Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=2)[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([N:39]3[CH2:44][CH2:43][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:41][CH2:40]3)[CH:36]=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:3]=[C:2]2[C:33]1[CH:34]=[C:35]([N:39]2[CH2:40][CH2:41][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:43][CH2:44]2)[CH:36]=[N:37][CH:38]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)c2)CC1
Temperature: 135 °C
Yield: 88.9 %

Procedure:
A mixture of 3-bromo-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (90 mg, 0.229 mmol), tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (115 mg, 0.286 mmol), Na2CO3, 2.0 M (0.229 mL, 0.458 mmol) and dichloro 1,1′-bis(diphenylphosphino) ferrocene palladium (II) (18.69 mg, 0.023 mmol, Strem) in dioxane (3 mL) was capped, degassed and backfilled with argon. The reaction was heated to 135° C. in a microwave for 45 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0-3% MeOH/DCM), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (120 mg, 89%). MS (ESI, pos. ion) m/z: 590.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=2[C:4]([OH:6])=[O:5])[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Solvent: CCOCC
Product: COCCOc1ccc(C(=O)O)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1

Procedure:
Using a procedure similar to that of Example 29-A, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (6.0 g, 26.52 mmol) is alkylated with trans-4-tert-butoxycarbonylamino-cyclohexanol (5.38 g, 26.52 mmol) to afford the ether (2.70 g), which is used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1.C(Br)(Br)(Br)[Br:32]>CCOCC>[Br:32][CH2:21][C:22]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1
Reactant: OCc1cc2ccccc2o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: BrCc1cc2ccccc2o1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
36.40 g (139 mmol) of triphenylphosphine are added, all at once and with vigorous stirring, to a solution, cooled to 0° C., of 10.40 g (70 mmol) of 2-hydroxymethyl-benzo[b]furan and 46 g (139 mol) of CBr4 in 220 ml of ether. After stirring for 4 hours at 20° C., the precipitate formed is suctioned off and washed with Et2O; the filtrate is dried and concentrated, and the residue is then chromatographed on silica, eluting with a mixture of cyclohexane/CH2Cl2 =80/20, to yield the expected compound in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:22])[CH3:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:22][S:30]([CH3:33])(=[O:32])=[O:31])[CH3:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(Oc1ccc(C(C)O)cc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Oc1ccc(C(C)OS(C)(=O)=O)cc1)c1ccccc1

Procedure:
0.5 g (1.7 mMol) of 1-[4-[(α-ethoxycarbonyl)benzyloxy]phenyl]ethanol and 0.22 g (2.2 mMol) of triethylamine are dissolved in 10 ml of methylene chloride. At 5° C., 0.23 g (2.0 mMol) of mesyl chloride are added dropwise with stirring. After one hour at ambient temperature the reaction mixture is poured onto ice water, extracted with methylene chloride and dried over sodium sulphate. The crude product obtained is reacted directly without any further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:11]1([O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:6]=2)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OC1CCCC1)c1ccc(=O)n(C2CCCC2)n1

Procedure:
6-Oxo-1,6-dihydropyridazine-3-carboxylic acid (1 g, 7.14 mmol) was stirred with cyclopentyl iodide (2.05 ml, 17.8 mmol) and potassium carbonate (3 g, 21.4 mmol) in 15 ml DMF for 14 h at room temperature. 50 ml CH2Cl2 was added and the reaction mixture was filtered. The filtrate was concentrated and the title compound was purified by prep HPLC. Yield: 20 mg (0.072 mmol, 1%, MS m/z: 277(100%, M+1)).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1.[OH:17]O>CC(O)=O>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1)=[O:17]
Reactant: OO
Reactant: COC(=O)Nc1cn2cc(SC)ccc2n1
Solvent: CC(=O)O
Product: COC(=O)Nc1cn2cc(S(C)=O)ccc2n1
Temperature: 0 °C

Procedure:
A suspension of 6-(methylthio)imidazo[1,2-a]pyridine-2-carbamic acid, methyl ester (prepared as described in Example 1) (0.447 mol) in 2700 ml of HOAc is treated dropwise with 535 ml of 30% H2O2. The suspension is stirred until a solution is obtained (~5 hours) and then poured into 8 l. of ice water. The product is collected by filtration and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+].[C:63]1([C:69]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[NH:70])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:63]1([C:69](=[N:70][C:2]2[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1ncc(N=C(c2ccccc2)c2ccccc2)cc1NS(C)(=O)=O
Temperature: 120 °C
Yield: 38.7 %

