Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.ClC1C(Cl)=CC=CC=1NN>CO>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1cccc(Cl)c1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CO
Product: N#Cc1cnn(-c2cccc(Cl)c2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(2,3-Dichlorophenyl)hydrazine hydrochloride (CAS no. 21938-47-6) (6.06 g, 28.4 mmol) was partitioned between EtOAc and 2M NaOH. Separated. The organic solution was dried (MgSO4), filtered and reduced to give the free base. 2-(Ethoxymethylene)malononitrile (3.47 g, 28.39 mmol) was added portionwise to a stirred solution of (2,3-dichlorophenyl)hydrazine in MeOH (50 mL), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 1 hour. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then was evaporated to afford the product (7.19 g, 100%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 6.75 (2H, s), 7.48-7.53 (2H, m), 7.77 (1H, s), 7.79-7.84 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[O:11])[CH:8]=1)#[N:2].[NH2:22][OH:23]>CCO>[OH:23][N:22]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[O:11])[CH:8]=1)[NH2:2]
Reactant: Cc1ccc(C#N)cc1NC(=O)c1cnc2ccccn12
Reactant: NO
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Temperature: 50 °C

Procedure:
To a stirred and cooled (0° C.) suspension of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) (10 g, 36.2 mmol) in EtOH (225 ml) was added NH2OH (6 mL, 50% in water solution). After the addition, the reaction was stirred at room temperature for 2 hours then heated at 50° C. for another 2 hours. After cooling to room temperature, the mixture was stored in the fridge overnight. The resulting precipitate was filtered, washed with cold EtOH and dried under vacuum to afford N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.40 (dt, J=6.8, 1.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.49 (s, 3H). MS m/z 310.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)CN
Solvent: CO
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 290 mg (0.93 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 3 ml of methanol was mixed with 3 ml of isobutylamine, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was triturated with hexane to afford 340 mg of the title compound as colorless crystals, melting at 125°-126° C.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:9]=1)(C)[C:4]([O-:6])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:23])[C:16]=1[CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH:3]([CH3:1])[C:4]([OH:6])=[O:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(C)(C(=O)[O-])c1cccc(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(C)C(=O)O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
9.3 g of an oil containing ˜60% ethyl-3-(2,6-dimethylbenzyloxy)phenylpropionate was dissolved in 75 ml of absolute ethanol in a single necked, 250 ml round bottom flask equipped with a stir bar and reflux condenser. 4.0 ml of 7.5N sodium hydroxide was added to the solution. The light yellow solution was heated to reflux (80° C.) and stirred for 1 hr. The reaction was analyzed and LC-MS showed the desired product and no starting ester. The reaction was cooled to room temperature and concentrated in vacuo to afford a yellow oil. The oil was dissolved in 25 ml of water and extracted 3× with 25 ml of ether. The aqueous layer was cooled to <5° C. in an ice bath and acidified to a pH=1 by slowly adding 15 ml of 6N aqueous HCl solution. The precipitated solid were collected by filtration, washed 3× with 25 ml of water and air-dried. The solids were slurried in 100 ml of hexanes and collect by filtration, washed 3× with 25 ml of hexanes and air-dried. LC-MS showed the solids to be ˜80% desired product. The solids were heated to 70° C. in 44 ml of 3:1, absolute ethanol: water mixture. The solution was stirred and allowed to cool to room temperature in a tap water bath. The solids were collected by filtration, washed with 20 ml of 3:1, absolute ethanol: water mixture and air-dried. LC-MS showed the solid to be ˜98.5% desired product. The solids were heated to 70° C. in 36 ml of 3:1, absolute ethanol: water mixture. The solution was stirred and allowed to cool to room temperature in a tap water bath. The solids were collected by filtration, washed with 20 ml of a 3:1, absolute ethanol: water mixture and air-dried. LC-MS and NMR showed the solids to be >99.5% desired product. The white solid was dried in a vacuum oven at 40° C. for 2 hrs. to afford 3.91 g (52.9%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[C:31]([F:34])([F:33])[F:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[C:31]([F:32])([F:33])[F:34]
Reactant: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(C(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
To a solution of crude N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (93 mg, 0.39 mmol) and 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (133 mg, 0.43 mmol) in DMF (5 mL) at rt was added TEA (60 μL, 0.43 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (50 mg; yield 25% over 3 steps) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.220 (s, 1 H), 7.837 (s, 2 H), 7.716-7.731 (m, 2 H), 7.650-7.666 (m, 1H), 4.423 (d, J=18.0 Hz, 1 H), 4.311 (d, J=18.0 Hz, 1 H), 1.432 (s, 6 H) ppm; HPLC purity: 99.3% at 220 nm and 99.4% at 254 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:33]([NH:32][C:23]3[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=3[F:21])=[O:34])=[C:3]([S:19][CH3:20])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 37 %

