Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[C:6]([O:12][CH3:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:14].CCN(CC)CC.[C:22](Cl)(=O)[CH2:23][CH3:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C@@H:3]([OH:14])[C@H:2]([NH:1][CH2:22][CH2:23][CH3:24])[CH2:11]2
Reactant: COc1cccc2c1C[C@@H](O)[C@H](N)C2
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN[C@@H]1Cc2cccc(OC)c2C[C@H]1O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Compound 13A (1.50 g) was suspended in THF (15 mL) and Et3N (1.80 mL) and propionyl chloride (0.60 mL) were added. The solution was stirred for 20 minutes. LAH (1M in THF, 10 mL) was added drop-wise under stirring at rt and the reaction mixture were heated to 90° C. for 1200 sec. in a sealed microwave process vial. The reaction was quenched with wet Na2SO4. The mixture was diluted with THF (50 mL), filtered over dry Na2SO4 and concentrated in vacuo. Yield: 1.21 g of compound 14A as an oil. LC/MS (method 350): RT 0.40 min, ELSD 100%, UV 100%. MH+: 235.9. 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 3H), 1.43-1.52 (m, 2H), 2.37-2.51 (m, 3H), 2.61-2.68 (m, 1H), 2.74-2.80 (m, 1H), 3.14 (dd, J=4.93, J=16.0, 1H), 3.22-3.29 (dd, J=16.9, J=5.9, 1H), 3.56-3.63 (m, 1H), 3.73 (s, 1H), 6.60 (d, J=8.05, 1H), 6.62 (d, J=7.89, 1H), 7.03 (t, J=7.86, 1H). 13C NMR (500 MHz, CDCl3) δ: 157.7 136.4, 127.0, 123.8, 121.2, 107.7, 71.0, 59.8, 55.7, 49.5, 35.7, 32.1, 24.1, 12.2.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].Cl>O1CCCC1>[N:1]([CH2:4][C:5]1[S:9][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)Cc1ccc(CN=[N+]=[N-])s1
Agent: Cl
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(CC(=O)O)s1
Yield: 62 %

Procedure:
Methyl 5-azidomethyl-2-thienylacetate (21.1 g., 0.10 mole) was dissolved in 300 ml. of tetrahydrofuran and 40 ml. of 3M hydrochloric acid was added. After heating at reflux for 6 hours the reaction mixture was cooled and the product isolated as described in Example 9 to obtain a 62% yield of oil. 1H--NMR (CDCl3), ppm. (δ): 9.0 (s, COOH), 6.85 (s, 2 aromatic-H), 4.4 (s, CH2N3), 3.75 (s, CH2COO); IR spectrum (neat, cm.-1 : 3000 (broad), 2100 (N3), 1710 (CO2H), 1680 and 1475.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[O:11])[N:3]=1.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1

Procedure:
A mixture of 2.0 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide and 11 ml. of 50% aqueous sodium hydroxide was warmed on a steam bath with shaking; 40 ml. of water was added and heating and shaking continued during the next half hour. The resulting solution was then filtered and the filtrate acidified with hydrochloric acid to pH 2 to yield a precipitate which was isolated by filtration to yield the title compound, 0.7 g melting at 160° with decomposition. The nuclear magnetic resonance spectrum showed resonance peaks for the methyl substituents on the pyrimidine ring at 2.66 ppm and the ring hydrogens at 7.2 to 8.4 ppm. The disappearance of the resonance peak at 4.0 ppm confirmed the conversion of the methyl ester to the carboxy group.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([C@@H:30]2[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]2[O:32][C:33](=[O:35])[CH3:34])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Cl)nc2c(Cl)c(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
A mixture of 2,4,5,6-tetrachloro-1H-benzimidazole (1.02 g, 4.0 mmol), acetonitrile (20 mL), and N,O-bis(trimethylsilyl)acetamide (1.5 mL, 6 mmol) was stirred at 70° C. for 15 min. Then 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (1.35 g, 5.2 mmol) in acetonitrile (5 mL) was added, followed by trimethylsilyltrifluoromethane sulfonate (1.16 mL, 6.0 mmol). The resulting mixture was allowed to stir at 70° C. for 20 min. Another portion of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (0.21 g, 0.8 mmol) in acetonitrile (2 mL) was added and stirring was continued at 70° C. for 10 min. The mixture was allowed to cool to RT and was diluted with ethyl acetate. The ethyl acetate layer was washed with a saturated NaHCO3/NaCl solution, dried over Na2SO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using chloroform as eluant. Recrystallization from methanol afforded 1.11 g (61 %) of the title compound as white crystals; m.p. 126-127° C.; 1H NMR (DMSO-d6) δ: 8.16 (s, 1H), 6.20 (d, 1H), 5.61 (t, 1H), 5.25 (dd, 1H), 4.24 (m, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]1[CH2:9][CH2:8][N:7](C(C)C)[CH2:6]1.C(Cl)(Cl)=O.C(N(CC)CC)C.C(Cl)(=O)N.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[C:4]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: CC(C)N1CCC(C(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C1
