Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][C:21]#[N:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]=1)#[N:24]>C1COCC1>[C:23]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]1[CH:20]([C:21]#[N:22])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:24]
Reactant: N#CCCc1ccccc1
Reactant: N#CC1=CCCc2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)C1CCc2ccccc2C1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 3.5 mL (25 mmol) of diisopropylamine in 40 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (9.5 mL of a 2.5M solution in THF, 23.7 mmol) and the resultant solution was stirred at -78° C. for 0.5 h. To the stirred solution was slowly added a solution of 2.75 g (21 mmol) of 3-phenylpropiononitrile in 40 mL of THF. The reaction mixture was stirred for 45 min at -78° C. and then a solution of 3.1 g (20 mmol) of 1-cyano-3,4-dihydronaphthalene (the product of Step 1 of Example 9) in 40 mL of THF was added. The reaction mixture was stirred at -78° C. for 0.5 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5.70 g (quantitative yield) of the title compound as a mixture of three diastereomers; MS DCl--NH3M/Z: 287 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH3:16][C:17]([CH2:21][OH:22])([CH2:19][NH2:20])[CH3:18]>>[CH3:16][C:17]([CH3:18])([CH2:21][OH:22])[CH2:19][N:20]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: CC(C)(CN)CO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(C)(C)CO

Procedure:
204 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride are reacted with 103 g of neopentanolamine for 4 hours at 120° C., and the product is isolated by distillation. 268 g (92.7% of theory) of a yellow oil with a refractive index n25D of 1.5190 and a viscosity of 6.21 Pa.s are obtained at a temperature in the range from 169° to 172° C. at 2.53 Pa.
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34].C(N(CC)CC)C>CN(C=O)C>[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[C:7]([S:8][CH3:9])=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:24])=[CH:20][CH:21]=3)[N:3]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1c(N2CCOCC2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea (120 mg, 0.26 mmol.), 1-methanesulfonyl-piperazine (65 mg, 0.39 mmol, 1.5 eq.), triethylamine (40 mg, 0.39 mmol, 1.5 eq.), and DMF (4.0 ml) was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at 80° C. for 5 hrs and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and NH4Cl(aq), the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified with flash chromatography on silica gel (Hexane/EtOAc 1:1) to give a pale yellow solid of 77.2 mg (50.3%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.C[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1)[O-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: [O-][N+](=Nc1ccccc1)c1ccccc1

Procedure:
The reduction reaction was carried out in the same manner as set forth in Example 6 except for using a mixture of 1.0 mmol of nitrobenzene and 1.0 mmol of o-methyl nitrobenzene instead of using nitrobenzene alone, and using 17 mg (the amount required for swelling of the reactant, i.e., the mixture, in 100%) of Polymer supported reagent-2, and thereby an azoxybenzene derivative of a symmetrical structure and an azoxybenzene derivative of an asymmetrical structure were obtained as a main product, respectively.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:9]2(=[O:22])=[O:21])=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C([SiH](CC)CC)C.O>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[O:22]=[S:9]1(=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:11][C:12](=[O:13])[NH:8]1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccncc3)S2(=O)=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2ccncc2)S(=O)(=O)N1
Temperature: 80 °C