Procedure:
Using Method F2 with 4-(4-amino-3-(methylthio)phenoxy)-3-nitropyridin-2-amine (1.04 g, 3.57 mmol) and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (664 mg, 37%) was obtained as a yellow powder.
Reaction SMILES: O=[C:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[NH2:18][OH:19].Cl>CCO>[OH:19][N:18]=[C:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2

Procedure:
A solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol, 1.0 eq) and NH2OH.HCl (462 mg, 3 mmol, 3.0 eq) in EtOH (10 mL) was refluxed for 2 h. The reaction mixture was concentrated to give tert-butyl 7-hydroxyimino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 104b as a white solid, which was used in next step without further purification. MS: calc'd (MH+) 267, measured (MH+) 267.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A 10.4 g portion of N-(3-acetylphenyl)acetamide was reacted with 25 ml of dimethylformamide dimethylacetal for 8 hours under argon giving N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)C>O1CCCC1>[CH3:50][O:49][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[CH:45][C:44]=1[O:47][CH3:48]
Reactant: COc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1OC
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCc2cc(O)c(=O)[nH]n2)cc1OC

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,4-dimethoxyphenyl)ethynyl]pyridazine (Intermediate 30) except that the solvent mixture used for the hydrogenation was ethanol and tetrahydrofuran (1:1) and the final material was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:18])/[C:6](/[C:16]#[N:17])=[C:7](\[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)/[CH3:8]>C(OCC)C.[Cu]I>[CH3:3][O:4][C:5](=[O:18])[CH:6]([C:16]#[N:17])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH3:1])[CH3:8]
Reactant: [Li]C
Reactant: COC(=O)/C(C#N)=C(/C)c1cccc(Br)c1
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C(C)(C)c1cccc(Br)c1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
To a chilled (0° C.) suspension of Soxhlet-extraction-purified CuI (14.28 g, 0.075 mol, 1.5 equiv.) in 150 mL of anhydrous diethyl ether, was added a 1.6M solution of methyl lithium (84.4 mL, 0.135 mol, 2.7 equiv.) in diethyl ether. The mixture was stirred for 10 minutes, cooled to −25° C. and a solution of (Z)-3-(3-bromophenyl)-2-cyanobut-2-enoic acid methyl ester (14.13 g, 0.05 mol) in 150 mL of anhydrous diethyl ether was added dropwise. The mixture was stirred at −25° C. for 30 minutes, warmed to room temperature, and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organics were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to afford a brown oil. The oil was purified via flash chromatography using a hexanes-ethyl acetate gradient to afford 3-(3-bromophenyl)-2-cyano-3-methylbutyric acid methyl ester. Yield: 8.88 g (60%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:18])([O:15]CC)[O:12]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:12])([OH:18])[OH:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CCCCc1ccccc1)OCC
Agent: Cl
Product: O=P(O)(O)CCCCc1ccccc1
Yield: 61.1 %