Procedure:
To a 5 mL microwave reaction tube was added N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (0.208 g, 0.739 mmol), xantphos (Acros, 0.044 g, 0.077 mmol), Pd2dba3 (Aldrich, 0.034 g, 0.037 mmol), NaOtBu (Aldrich, 0.178 g, 1.85 mmol) and diphenylmethanimine (Aldrich, 0.130 mL, 0.776 mmol) in DMF (3 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between tris-HCl buffer (1 M, pH 7.0) (20 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: EtOAc in hexanes 20% to 80%) to afford N-(5-(diphenylmethyleneamino)-2-methoxypyridin-3-yl)methanesulfonamide (0.109 g, 39% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69-7.74 (m, 2H) 7.53 (d, J=2.35 Hz, 1H) 7.46-7.51 (m, 1H) 7.38-7.44 (m, 2H) 7.30-7.36 (m, 3H) 7.12-7.18 (m, 3H) 6.60 (s, 1H) 3.94 (s, 3H) 2.69 (s, 3H).
Reaction SMILES: [CH:1]([N:4]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[CH2:13][CH2:14][O:15][C:16]3=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)N(C(N)=O)c1cccc2c1OCC2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)OCC3

Procedure:
A solution of 4.8 g. of 1-isopropyl-1-(2,3-dihydro-7-benzofuranyl)urea, 3.4 ml of benzaldehyde, 3 drops of methanesulfonic acid and 150 ml. of toluene is stirred and refluxed under a water separator for 18 hours. The cooled solution is washed with 150 ml. of water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[I:11]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(F)ccc1I
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 5-fluoro-2-iodo-benzoic acid (10.05 g, 39.47 mmol) and conc. H2SO4 (10 mL) in MeOH (100 ml) was reflux for 6 hours. After cooling to room temperature, NaOH (2N) was added dropwise to adjust the pH˜8. After most of organic solvent was removed under reduced pressure, the mixture was extracted with dichloromethane three times. The combined organic layers were washed with water, dried and concentrated to give the titled compound (10.80 g, yield 98%)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](O)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 83A from 300 mg (0.85 mmol) of (2S)-4-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]butanoic acid in 10 ml of tetrahydrofuran with 86 mg (0.85 mmol) of 4-methylmorpholine, 92 mg (0.85 mmol) of ethyl chloroformate and 1.7 ml (1.70 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The product is reacted without further purification.
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][C:5]1([O:13][CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[N:11][OH:12].Cl>C(Cl)Cl>[Cl:1][CH:10]1[CH2:9][CH2:8][CH2:7][C:6](=[N:11][OH:12])[C:5]1([O:4][CH3:3])[O:13][CH3:14]
Reactant: COC1(OC)CCCCC1=NO
Reactant: ClCl
Agent: Cl
Solvent: ClCCl
Product: COC1(OC)C(=NO)CCCC1Cl
Reaction time: 0.5 h

Procedure:
Following the general procedure of Example 1, about 7.5 parts of elemental chlorine were added over a 21/2 hour period to a solution of 17.3 parts of 2,2-dimethoxycyclohexanone oxime and a catalytic amount of anhydrous hydrogen chloride dissolved in about 85 parts dry methylene chloride. The reaction contents were maintained at a temperature of about 25° to 35° C. under a dry nitrogen atmosphere. After the addition was completed, the contents were allowed to stir for an additional half hour and were then treated by the procedure as described in Example 1. There was obtained 19.9 parts (90% of theory) of product 3-chloro-2,2-dimethoxycyclohexanone oxime as determined by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.C(O)(=O)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:27])[C:25]=1[CH3:26])[NH:22][CH2:21][C:20]1([CH2:30][CH2:29][CH2:28]1)[CH:19]2O>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:27])[C:25]=1[CH3:26])[NH:22][CH2:21][C:20]1([CH2:28][CH2:29][CH2:30]1)[CH2:19]2
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Reaction time: 0.25 h

