Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]([O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6])(=O)[CH3:2].[NH2:20][C:21]([CH3:29])=[CH:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(O)(C)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[C:4]([C:5]([O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6])=[C:1]([CH3:2])[NH:20][C:21]([CH3:29])=[C:22]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: COCCOC(=O)C(=Cc1ccccc1F)C(C)=O
Reactant: CC(N)=CC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1F
Yield: 47.7 %

Procedure:
4.0 g (about 15 mmol) of the compound from Example I are heated to reflux overnight in 100 ml of isopropanol with 2.2 g (15 mmol) of isopropyl 3-amino-2-butenoate. After thin-layer chromatographic checking (SiO2, toluene/ethyl acetate 5:1) shows complete conversion, the reaction mixture is concentrated, the residue is-taken up with toluene, the solution is concentrated again and the residue is then purified by filtration on silica gel (eluent: toluene/ethyl acetate 100:1-5:1). A crystallizing yellow oil is obtained, which is recrystallized from methanol at about −15° C. 2.8 g (48%) of the target compound are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[C:11]([O:15][CH:16]([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C(O)(=O)C>CCOCC>[CH2:1]([N:3]([CH2:13][CH2:12][C:11]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: C=CC(=O)OC(C)C
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN(CCC(=O)OC(C)C)c1cccc(C)c1
Yield: 88.2 %

Procedure:
A mixture of 13.5 g (0.1 mole) N-ethyl-m-toluidine, 11.4 g (0.1 mole) isopropyl acrylate and 2 ml glacial acetic acid was heated over the steam bath for 16 hours. The mixture was cooled and diluted with ether. The ether solution was washed with 10 ml water, twice with 10 ml portions of 5% sodium carbonate solution, once with 10 ml of water and then dried over sodium sulfate. Removal of the ether with a rotary evaporator at 50° C. and reduced pressure gave 22.0 g (86%) of oil, which was pure by thin layer chromatography and was used as isolated.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([N:51]3[CH2:52][CH2:53][C:48]([F:54])([F:47])[CH2:49][CH2:50]3)=[O:14])=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3nc2Cl)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3nc2Cl)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 1 from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4,4-difluoro-piperidine and N,N-diisopropylethylamine in DMF to give the desired product as a light yellow foam (40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH:26]=[O:27].O>CC(=O)CC>[CH2:24]([O:25][C:26](=[O:27])[NH:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=[CH:13][N:12]=1)[CH3:23]
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a mixture of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (1.0 g, 4.9 mmol) and potassium carbonate (4.0 g, 29 mmol) in 2-butanone (10 ml), chloroethylformate (0.50 ml, 4.9 mmol) was added and the mixture was refluxed for 3 hours at 80° C. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.60 g of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.Cl[C:11](Cl)(Cl)[CH:12]([OH:14])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:25][OH:26]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])/[CH:11]=[N:25]/[OH:26])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccc(F)cc1
Temperature: 100 °C

Procedure:
4-Fluoroaniline (58.2 g, 0.50 mol) was added slowly to 10% aqueous HCl solution. This suspension was added to a mixture of chloral hydrate (95 g, 0.55 mol) and sodium sulfate (0.5 kg) in 750 mL water with mechanical stirring. Hydroxylamine hydrochloride (116 g, 1.63 mol) dissolved in water (250 mL) was added, and the resulting slurry was heated at 100° C. After this temperature was reached, the heating mantle was removed immediately, and the solution was cooled to room temperature. The formed precipitate was collected by filtration, washed with water (2×300 mL), and dried in a vacuum oven at 60° C. Yield: 78.2 g of N-(4-fluorophenyl)-2-hydroxyiminoacetamide as an off-white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O-2].[O-2].[O-2].[Cr+6:10]>O>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Cr+3:10].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Cr+3:10]
Reactant: O=C(O)C(=O)O
Reactant: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Product: [Cr+3]

Procedure:
Oxalic acid (10.18 Kg) was added to water (9 l). Chromium trioxide (2720 g) was gradually added to the mixture with stirring while heating the mixture on a water bath to form a solution of chromium oxalate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][CH2:16][N:19]([CH3:20])[CH3:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reactant: CNC
Solvent: CCO
Product: CN(C)CCC1=NC=C(OCc2ccccc2)C(=O)C1
Temperature: 100 °C