Procedure:
A mixture of diethyl (4-phenylbutyl)phosphonate (3.5 g, 13.0 mmole) and 6N HCl (45 ml) was refluxed under argon for 16 hours. The cooled reaction mixture was extracted with EtOAc. The organic phase was washed with saturated NaCl, dried (MgSO4), and evaporated. The crude product (2.3 g) was recrystallized from diisopropyl ether to give pure (4-phenylbutyl)phosphonic acid (1.7 g, 61%) as white needles, m.p. 92°-93° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:32])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCCO
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCCCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-hydroxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (118 mg, 0.270 mmol, 1.00 equiv) in CH2Cl2 (2.7 mL, 0.1 M) were added Proton Sponge™ (87 mg, 0.41 mmol, 1.5 equiv) and trimethyloxonium tetrafluoroborate (44 mg, 0.30 mmol, 1.1 equiv). A white precipitate quickly formed. The resulting mixture was stirred at room temperature for 16 h, quenched with 1 N HCl (2 mL), diluted with H2O (20 mL), and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a white solid. Purification by automated silica gel column chromatography (4-30% acetone in hexanes) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (118 mg, 72%) as a colorless oil: IR (ATR) 3347, 2978, 2928, 2875, 1750, 1710, 1496, 1354, 1367, 1385, 1327, 1163, 1088, 910, 855, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J=8.6, 6.9 Hz, 2H), 7.24-7.14 (m, 3H), 5.13 (d, J=8.1 Hz, 1H), 4.94 (dq, J=9.3, 6.4 Hz, 1H), 4.60 (dd, J=14.9, 7.3 Hz, 1H), 3.88 (dd, J=11.5, 7.3 Hz, 1H), 3.76 (dt, J=12.7, 6.3 Hz, 1H), 3.63 (dt, J=8.7, 6.3 Hz, 1H), 3.53-3.42 (m, 3H), 3.41-3.33 (m, 1H), 3.30 (s, 4H), 3.28-3.22 (m, 1H), 3.18-3.05 (m, 2H), 2.29 (t, J=12.7
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][O:15][CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1.C1COCC1.[N:22]1[O:23][N:24]=[C:25]2[CH:30]=[C:29]([C:31](Cl)=[O:32])[CH:28]=[CH:27][C:26]=12.OS(O)(=O)=O>CO.C(O)=O.ClCCl.[Pd].O.C(N(CC)CC)C>[N:22]1[O:23][N:24]=[C:25]2[CH:30]=[C:29]([C:31]([N:8]3[CH:13]4[CH2:14][O:15][CH2:16][CH:9]3[CH2:10][O:11][CH2:12]4)=[O:32])[CH:28]=[CH:27][C:26]=12
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: c1ccc(CN2C3COCC2COC3)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc2nonc2c1)N1C2COCC1COC2
Reaction time: 0.5 h

Procedure:
9-Benzyl-3,7-dioxa-9-azabicyclo-(3.3.1)nonane (650 mg, 2.96 mmol, see: JOC, Vol. 71, No. 1, 2006, 413-415) was dissolved in methanol (20 ml) and formic acid (4 ml). 10% Pd/C (0.3 g) was added and the mixture was hydrogenated over night. The solids were filtered off, and the solvent evaporated. The residue was dissolved in methanol (20 ml) and a solution of HCl in dioxane (2 ml, 4N) was added and the solvent evaporated. The residue was dissolved in dichloromethane (80 ml), THF (20 ml) and triethylamine (3 ml) and a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (1.0 g, 5.5 mmol) in dichloromethane (10 ml) was added. After stirring the mixture for 0.5 h, water (100 ml) and H2SO4 (→pH2) were added and the organic phase extracted with sodium bicarbonate solution (100 ml), the aqueous was re-extracted with dichloromethane (50 ml) and the combined organics were dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with hexane/THF (50/50). The product was crystallized from dichloromethane/ethanol, which gave the title compound as an off white solid (590 mg): mp=197-199° C., LC-MS, MH+=276.2; 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 2H, J=9.0 and 1.2 Hz); 7.94 (t, 1H, J=1.2 Hz); 7.50 (dd, 1H, J=9.0 and 1.2 Hz); 4.52 (s, 2H); 4.21 (d, 2H, J=11.4 Hz); 4.09-4.02 (m, 4H); 3.90 (dd, 2H, J=10.8 and 2.4 Hz); 3.61 ppm (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1([CH2:8][C:9](Cl)=[O:10])[CH2:7][CH2:6]1.[CH3:13][Mg]Cl.Cl.O>O1CCCC1.C1(C)C=CC=CC=1.C(OC)(C)(C)C.[Fe](Br)(Br)Br>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1([CH2:8][C:9](=[O:10])[CH3:13])[CH2:7][CH2:6]1
Reactant: COC(=O)CC1(CC(=O)Cl)CC1
Reactant: C[Mg]Cl
Agent: Br[Fe](Br)Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(CC(C)=O)CC1
Temperature: -50 °C
Reaction time: 0.67 h