Procedure:
The title C compound, 2-(4-methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one (73 mg, 0.21 mmol) in a mixture of TFA (4.75 mL) and triethylsilane (0.25 mL) in a 20 mL scintillation vial with polyseal cap is heated in an 80° C. oil bath for 16 h. The reaction solvents are removed by overnight evaporation on a Savant SpeedVac system. This gives a white solid which is dissolved in water, filtered through a 0.45 micron PTFE filter disc, and water is removed by lyophilization to give 1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one TFA salt as an amorphous white solid: [M+1]+=228.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].IC.[CH3:39]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH3:39])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 3.98 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D7) (80 mg) in dry DMF (2 mL) at RT. After stirring for 5 min, iodomethane (0.016 mL) was added. The resulting solution was stirred at RT for 45 min. EtOAc (50 mL) was added and the resulting solution was washed with aqueous HCl (20 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D8) (85 mg) as a pale yellow oil. MS (ES): C27H30ClN3O4 requires 495; found 496.0 (M+H+).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16](/[CH:20]=[CH:21]/[C:22](OCC)=[O:23])=[C:15]([NH:27][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[N:14]=1>O>[NH2:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][C:22](=[O:23])[N:27]([C@@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)[C:15]=2[N:14]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@@H]1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(N)nc2c1ccc(=O)n2[C@@H]1CCOC1
Temperature: 170 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
To a flask were added DBU (20 mL) and (R,E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl)acrylate (3.9 g, 13.4 mmol). The reaction mixture was stirred at 170° C. for 24 h under nitrogen. The mixture was allowed to cool to room temperature and was diluted with water. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, separated and dried with MgSO4. The mixture was purified by chromatography to give (R)-2-amino-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 48% yield); MS (EI) for C12H14N4O2: 247.1 (MH+).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[S:10][CH:11]=[C:12]([Br:14])[CH:13]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16]>C1COCC1.[Cu]I>[Br:14][C:12]1[CH:13]=[C:9]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])[S:10][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1csc(Br)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 0.37 g (1.94 mmol) CuI, 2.24 g (1.94 mmol) tetrakis-triphenylphosphane-palladium and 16.2 mL triethylamine are added to a solution of 10.0 g (38.85 mmol) 2,4-dibromothiophene in 300 mL THF, the reaction mixture is cooled to −78° C. and then at this temperature a solution of 5.6 mL (38.85 mmol)) ethynyl-trimethyl-silane in 250 mL THF is slowly added dropwise. After the addition has ended the mixture is allowed to heat up slowly to RT and stirred overnight. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with DCM and the combined organic phases are dried over MgSO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, filtered to remove insoluble ingredients and the solvent is evaporated down. The residue is purified by chromatography (silica gel, PE).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=3)[C:20]=1[S:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)[C:20]=1[S:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
2M aqueous sodium hydroxide (1.671 mL, 3.34 mmol) was added in one portion to methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoate (Intermediate#84) (330 mg, 0.67 mmol) in methanol (10 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with water (50 mL), and washed with ether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and the combined extracts washed sequentially with water (2×20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid (321 mg, 100%).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=1)[NH2:3]
Reactant: NN
Reactant: Clc1cc(N2CCCOCC2)ncn1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCCOCC2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 8.8 ml (9.0 g, 180.2 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 3.9 g (18.0 mmol) of 4-(6-chloropyrimidin-4-yl)-1,4-oxazepane in 25 ml of ethanol. After 16 h of stirring at 80° C., the reaction solution is concentrated under reduced pressure. The residue is triturated with cold ethanol, the precipitated solid is filtered off and the filter residue is washed with 25 ml of diethyl ether. The product is dried under reduced pressure. Yield: 1.4 g (36% of theory)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Br:1][C:2]1[C:3]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: Clc1ncc(Br)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 5-bromo-2,4-dichloropyrimidine and 1H-indole. m/z 309.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)=[N:3]1.[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:24][C:5]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Br)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 21 h
Yield: 77.5 %

Procedure:
4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-dinitrobenzene (17.7 g, 54.9 mmol) was dissolved in a mixture of glacial acetic acid (90 cm3) and acetic anhydride (10 cm3) and the solution was warmed to 80° C. N-Bromosuccinimide (14.7 g, 82.4 mmol) was added, and the mixture was stirred at 80° C. for 21 hours, and then cooled to room temperature. The precipitate was collected, washed with water, and then taken up in ethyl acetate (500 cm3). The solution was washed with saturated sodium bicarbonate solution (2×300 cm3), dried (MgSO4), filtered and evaporated under reduced pressure to give 4-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-dinitrobenzene (17.5 g) as a colourless solid m.p. 152°-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH2:26]([N:22]1[CH2:23][C:24](=[O:25])[N:9]2[C@H:10]([CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][CH:4]=2)[C:21]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NS(C)(=O)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O

Procedure:
To a solution of Example 98 (0.2 g) in THF (5 mL) was added triethylamine (228 μL) and methanesulfonyl chloride (126 μL) and the solution was heated at reflux for 6 hours. After evaporation of THF, the residue was taken up in CH2Cl2, washed with water and dried over Na2SO4. After evaporation of CH2Cl2, the residue was purified by radial chromatography eluting with CH2Cl2 /MeOH (95/5) to give the title compound as a brown powder (30 mg) m.p.:188° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: OB(O)c1ccccc1Cl
Product: Nc1c(Cl)cc(-c2ccccc2Cl)cc1Cl
Yield: 69.9 %