Procedure:
A mixture of 5-benzyloxy-2-vinyl-4-pyridone (3.12 g), 50% aqueous solution of dimethylamine (15 ml) and ethanol (35 ml) was heated at 100° C. in a sealed tube for 8 hours. The resulting mixture was cooled and concentrated under reduced pressure to dryness. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give 5-benzyloxy-2-[2-(N,N-dimethylamino) ethyl]-4-pyridone (3.45 g) as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9](=[O:21])[N:10]([C:13]3[C:14]([Cl:20])=N[CH:16]=[CH:17][C:18]=3[Cl:19])[C:11](=[NH:12])[C:5]2=[CH:4][N:3]=1.[CH3:23][N:24]([CH2:26][CH:27]1[O:32][CH2:31][CH2:30][N:29]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28]1)[CH3:25].[CH2:40](O)CCC>>[Cl:20][C:14]1[CH:40]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[N:10]1[C:11](=[NH:12])[C:5]2[C:6](=[N:7][C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][N:24]([CH3:23])[CH3:25])[CH2:28]4)=[CH:39][CH:38]=3)=[N:3][CH:4]=2)[N:8]([CH3:22])[C:9]1=[O:21]
Reactant: CCCCO
Reactant: Cn1c(=O)n(-c2c(Cl)ccnc2Cl)c(=N)c2cnc(Cl)nc21
Reactant: CN(C)CC1CN(c2ccc(N)cc2)CCO1
Product: CN(C)CC1CN(c2ccc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)cc2)CCO1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
30 mg of the 7-chloro-3-(2,4-dichloropyridin-3-yl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 2, and 16 mg of TSOH monohydrate were added to a 5-ml n-butanol solution containing 20 mg of 4-{2-[(dimethylamino)methyl]morpholin-4-yl}aniline, and the mixture was heat stirred for 15 minutes at 100° C. The reaction mixture was concentrated under reduced pressure, and purified by basic column chromatography. As a result, 27 mg of a white solid was obtained as a subject compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:39][CH3:40])[C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:39][CH3:40])[C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7]/[N:8]=[C:9](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)\[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated to give E-4-[3,5-dimethoxy4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (880 mg, yield 93%) as crystals. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles. m.p. 89-90° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([CH3:12])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10])=O.C[O-].[Na+]>CN(C)C=O>[OH:10][C:9]1[C:8]2[NH:7][N:6]=[C:5]([CH3:12])[C:4]=2[N:3]=[CH:1][N:11]=1
Reactant: Cc1n[nH]c(C(N)=O)c1NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(O)ncnc12

Procedure:
An intramolecular ring closure is then performed to produce a pyrazolo[4,3-d]pyrimidine nucleus. This can be done by introducing 4-formylamino-3-methylpyrazole-5-carboxamide into refluxing dimethylformamide containing a catalytic amount of sodium methoxide to produce 7-hydroxy-3-methylpyrazolo[4,3-d]pyrimidine in high yield and excellent purity.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10](O)([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[OH-:19].[Na+].[C:21](#[N:23])[CH3:22]>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:23][C:21](=[O:19])[CH3:22])([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccnc(C2CC2)n1
Reactant: CC#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(C)(C)c1ccnc(C2CC2)n1
Temperature: 95 °C
Reaction time: 96 h
Yield: 41 %

Procedure:
Heat a solution of acetonitrile (150 mL) and 2-(2-cyclopropyl-pyrimidin-4-yl)-propan-2-ol of (8.85 g, 50 mmol) to 90° C. In a separate reaction vessel, cool acetonitrile (50 mL) to 0° C. and add sulfuric acid (11.9 mL, 223 mmol) at such a rate that the temperature does not exceed 10° C. Add the cooled sulfuric acid solution to the heated solution of 2-(2-cyclopropyl-pyrimidin-4-yl)-propan-2-ol and acetonitrile and stir at 95° C. for 4 days. Cool to room temperature and add aqueous 5N NaOH (100 mL). Extract the aqueous layer with ethyl acetate (3×). Concentrate under reduced pressure the combined organic layers to yield N-[1-(2-cyclopropyl-pyrimidin-4-yl)-1-methyl-ethyl]-acetamide (4.5 g, 41%) as a yellow oil. MS (m/z): 220.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:11])[CH:5]([CH3:10])[CH:6]([CH3:9])[C:7]=1[CH3:8].Cl>>[OH:11][C:4]1[C:3](=[O:2])[CH:7]([CH3:8])[CH:6]([CH3:9])[C:5]=1[CH3:10]
Reactant: COC1=C(C)C(C)C(C)C1=O
Agent: Cl
Product: CC1=C(O)C(=O)C(C)C1C
Yield: 72.8 %

Procedure:
5.39 g (35 mmol) of 2-methoxy-3,4,5-trimethyl-2-cyclopenten-1-one are held at reflux temperature for 90 minutes with 53.9 g (10 fold amount by weight) of 5N hydrochloric acid. The reaction mixture is extracted 3 times with 50 ml of ether each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product is distilled at 45°-48° C./0.03 mbar and yields 3.57 g (72.9%) of 2-hydroxy-3,4,5-trimethyl-2-cyclopenten-1-one.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>C(O)C(C)C>[Cl:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: NN
Reactant: Clc1ccc(-c2cnnc(Cl)c2Cl)cc1
Solvent: CC(C)CO
Solvent: O
Product: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
3,4-Dichloro-5-(4-chlorophenyl)-pyridazine (6.0 g, 23.1 mmol) was suspended in isobutanol (150 mL) at 0° C. and hydrazine monohydrate (11.1 g) was added dropwise over 10 min. The reaction mixture was slowly warmed up to RT and stirred for 24 h. The mixture was cooled in an ice/water bath for 15 min and filtered. The white solid thus obtained was washed with cold isopropanol and dried to give the title compound, 1-[4-chloro-5-(4-chloro-phenyl)-pyridazin-3-yl]-hydrazine, (5.0 g) as a white solid. HPLC: 1.65 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:31]=[CH:30][C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:18]([N+:32]([O-])=O)[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:35]2[CH:50]=[CH:49][C:38]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[C:37]([N+:51]([O-])=O)[CH:36]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.C(OCC)(=O)C.[Pt]=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:12]([C:35]3[CH:36]=[C:37]([NH2:51])[C:38]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)=[CH:49][CH:50]=3)[CH2:13][CH2:14][CH:15]2[C:16]2[CH:17]=[C:18]([NH2:32])[C:19]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:30][CH:31]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c(N)c4)N3c3ccc(C(C)(C)C)cc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.8 %