Procedure:
207.2 g crude (1-chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester (approx. 1.07 mole, 97% purity, from step 4) are dissolved in 1428 ml of a 3:1 mixture of tetrahydrofuran and toluene. The mixture is cooled to −50° C. and 6.3 g of iron(III)bromide (0.02 mole, 0.02 eq) are added. Then 357 ml of methylmagnesium chloride in tetrahydrofuran (3 M solution in tetrahydrofuran, 1.07 mole, 1.0 eq) are added dropwise over two hours. After in-process control another 55 ml of methylmagnesium chloride in tetrahydrofuran (3 M solution in tetrahydrofuran, 0.17 mole, 0.15 eq) are added dropwise. Stirring is continued for 40 min, then the mixture is warmed to approx. 0° C., and diluted with 750 ml of methyl tert-butyl ether. Then the mixture is transferred onto a mixture of 27 ml of 37% hydrochloric acid and 480 ml of water. The phases are separated and the aqueous phase is extracted with 480 ml of methyl tert-butyl ether. The combined organic phases are washed twice with 480 ml of water (each) and then with 210 ml of brine, then dried over magnesium sulfate and evaporated to dryness to yield a dark red/brown oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F:15][C:16]([F:33])([F:32])[C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[CH2:30]O)=[O:24])[CH2:19][CH2:18]1.N1CCC[C@@H]1CO>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([O:1][CH2:30][C@H:26]2[CH2:27][CH2:28][CH2:29][N:25]2[C:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([C:16]([F:32])([F:15])[F:33])[CH2:18][CH2:19]2)=[O:24])[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=1
Reactant: CCOC(=O)c1ncc(OC)cc1O
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO
Agent: OC[C@H]1CCCN1
Product: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using ethyl 3-hydroxy-5-methoxypicolinate (EXAMPLE 31 Step 2) and [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (EXAMPLE 31 Step 1) instead of 5-chloropyridin-3-ol and (R)-pyrrolidin-2-ylmethanol.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[CH:47]=[C:46]([NH2:48])[N:45]=[C:44]([NH2:49])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[N:43]=[C:44]([NH2:49])[N:45]=[C:46]([NH2:48])[CH:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Nc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(N)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-2,6-diaminopyrimidine. MS (ESI) mass calcd. for C19H20FN9O, 409.4; m/z found, 410.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To 3.2 g (0.0093 mol) of the product from Step A was added 100 mL methanol and 100 mL 1N sodium hydroxide. The reaction mixture was heated at reflux for 18 h, cooled to room temperature, poured into 200 mL water and extracted with ether (1×100 mL). The aqueous phase was acidified with concentrated HCl and extracted with ether (3×100 mL), washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 3.0 g of a yellow solid, mp 157°-158° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.[C:30](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:30])[S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3nccn3C)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Reaction time: 15.5 h
Yield: 91.8 %

Procedure:
Ethyl 5-(2-methoxyethoxy)-7-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylate (780 mg) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (256 mg) and methyl iodide (0.15 mL) were added, and the mixture was stirred at room, temperature for 15.5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (740 mg, yield 92%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:1]
Reactant: OCc1cc2ccccc2o1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cc2ccccc2o1
Temperature: 30 °C
Reaction time: 72 h
Yield: 73.5 %

Procedure:
A mixture of 2-hydroxymethylbenzofuran (6.91 g) and MnO2 (37.4 g) in CH2Cl2 (250 ml) was stirred at 30° C. for 3 days. Insoluble materials were filtered off and the filtrate was concentrated to give the titled compound (5.01 g) as colorless oil.