Procedure:
To a cold solution of 6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (2 g) in a mixture of 13 mL of THF and 5 mL of CH3OH cooled in ice bath, was added NaBH4 (2.4 g). After 2 hours, the mixture was quenched with ice, evaporated to dryness to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol as a crude mixture (11 g). NaBH4 (3 g) was added in portions to a mixture of trifluoroacetic acid and acetic acid (25 mL, v/v:1/1) cooled in ice bath, and to this mixture was added the above obtained mixture of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol dissolved in 10 mL of THF. After 15 min, the mixture was quenched with ice, extracted with dichloromethane, and washed with brine. The organic phase was then washed with NaOH (2 M) and brine, dried, evaporated to dryness and passed through a silica column (Hexane: EtOAc; 10:1) to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.3 g) as a liquid with slightly yellow color. 1H-NMR (300 MHz, CDCl3) δ=6.44071 (s, 1H), 3.74 (s, 3H), 3.59-3.24 (s, 1H), 3.18 (s, 2H), 2.75 (s, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 2.01-1.73 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=149.88, 136.21, 123.51, 131.91, 118.09, 110.83, 56.51, 51.91, 40.82, 36.09, 30.84, 15.25, 13.07, and 12.03 ppm.
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=1>CN(C=O)C>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=2)=[O:16])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg) and triethylamine (0.40 mmol, 0.056 mL) in 1.6 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 15 min at rt, meta-toluidine (0.30 mmol, 0.032 mL) was added and the reaction stirred at rt for 18 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The resulting solid was chromatographed eluting with CHCl3/EtOAc and then recrystallized from EtOAc/hexane to give the title compound as an off-white solid (38 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: COc1ccc(Br)c(O)c1
Reactant: BrCC1CC1
Product: COc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-methoxy-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: N1(C([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:23](=[O:24])[NH:22][C:21]4[C:16]3=[N:17][C:18]([N:25]3[C:29]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=5[N:27]=[CH:26]3)=[N:19][CH:20]=4)[CH2:11][CH2:10]2)=O)C=CN=C1.Cl.[OH-].[Na+]>CS(C)=O.CCOC(C)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]2[N:27]=[CH:26][N:25]([C:18]3[N:17]=[C:16]4[C:21]([NH:22][C:23](=[O:24])[N:15]4[C@H:12]4[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]4)=[CH:20][N:19]=3)[C:29]=2[CH:30]=1
Reactant: O=C(O[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 50 °C

Procedure:
A solution of trans-4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl 1H-imidazole-1-carboxylate (30 mg) in DMSO (5 ml) was treated with concentrated HCl (1 ml). The mixture was heated at 50° C. for 3 hours. The mixture was diluted with EtOAc and made basic with 3N NaOH (10 ml) The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated to provide 20 mg of the title compound. 1H-NMR (300 MHz, CD3OD) δ 10.5 (s, 1H), 8.8 (dd, 1H), 8.6 (s, 1H), 8.1 (dd, 1H), 7.7 (td, 1H), 4.6 (m, 1H), 4.7 (m, 1H), 4.0 (m, 1H), 2.7 (m, 2H), 2.3 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8](=[O:14])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH:15]([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)=[CH2:16]>CO>[CH2:1]([O:6][C:7]1[C:8](=[O:14])[C:9]2[C:10](=[CH:16][CH:15]=[C:17]3[C:18]=2[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCOC1=CC(=O)C=CC1=O
Reactant: C=CC1=CCCCC1
Solvent: CO
Product: CC(C)=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Yield: 34.8 %