Agent: NC(=O)Cl
Agent: O=C(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1

Procedure:
A solution containing 25.2 g. (0.0720 mole) of N,N-dimethyl-α,α-diphenyl-α-(1-isopropyl-3-pyrrolidinyl)acetamide, 14.3 g. (0.153 mole) of phosgene, and 7.27 g. (0.0720 mole) of triethylamine in 275 ml. of benzene was stirred at room temperature for one hour. After extraction with dilute acid the benzene layer produced 25.6 g. of neutral material which showed a good carbamoyl chloride band at 5.85 μ. The material was hydrolyzed in refluxing 10% sulfuric acid for one hour to give 19.5 g. of crude product. Acid-base extraction removed some neutral material and the free base was converted to the fumarate salt which was recrystallized from ethanol-isopropyl ether; m.p. 159°-160° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:12][CH:11]=2)=[O:8])=[C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH:4]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO.C=O>[ClH:2].[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:12][CH:11]=2)=[O:8])=[C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH:4]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3)cc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
4-Chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(piperidin-2-ylmethyl)amino]benzamide hydrochloride (100 mg) was dissolved in a mixed solution of acetic acid (3 mL) and methanol (2 mL), and 1 ml of formaldehyde aqueous solution (36%) was added thereto. Sodium triacetoxyborohydride (252 mg) was added to this solution at 0° C., followed by stirring at room temperature for 30 minutes. After concentration under a reduced pressure, this was made basic by adding a saturated sodium bicarbonate aqueous solution, followed by extraction with chloroform. After drying the organic layer with magnesium sulfate, the solvent was evaporated under a reduced pressure. By purifying the residue by silica gel column chromatography (chloroform:methanol, 10:1) and treating the resulting free base with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1-methylpiperidin-2-yl)methyl]amino}benzamide hydrochloride (45 mg) was obtained as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13]C)=[O:11])=[CH:7][C:6]=2[CH:15]=1.C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.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>[CH3:13][O:12][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:6]=2[CH:7]=1)=[O:11]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(-c3cccnc3)ccc2o1
Temperature: 100 °C
Yield: 184.2 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate 15 (6 g, 22.3 mmole), diethyl 3-pyridylborane (3.66 g, 25 mmole), tetrakis(triphenylphosphine)palladium (0) (270 mg), and potassium phosphate (11.4 g, 53.7 mmole) in DMF (60 ml) was stirred under an argon atmosphere and heated to 100° C. for 16 hrs. The mixture was allowed to cool to room temperature, poured into ethyl acetate and washed with 10% HCl. The organic layer was washed with brine, dried, and evaporated to give 10.4 g of 5-pyridin-3-yl-benzofuran-2-carboxylic acid methyl ester. 534 mg the carboxylic ester were then dissolved in 11 ml t-butanol and stirred under nitrogen. Addition of 198 mg NaBH4 followed by 1.75 ml methanol and the reaction was stirred at 55° C. overnight. After cooling, the reaction was poured into brine and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography to give 330 mg of (5-pyridin-3-yl-benzofuran-2-yl)-methanol 61.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([C:12]([OH:14])=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>>[O:26]=[C:20]1[CH:19]([N:18]2[C:12](=[O:14])[C:5]3[C:6](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=3[N+:15]([O-:17])=[O:16])[C:7]2=[O:9])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1[N+](=O)[O-]
