Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH3:28])=[CH:5][CH:4]=1)=O.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:37]=[C:32]1[NH:33][C:34](=[O:36])/[C:35](=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]4)[C:9]=3[CH3:28])=[CH:29][CH:30]=2)/[S:31]1
Reactant: Cc1c(Oc2ccc(C=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1c(Oc2ccc(/C=C3\SC(=O)NC3=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Yield: 66.3 %

Procedure:
To a solution of tert-butyl 4-((6-(4-formylphenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (950 mg, 0.002298 mole), thiazolidine-2,4-dione (241 mg, 0.00206 mole) and benzoic acid (0.0364 mg, 0.000298 mole) in toluene (30 ml), piperidine (0.033 ml, 0.00344 mole) was added and reaction mixture was refluxed for 7 hours using Dean-Stark apparatus. Then reaction mixture was cooled to 30° C. and solid product was filtered, washed with ice cold toluene and dried to yield 700 mg white solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1[S:54](Cl)(=[O:56])=[O:55]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH:40][S:54]([C:45]2[CH:46]=[CH:47][C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:44]=2)(=[O:56])=[O:55])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of compound B (28.0 g, 46.2 mmol) in THF (250 mL) was added aqueous 1N NaOH (171 mL). The reaction mixture was cooled to ˜5° C., a solution of 2-naphthalene sulfonylchloride (26.19 g, 115.6 mmol) in THF (125 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 10 min, with stirring continued at room temperature for 2 h. The reaction mixture was diluted with EtOAc (1 L), washed with aqueous 1N NaOH (1 L), water (1 L) and brine (1 L). The organic layer was separated, dried over Na2SO4 and removal of the solvent in vacuo to afford compound C (36.6 g, 46.2 mmol). LC-MS [M+H] 785.5 (C38H52N6O8S2+H, calc: 785.9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O-])=[O:8].[Na+].C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH2:20])=[O:8]
Reactant: O=C([O-])c1cc(Br)cnc1Cl
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cnc1Cl
Temperature: 23 °C
Reaction time: 1 h
Yield: 427.3 %

Procedure:
Sodium 5-bromo-2-chloronicotinate (229 mg, 0.798 mmol) was suspended in CH2Cl2 (7.9 mL). Oxalyl chloride (0.084 ml, 0.957 mmol) was added followed by DMF (0.002 mL, 0.080 mmol) and the reaction mixture was stirred at 23° C. for 1 h. The solvent was removed by evaporation and the intermediate residue was dried under vacuum for 90 minutes. The crude acid chloride was suspended in CH3CN (7.9 mL) and NH3 (7M in MeOH, 0.125 mL, 0.877 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed by evaporation and the residue was partitioned between EtOAc (20 mL) and H2O (20 mL). The EtOAc layer was removed and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated. The resulting solid was triturated with cold CH2Cl2 to provide the desired product as a tan powder (80.5 mg, 43%). 1H NMR (CDCl3) δ 6.08 (s, 1H), 6.66 (s, 1H), 8.36 (d, 1H, J=2.54 Hz), 8.54 (d, 1H, J=2.54 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C@:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CN1C(=O)[C@]2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) and eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether (1:1). (7S)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.13 g, 81%) was the second enantiomer to elute and was isolated as a crystalline colorless solid: mp 226-227° C. (acetonitrile/tert-butylmethylether); 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7 Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[O:29][C:28]([Si](C(C)C)(C(C)C)C(C)C)=[N:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc2c(Br)cc(F)cn12
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: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(F)cn12
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 20 %

Procedure:
A mixture of ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (1.0 g), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (1.2 g), tetrakis(triphenylphosphine)palladium(0) (403 mg) and potassium carbonate (963 mg) in DME/water (15/4 mL) was stirred with microwave irradiation at 120° C. for 40 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (15 mL), and 1N hydrochloric acid (4 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (188 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[NH3:12]>C(O)C>[NH2:12][C:8]1[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: N#Cc1c(F)cc(Br)cc1F
Solvent: CCO
Product: N#Cc1c(N)cc(Br)cc1F
Temperature: 25 °C