Procedure:
2-Prenyloxy-1,4-benzoquinone (3.0 g, 15.6 mM) and 1-Vinylcyclohexene (6.75 g, 62.5 mM) were dissolved in 50 ml of MeOH, and refluxed for 3 hours. 3-Prenyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone (1.61 g, 5.44 mM) was obtained in the same manner as in Example 1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)NCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinolin-7-ol (200 mg, 1.34 mmol) from step 1 in anhydrous N,N-dimethyl-formamide (5 mL) was added bromomethyl-benzene (229 mg, 1.34 mmol), and potassium carbonate (556 mg, 4.02 mmol). The reaction mixture was stirred at 60° C. overnight. Added some water to the reaction mixture and extracted it with methylene chloride several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by MPLC (biotage) to afford 297 mg (93%) of the title compound. 1H-NMR (CDCl3) δ 7.35–7.20 (m, 5H), 6.81 (d, J=8.1 Hz, 1H), 6.05 (dd, J=7.8 Hz, 2.2 Hz, 1H), 5.98 (d, 2.5 Hz, 1H), 4.53 (bs, 1H), 4.44 (s, 2H), 3.34 (t, J=5.0 Hz, 2H), 2.73 (t, J=5.8 Hz, 2H), 1.98 (m, 2H); MS LC-MS (MH+=240.1), LC MS RT: 3.08 min.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]2[O:30][CH2:29][CH2:28][O:27]2)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]2[O:27][CH2:28][CH2:29][O:30]2)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Fifty mg of Pd/C was added to a solution of 7.18 g (16.8 mmol) 2-(3-{2-[2-(2-{2-azidoethoxy}ethoxy)ethoxy]ethoxy}-4,5-dimethoxyphenyl)-1,3-dioxolane 11 in 100 ml ethanol. The mixture was stirred at ambient temperature under a hydrogen atmosphere overnight, filtered and purified by silica gel column chromatography to give 5.69 g (14.2 mmol, 84%) of the product as a clear oil. 1H-NMR (CDCl3) δ=6.73 (dd, 2H, J=5.2 Hz, J=1.7 Hz), 5.72 (s, 1H), 4.19 (m, 2H), 4.11 (m, 2H), 4.02 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.87-3.85 (m, 2H), 3.75-3.69 (m, 2H), 3.69-3.59 (m, 6H), 3.57 (t, 1H, J=5.4 Hz), 3.49 (t, 1H, J=5.4 Hz), 2.84 (t, 1H, J=5.2 Hz), 2.79 (t, 1H, J=5.2 Hz), 1.74 (br, 2H) ppm. 13C-NMR δ=153.2, 152.3, 139.1, 133.0, 105.3, 103.5, 103.3, 73.2, 70.6, 70.5, 70.4, 70.1, 69.5, 68.6, 65.0, 60.5, 55.9, 41.6 ppm. MS: m/z=424 [M+Na]+, 402 [M+H]+. HRMS: Calcd. for C19H32NO8+ 402.2122, found 402.2122.
Reaction SMILES: [H-].[Na+].[Si]([CH:10]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11]1)(C(C)(C)C)(C)C.[CH3:23][O:24][C:25](=[O:28])[CH2:26]Cl.Cl>CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:28])[CH2:26][N:14]1[C:13]2[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:12]=2[O:11][CH2:10][C:15]1=[O:16]
Reactant: CC(C)(C)[Si](C)(C)C1Oc2ccc(CO)cc2NC1=O
Reactant: COC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)COc2ccc(CO)cc21
Temperature: 0 °C
Yield: 70.2 %

Procedure:
To a suspension of NaH (0.3 g, 0.01 mol) in dry DMF (15 mL) was added TBDMS-6-(hydroxymethyl)2H-1,4-benzoxazin-3(4H)-one (2 g, 0.0068 mol) at 0° C. with stirring and allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C., added methylchloroacetate (1 g, 0.0088 mol) and stirred at RT for 12 h. The reaction mixture was further cooled to 0° C., added 50 mL of 1.5N HCl solution and stirred at RT for 12 h. The reaction mixture was diluted with water (200 mL), extracted with ethylacetate (3×150 mL). The combined organic layer was washed with 10% aqueous NaHCO3 solution, brine and dried. The solvent was removed under vacuum and crude purified by column chromatography over silica gel (CHCl3/Methanol, 99.5:0.5) to give methyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.2 g, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.Cl.[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][N:25](C3CCCCO3)[C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CCCCO>[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2[nH]cnc2c1Cl)c1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (55, 95 mg, 0.37 mmol, CASRN 854434-98-5), the bis-HCl salt of 220 (185 mg, 0.52 mmol), DIPEA (0.33 mL) and n-BuOH (0.8 mL), sealed and heated at 120° C. for 96 h. The reaction mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC to afford 93.2 mg (60%) of I-86: MS (ESI) m/z=413.1 [M+1]+.