Procedure:
The product from Example 28E (2 g, 2.79 mmol) was dissolved in a mixture of THF (15 mL), ethanol (15 mL), and ethyl acetate (5 mL) then platinum oxide (0.254 g, 1.12 mmol) was added via THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room temperature for 20 h, then filtered through celite, concentrated, and purified by chromatography on silica gel with an 80 g column, eluting with 0-40% ethyl acetate/dichloromethane to give the first peak of trans product 0.508 g (28%).
Reaction SMILES: C(OC(=O)C[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4)=CC=3)=CC=2)=C(OC)C=1.[CH2:62]([O:64][C:65](=[O:68])CBr)[CH3:63]>>[CH2:62]([O:64][C:65](=[O:68])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:63]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Product: CCOC(=O)Cn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21

Procedure:
[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester from starting materials 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and bromo-acetic acid ethyl ester to yield the product as a white solid/wax (25 mg, 56%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.S(=O)(=O)(O)O>O>[OH:1][N:4]1[C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:11]
Reactant: NO
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 42 g (1.05 mole) of sodium hydroxide in 500 ml of water, there was added 73.0 g (1.05 mole) of hydroxylamine hydrochloride. Subsequently, 148 g (1.0 mole) of phthalic anhydride was added to the solution and the resulting mixture was stirred at 90° C. for one hour. A solution of 30 g of sulfuric acid in 100 ml of water was added to the reaction mixture from which pale yellow solids had been precipitated out and the mixture was stirred for additional 30 minutes. The pale yellow solids were filtered off and recrystallized from a benzene/ethanol mixed solvent to give 132 g of the title compound: N-hydroxyphthalimide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[NH2:20][C:21]([NH2:23])=[NH2+:22]>>[NH2:22][C:21]([NH2:23])=[N:20][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: NC(N)=[NH2+]
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: [Cl-]
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
in stage e) 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride is reacted with guanidinium chloride to give N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.B(O)(O)[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[N:26]1[CH:27]=[CH:28][C:23]([C:3]2[N:4]=[C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]3=[N:7][C:2]=2[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(Cl)nc21
Reactant: Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(-c3ccc(C)cc3)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(3-chloro-2-(pyridin-4-yl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 3) (58 mg, 0.144 mmol), p-tolylboronic acid (39.1 mg, 0.288 mmol) and potassium carbonate (59.7 mg, 0.432 mmol) in dioxane (2 ml) was degassed by bubbling nitrogen through (×3). Pd(Ph3P)4 (33.3 mg, 0.029 mmol) was added and the mixture was degassed by bubbling nitrogen through (×3). The mixture was heated at 150° C. for 2 hours using microwave irradiation. The mixture was diluted with water and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The crude product was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane followed by 5-10% THF in DCM. The fractions were evaporated under vacuum and the residue was purified by ion exchange using a Isolute SCX-2 cartridge, loading and washing with methanol and eluting with 2M NH3 in MeOH to afford the title compound;
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].Cl.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@:3]([CH3:17])([C:1]2[N:26]=[N:27][NH:28][N:2]=2)[CH2:7][O:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C#N
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nn[nH]n1
Temperature: 103 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a mixture of 6.96 g of tert-butyl (4R)-4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 12.5 g of triethylamine hydrochloride, and 105 ml of toluene was added 5.84 g of sodium azide, followed by stirring at 103° C. for 3 hours. The insoluble materials were separated by filtration and the filtrate was concentrated. The obtained residue was purified twice by silica gel column chromatography to obtain 7.65 g of tert-butyl (4R)-2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([NH2:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[CH3:20].O>O1CCCC1>[CH3:20][C:11]1[CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[C:14]([NH2:16])=[N:15][C:10]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(N)nc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoroethanol (340 mg, 3.4 mmol) was dissolved in the tetrahydrofuran (10 ml), sodium hydride (60%) (120 mg, 3.0 mmol) was added thereto, and the reaction mixture was stirred for 30 minutes at room temperature under nitrogen atmosphere. A solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine crude product (400 mg) in tetrahydrofuran (10 ml) was dropped, and the reaction mixture was stirred at room temperature for 2.5 days. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with a sodium bicarbonate solution, dried over magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=15/85) to yield the title compound (225 mg, 0.90 mmol) as a yellow solid.