Product: COc1ccc2c(c1[N+](=O)[O-])C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 4-methoxy-3-nitro-phthalic acid with 3-aminopiperidine-2,6-dione, in one embodiment, in the presence of a coupling reagent, to form 2-(2,6-dioxopiperidin-3-yl)-5-methoxy-4-nitroisoindoline-1,3-dione;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: C[C@@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (xi), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester, by condensing 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and R-(−)-2-methylpyrrolidine (obtained from Advanced Asymmetrics).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[CH2:13]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][OH:12])=[CH:4][C:5]=1[O:6][CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CCO)ccc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CCO)ccc1OCc1ccccc1
Yield: 80 %

Procedure:
A mixture of homovanillyl alcohol (100 mmol, 17.0 g), benzyl bromide (105 mmol, 18.33 g) and 5M aqueous NaOH (24 mL) in ethanol (200 mL) was refluxed for 6 h. The organic solvent was evaporated in vacuo. The residue was partitioned between brine (200 mL) and diethyl ether (200 mL). The aqueous layer was separated from the organic layer and extracted again with ether. The combined organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Purification by dry-column chromatography with mixtures of ethyl acetate-hexanes (1:4, 1:3, v/v) yielded 20.66 g (80% yield) of (DC-61) as pale yellow oil. Rf 0.25 (EtOAc-hexanes, 1:1, v/v); 1H-NMR (300 MHz, CDCl3) δ 7.44-7.25 (m, 5H, Ar), 6.84-6.67 (m, 3H, Ar), 5.12 (s, 2H, PhCH2O), 3.88 (s, 3H, CH3O), 3.81 (t, 2H, CH2CH2OH), 2.79 (t, 2H, CH2CH2OH), 1.54 (s, 1H, OH); 13C-NMR (75 MHz, CDCl3, APT) δ 149.63 (+), 146.75 (+), 137.21 (+), 131.60 (+), 128.43 (−), 127.70 (−), 127.17 (−), 120.84 (−), 114.25 (−), 112.74 (−), 71.07 (+), 63.58 (+), 55.90 (−), 38.67 (+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[O:8][CH2:9][C:10]=2[CH:16]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1CNC1=Nc2ccc(N)cc2CO1
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Yield: 52.6 %

Procedure:
Prepared from N2-(2-methoxy-benzyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 4) (1.26 g, 4.45 mmol) and chloroacetyl chloride (0.39 ml, 4.89 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (842 mg, 42%, HPLC 0.889 min 81%), MS (ISP) m/e=360.3 [(M+H)+] and 362.1 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[N:35][CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc(OC)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 2-methoxypyrimidine-5-boronic acid (10, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (≈1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimetheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound P-0001. MS(ESI)[M+H+]+=487.9.
Reaction SMILES: [C-:1]#[N:2].[K+].S(O[CH2:9][CH2:10][CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)(=O)C>CS(C)=O>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][CH:13]=[C:12]2[CH2:11][CH2:10][CH2:9][C:1]#[N:2])=[CH:17][CH:18]=1
Reactant: [C-]#N
Reactant: COc1ccc2cccc(CCCOS(C)(=O)=O)c2c1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2cccc(CCCC#N)c2c1

Procedure:
In a 100-cm3 flask, the 3-(7-methoxy-1-naphthyl)propyl mesylate obtained in stage D is dissolved in DMSO. KCN is added and the mixture is brought to reflux for 2 h. It is allowed to cool. It is poured into a water/ice mixture. The resulting mixture is extracted with ether. The organic phase is washed with water, dried over CaCl2 and evaporated. The product obtained is recrystallized.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:13]#[C:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540 g, 1.9 mol) in acetic acid (3.7 L) was heated at 55-59° C. The heating was discontinued and the reaction mixture was flushed with nitrogen and treated with a solution of nitric acid (120 mL, 2.9 mol) in acetic acid (200 mL, 3.6 mol) over 30 minutes. The reaction temperature reached 98.9° C. The resulting solution was stirred for 30 minutes at which time the temperature went from 98.9 to 87.5° C. The reaction was cooled to room temperature and treated with crushed ice (3.5 kg) in one portion. The reaction mixture temperature dropped to −12° C. The reaction mixture was treated with water (3.5 kg) and and stirred at room temperature for 1 hour. The product was filtered, rinsed with water (2 L), and dried on the filter under vacuum overnight to give the desired product (450 g, 72%) as a yellow solid. HPLC 92.9% pure @ 220 nm. LCMS for C13H15ClNO5Si (M+H)+: m/z=328.0; Found: 327.9; 1H NMR (300 MHz, DMSO-d6): δ 11.2 (br s, 1 H), 8.00 (s, 1 H), 3.89 (s, 3 H), 0.23 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.Cl[CH2:34][C:35]([NH:37][CH3:38])=[O:36]>>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: CNC(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(-c5ccccc5)nc4c3)c12
