc1c(CCl)cc(F)cc1CCl
Reactant: N#Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(O)c(Cc2cc(F)cc(Cc3cc(C#N)ccc3O)c2O)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 3 %

Procedure:
p-Cyanophenol (19.4 g) and 2,6-bis(chloromethyl)-4-fluorophenol (17.0 g) were dissolved in nitrobenzene (250 ml) at 20°. The solution was cooled to 10° and crushed aluminium chloride (anhydrous 65 g) was added in 5 g portions over two hours. During the addition the temperature was maintained at 10°-12°. Stirring was continued at 20° for 14 hrs. The viscous black mixture was poured onto a vigorously stirred mixture of ice (2 l) and dichloro methane (2 l). The organic solvent layer was dried, dichloro methane and nitrobenzene removed by vacuum distillation and the residual tar passed through a silica column. The product, 2,6-bis(5-cyano-2-hydroxybenzyl)-4-fluorophenol (mp 222°) was obtained in 3% yield.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)#[N:25]
Reactant: N#Cc1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C#N)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
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[O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[OH-].[Na+]>O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCOc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-[(2-naphthalenyl)oxy]butanol (2.4 g), 1.6-dibromohexane (5.3 ml), TAB (1 g) and 50% sodium hydroxide solution (24 ml) was stirred at room temperature for 19 h. The mixture was diluted with water (100 ml) and extracted with ether (2×150 ml). The combined organic fractions were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane followed by hexane-ether (19:1→8:1) gave the title compound as a colourless oil, (2.34 g), t.l.c. (ether-hexane 1:1) Rf 0.85.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C(C)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C@@H:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Temperature: 80 °C
Reaction time: 13 h
Yield: 74 %

Procedure:
2.07 g of N-(2-amino-4,6-dichloro-5-pyrimidinyl)formamide were heated to 80° C. in 40 ml of isobutanol (white suspension). A solution of 1.97 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride, 3.8 g of triethylamine and 15 ml of isobutanol was added to the mixture. The mixture was stirred at 80° C. for a further 13 h. 10 ml of 1N NaOH were added to the clear solution at 20° C., followed by evaporation to dryness. The residue underwent flash chromatography (silica gel 60 column, length 8 cm, diameter 6.5 cm, eluent ethyl acetate/methanol 95/5). After evaporating off the eluent and drying the residue, 2.1 g of title compound were obtained. The yield was 74%.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1.O.CCOC(C)=O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccncc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OC(CNc1ccncc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound of Example 41 was prepared as follows. LiOH.H2O (0.0157 g, 0.373 mmol) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-4-yl)oxazolidin-2-one (0.0187 g, 0.0373 mmol) in a mixture of 428 μL THF and 48 μL H2O (v/v=9:1). The mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with 30 mL EtOAc and washed with brine 3×30 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which did not require purification (0.0013 g white solid, 7.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:10]=3[N:9]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:25])=[C:4]([O:28][CH3:29])[CH:3]=1.Cl[CH2:31]/[CH:32]=[CH:33]\[CH2:34]Cl.C(N(CC)CC)C>CN(C=O)C>[CH:19]1([N:9]2[C:10]3[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:11]=3[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([N:1]4[CH:34]=[CH:33][CH:32]=[CH:31]4)=[CH:3][C:4]=3[O:28][CH3:29])[C:8]2=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClC/C=C\CCl
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(N)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(-n2cccc2)cc1OC
Yield: 44.4 %

Procedure:
A mixture of 1 g of the compound obtained in Example 6, 1 g of cis-1,4-dichloro-2-butene and 1 ml of triethylamine in 20 ml of DMF is heated at reflux for 1 hour 30 minutes under nitrogen atmosphere. After cooling, the reaction mixture is poured into a water/ice mixture, extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with DCM. 0.5 g of the expected product is obtained.
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:11]([NH:13][C:14](=[S:17])[NH:15][NH2:16])[CH3:12].[OH-].[Na+]>N1C=CC=CC=1>[CH2:11]([N:13]1[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:16][NH:15][C:14]1=[S:17])[CH3:12]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCNC(=S)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(-c2ccncc2)n[nH]c1=S
Yield: 57.5 %

Procedure:
The title compound (pale yellow solid, 16.7 g, 58%) was prepared from isonicotinoyl chloride hydrochloride (25.1 g, 140.8 mmol) and 4-ethyl-3-thiosemicarbazide (16.87 g, 141.5 mmol) in pyridine (185 ml) with sodium hydroxide (220 mL, 2M, 440 mmol) added to the intermediate formed to effect cyclization. 1H NMR (DMSO-d6) δ (ppm): 8.80 (dd, 2H), 7.72 (dd, 2H), 4.11 (q, 2H), 3.59 (t, 3H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OC([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[C:29]([C:40]#N)=[C:28](Cl)[N:27]=1)=O)(C)(C)C.C[N:44]([CH:46]=[O:47])C>>[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:27]=[C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:29]([CH2:40][C:46]([NH2:44])=[O:47])=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[N:31]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Cl)c2C#N)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)nc(OCc3ccccc3)c2CC(N)=O)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
To a mixture of benzyl alcohol and DMF was added 60% sodium hydride under ice cooling and then 2-[cis-2-(tert-butoxycarbonylamino)cyclohexylamino]-6-chloro-4-(3-methylanilino)pyrimidine-5-carbonitrile was added thereto, followed by stirring at 60° C. for 40 minutes. Then, distilled water was added to the reaction liquid and the resulting precipitate was collected by filtration. The filtration product was treated in a similar manner to Reference Example 4 to obtain 2-(cis-2-aminocyclohexylamino)-4-benzyloxy-6-(3-methylanilino)pyrimidine-5-carboxyamide (colorless solid).