Procedure:
The title compound (0.4 g) was prepared from 4-bromo-2,6-dichloroaniline (0.5 g, 2.1 mmol) and 2-chlorophenylboronic acid (0.421 g, 2.7 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.55-7.50 (m, 1H), 7.40-7.32 (m, 3H), 7.29 (s, 2H), 5.72 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CO[CH:31](OC)[N:32]([CH3:34])[CH3:33]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17](/[N:21]=[CH:31]/[N:32]([CH3:34])[CH3:33])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC1=N[C@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Product: CN(C)/C=N/C1=N[C@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 100 %

Procedure:
In a 25-mL flask, the (R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.350 g, 0.793 mmol) was suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (5.29 mL, 39.7 mmol). The reaction mixture was heated to 100° C. for 1 h. The reaction was concentrated, and the residue was taken up in 5% MeOH/DCM (60 mL) and the organic phase was extracted with dilute brine (2×8 mL), then was dried over sodium sulfate and concentrated. The residue was purified by chromatography (3.5% MeOH/DCM) to afford (R,E)-N′-(3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (394 mg, 0.793 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].C(N(CC)CC)C>O1CCCC1.[Cu](I)I>[CH:15]1([C:13]#[C:14][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with bis(triphenylphosphine)palladium bischloride (151 mg, 0.216 mmol) and copper iodide (82 mg, 0.431 mmol), and the flask was degassed with nitrogen. Tetrahydrofuran (40 mL) was added through a septum, and nitrogen was bubbled through the mixture for 30 minutes. To this was added dropwise a nitrogen-degassed solution of 4-nitrobenzoyl chloride (2g, 10 8 mmol), ethynylcyclopropane (784 mg, 11.9 mmol) and triethylamine (1.31 g, 12.9 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:33])[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:32][O:31][C:27]1[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=[C:25]([CH3:33])[C:26]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CCOC(=O)CCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under cooling with ice, aluminum chloride (4.08 parts) was added in small portions to a mixed solution of ethyl 9-chloroformylnonanoate (3.52 parts) and 3,4,5-trimethoxytoluene(formula VII wherein R32H3CO, X=H, Y=H3CO) (2.21 parts) in nitrobenzene (20 volume parts). The mixture was stirred at 0° C. for 16 hours and, then, at room temperature for 1.5 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. By a procedure similar to that described in Example 1 (2), the extract was hydrolyzed and subjected to column chromatography on silicic acid. The fraction eluted by benzenediethyl ether (9:1) yielded 9-(2', 3', 4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OCH3, n=8, in the free form) (1.82 part). From the fraction eluted by benzene-diethyl ether (5.7:1), there was obtained 9-(2'-hydroxy-3', 4' -dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 , R=H3CO, X=H, Y=OH, n=8, in the free form) (0.67 part) as colorless needles melting at 75°-76.5° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:40])([F:22])[F:39])=[CH:25][CH:26]=3)[O:31][C:32]=2[CH3:38])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 50 was prepared from 185 mg of N-(Boc)-L-Tyrosine methyl ester and 170 mg of Intermediate 13 to yield 130 mg (48% overall yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ8.16 (d, 2H, J=8.2), 7.92 (d, 2H, J=8.4), 7.21 (d, 2H, J=8.5), 6.93 (d, 2H, J=8.5), 4.25 (t, 2H, J=6.5), 3.1 (dd, 1H, J=14.4, 4.8), 3.0 (t, 2H, J=6.5), 2.76 (dd, 1H, J=14.4, 7.9), 2.46 (s, 3H); low resolution MS (ES+)m/e 434.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C@H:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:19][C@H:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH3:21])=[O:9])[C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1cncc(Cl)c1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cncc(Cl)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-3-yl)oxy]nicotinic acid (step 1) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 44): 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.7 Hz), 8.55–8.54 (1H, m), 8.42–8.41 (1H, m), 8.13 (1H, d, J=2.7 Hz), 7.99–7.96 (2H, m), 7.80–7.82 (1H, m), 7.58 (1H, t, J=2.3 Hz), 7.42–7.39 (2H, m), 5.42–5.31 (1H, m), 1.62–1.58 (12H, m); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.