Product: CNC(=O)CN1CCC(c2cc(-c3ccc4c(N)n(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 38 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 298 and using 5-(3-amino-2-phenyl-2H-indazol-6-yl)-7-piperidin-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 2-chloro-N-methylacetamide as starting materials, 42.3 mg (38%) of the desired product was isolated. 1H NMR (300 MHz, CD3OD) δ 7.81 to 7.78 (m, 2H), 7.70 to 7.67 (m, 2H), 7.61 (t, 2H), 7.53 to 7.49 (m, 1H), 7.35 (s, 1H), 6.95 (dd, 1H), 6.61 (s, 1H), 3.26 to 3.19 (m, 1H), 3.07 (s, 2H), 2.99 (d, 2H), 2.79 (s, 3H), 2.36 (t, 2H), 2.11 (d, 2H), 1.97 to 1.87 (m, 2H); ES-MS m/z 496.2 [M+H]+, RT (min) 1.25.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[S:19][C:20]=2[CH:21]=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:29][N:30]([CH3:38])[C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)=[O:32].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[Cl-]>ClCCl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[S:19][C:20]=2[CH2:21][N:34]2[CH2:35][CH2:36][CH2:37][C@H:33]2[C:31]([N:30]([CH3:38])[CH3:29])=[O:32])=[CH:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C=O)s1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(CN2CCC[C@H]2C(=O)N(C)C)s1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained in Step 2 (200 mg) in dichloromethane (6 mL) were added (2S)-2-(N,N-dimethylaminocarbonyl)pyrrolidine hydrochloride and diisopropylethylamine (0.27 ml) at 5° C. The mixture was stirred at 5° C. for 10 min. Then sodium triacetoxyborohydride (327 mg) was added, and the mixture was stirred for 3 hrs. aq. NH4Cl was added, and the mixture was extracted with dichloromethane. The organic layer was dried over MgSO4. The layer was concentrated under reduced pressure. The resulting crude mixture was purified by silica gel column chlomatography with mixed solvent (dichloromethane/methanol=15/1) as an eluent to give tert-butyl(4-{2-[2-(acetylamino)-5-({(2S)-2-[(N,N-dimethylamino)carbonyl]-1-pyrrolidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate as a pale yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:18][C@@H:17]4[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][C@@H:16]4[CH2:15]3)=[CH:10][CH:9]=2)=[C:4]([OH:29])[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41](C(OC(C)(C)C)=O)[CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CC(C1C=C(C(C)C)C(C2C(OC)=CC(Cl)=C(OC)C=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.[Pd+2].O>[CH2:15]1[C@@H:16]2[CH2:21][NH:20][CH2:19][C@@H:17]2[CH2:18][N:14]1[C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)=[CH:3][C:4]=2[OH:29])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(-c4ccc(Cl)cc4O)nn3)C[C@@H]2C1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: COc1cc(Cl)c(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a 10 mL microwave vial, was added (3aR,6aS)-tert-butyl 5-(6-(4-chloro-2-hydroxyphenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.182 g, 0.437 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.385 g, 1.310 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (0.035 g, 0.044 mmol) and Cs2CO3 (0.427 g, 1.310 mmol), followed by adding 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was evacuated and filled with N2 twice then heated at 90° C. overnight. The reaction mixture was filtered through celite and washed with DMSO and MeOH. The filtrate was acidified with 1N HCl and stirred at RT for 3 hour, then extracted with DCM. The aqueous layer was basified with 2M NH2 in MeOH and a brownish precipitate formed, which was filtered and washed with DMSO to afford a grey solid 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (82 mg, 0.224 mmol, 51.2% yield). MS (M+1)=349.1. The DMSO wash solution was concentrated to afford a DMSO solution of desired (3aR,6aS)-tert-butyl 5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (75 mg, 0.167 mmol, 38% yield), MS (M+1)=449.1, which was used directly in the next step.