Procedure:
5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile in 200 ml of a solution of NH3 in ethanol and heated in a pressure vessel to 90° C. for 20 h. After cooling to RT the solvent is evaporated and the residue taken up in water/DCM. The organic phase is separated, dried and evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3ccccc3)c2)C(=O)O1
Yield: 20.8 %

Procedure:
To a solution of 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in THF (2 mL) was added a solution of NaHCO3 (31 mg, 0.29 mmol) in H2O (2 mL) followed by Pd(PPh3)Cl2 (9 mg, 0.01 mmol). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography, followed by preparative HPLC to afford 3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1H NMR: (400 MHz, CDCl3): δ 1.71 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 7.08 (m, 1H), 7.30 (m, 3H), 7.7.32-7.42 (m, 8H), 7.46 (m, 2H). LC-MS Method 3, tR=1.362 min, m/z=344. 1H NMR (CDCl3) 1.75 (s, 3H), 2.32-2.43 (m, 1H), 2.50 (m, 1H), 3.20 (m, 1H), 3.52 (m, 1H), 7.10 (d, 1H), 7.25-7.45 (m, 11H), 7.50 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(Cl)cc1)C2

Procedure:
A mixture of 3-(4-chlorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane (8.06 g, 30.12 mmol), 2,2,2-trichloroethyl chloroformate (4.56 mL, 33.13 mmol), and potassium carbonate (4.58 g, 33.13 mmol) in benzene (150 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3×4 inches) with elution proceeding as follows: hexane (350 mL), nil; 10% ethyl acetate/hexane (500 mL), discarded forerun; 10% ethyl acetate/hexane (500 mL), 20% ethyl acetate/hexane (500 mL), and 30% ethyl acetate/hexane (250 mL), 9.26 g (72%) of 3-(4-chlorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane as a yellow solid which had: mp 70-71.5° C.; NMR δ 7.33 (long range coupled d, J=8.5 Hz, 2 H), 7.26 (long range coupled 6, J=8.5 Hz, 2 H), 4.73 (ABq, Δv1-3 =58 Hz, J=12 Hz, 2 H), 4.43-4.30 (m, 2 H), 3.40 (septet, J=6 Hz, 1 H), 2.10-1.56 (m, 8 H).
Reaction SMILES: C1(OP(O)OC2C=CC=CC=2)C=CC=CC=1.[CH:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=1.[NH:27](C(OCC1C=CC=CC=1)=O)[CH2:28][C:29](O)=[O:30]>N1C=CC=CC=1>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([O:26][C:29](=[O:30])[CH2:28][NH2:27])=[CH:18][CH:17]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: OP(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
A mixture of 2.93 g. (0.0125 mole) of phosphorous diphenyl ester and 3.37 g. (0.0125 mole) of mercuric chloride was refluxed for 1 hour in 20 ml. of pyridine. Thereafter, 1.74 g. (0.0125 mole) of p-nitrophenol and 10 ml. of pyridine were added, and the mixture was further reacted for 1 hour. To the reaction mixture were added 2.61 g. (0.0125 mole) of Z-Gly.OH having an amino group protected with Z and 10 ml. of pyridine, and the mixture was reacted under reflux for 1 hour. After completion of the reaction, pyridine was removed by distillation under reduced pressure, and the residue was extracted with 100 ml. of ethyl acetate. The ethyl acetate layer was washed with 2 N--HCl, a saturated aqueous NaHCO3 solution and water in this order and then dried over anhydroush Na2SO4, and thereafter ethyl acetate was removed by distillation under reduced pressure. The resulting residue was allowed to stand to form a solid, which was then recrystallized from ethanol to obtain N-benzyloxycarbony glycine p-nitrophenyl ester (hereinafter represented by ##STR9## in a yield of 75% (3.0 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.FC(F)(F)S(O[Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])(=O)=O.CC1C=CC=C(C)N=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxybiphenyl-2,4-diol (10.6 g) in toluene (80 mL) were added triisopropylsilyl trifluoromethanesulfonate (18 mL) and 2,6-dimethylpyridine (8.0 mL) at −15° C., and the mixture was stirred for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.5 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[C:10]([I:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:18]([C:4]2[C:5]3[C:10]([I:11])=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:20])[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(I)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (17 g, 42 mmol) in a mixture of tetrahydrofuran (250 mL) and N,N-dimethylacetamide (40 mL) were added 1-boc-piperazine (8.6 g, 46 mmol), 1-hydroxybenzotriazole (0.56 g, 4.2 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (8.03 g, 42 mmol). The reaction mixture was stirred at room temperature for 20 hours and then the THF was evaporated under vacuum. An aqueous solution of bicarbonate (200 mL) was then added and the mixture stirred for 1 hour. The precipitate was filtered, washed with water, and then dried to afford the title compound as a yellow solid (24 g, 100%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Cc1cccc(N)c1Cl
Solvent: CS(C)=O
Product: Cc1cccc(Nc2c(Nc3ccccc3O)c(=O)c2=O)c1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-chloro-3-methylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 329 (M+).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[Br-].CCO[CH2:16][CH3:17]>C1COCC1.[Cu]I>[C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([C:10]([OH:9])=[O:11])[CH2:2]1)(=[O:8])[C:17]1[CH:16]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: O=C1OC(=O)C2CCCC1C2
Reactant: CCOCC
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A stirred solution of 1,3-cyclohexanedicarboxylic anhydride (67 mg, 0.43 mmol) (prepared from 1,3-cyclohexanedicarboxylic acid as described in patent application US 2004010005) and copper(I) iodide (8 mg, 0.04 mmol) in dry THF (3 mL) was cooled to −70° C. and phenmagnesium bromide in THF (0.4 mL of 1 M, 0.40 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h and allowed to warm slowly to rt. After 2 h the mixture was poured into ether (75 mL) and extracted with satd aqueous NaHCO3 (2×30 mL). The combined aqueous extracts were acidified to pH 1 by cautious addition of concentrated HCl and back extracted with ether (2×50 mL). These ether extracts were combined, dried over Na2SO4 and evaporated under reduced pressure to afford cis-3-benzoylcyclohexane-1-carboxylic acid (78 mg, 77%) as an oil which solidified on standing. 1H NMR (CDCl3) δ 1.3-2.8 (9H), 3.32 (m, 1H), 7.45 (m, 2H), 7.55 (1=m, 1H), 7.92 (m, 2H). MS ESI+ve m/z 233 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2([F:35])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2-c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
A solution of EXAMPLE 263E (2.0 g) and diethylaminosulfur trifluoride (1.39 mL) in dichloromethane (40 mL) was stirred for 24 hours. The reaction was quenched with water (30 mL), extracted twice with ether, and the combined extracts were washed with water, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1([NH2:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28][NH:12][C:3]2([CH2:1][CH3:2])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: CCC1(N)Cc2ccccc2C1
Solvent: CC#N
Product: CCC1(NCC(=O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2C1

Procedure:
A mixture of 2-ethyl-indan-2-ylamine and N-(2-benzyloxy-5-bromoacetyl-phenyl)-methanesulfonamide is stirred in acetonitrile at room temperature for 20 hours. The product is isolated by filtration. ES+ MS m/e 479 (MH+)
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[N:11]1([CH2:17][C:18]#[C:19][C:20](=O)[CH3:21])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl>CCO>[CH3:21][C:20]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[C:18]([CH2:17][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:19]=1
Reactant: CC(=O)C#CCN1CCOCC1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol), 1-methylpiperazine (0.65 g, 6.40 mmol), and ethyldiisopropylamine (2.8 mL, 16.22 mmol) in ethanol (13 mL) was stirred at −10° C. for 2 h and then at r.t. overnight. The mixture was partitioned between H2O/brine (3:1; 100 mL) and chloroform (3×70 mL). The combined organic phases were washed once with brine (50 mL) an dried over MgSO4. Removal of solvent yielded a pale-beige solid, which was washed with ethyl acetate/ultrasound to give the desired product as a colourless powder, which was further washed with Et2O. Additional product was obtained upon fractional crystallization of the washing solution. A total of 0.741 g (3.48 mmol, 54%) of 2-chloro-4-(4-methylpiperazin1-yl)pyrimidine was obtained. LC/ESI-MS: m/z=213 [M(35Cl)+H]+; Rt=0.5 min.