Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH:10]1[N:18]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:7])=[O:6])([CH3:4])[CH3:3].Cl>C1COCC1>[CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH2:17][C:12](=[O:13])[CH2:11][CH:10]1[N:18]([C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:6])=[O:7])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC(=O)CC1NS(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl N-[8-(2-methylpropane-2-sulfonamido)-1,4-dioxaspiro[4.4]nonan-7-yl]-N-[(1R)-1-phenylethyl]carbamate (331 mg, 0.64 mmol) in THF (1.1 ml) was added HCl (aq, 2M, 1.65 ml, 3.30 mmol) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29](OCC)=[O:30])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[O:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1>CCOCC>[C:25]([C:16]1[O:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[C:15]=1[CH2:29][OH:30])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1c(C(C)(C)C)oc(-c2ccccc2)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1oc(-c2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
Under a dry nitrogen atmosphere, to a slurry of 1.15 g (30.4 mmol) of lithium aluminum hydride in 50 ml of dry ether at about 0° was added 5.56 g (15.2 mmol) of 4-(4-fluorophenyl)-2-tert.-butyl-5-phenyl-3-furyl-carboxylic acid, ethyl ester in 25 ml of dry ether. The mixture was heated at reflux for one-half hour.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][CH:22]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 6-chloronicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 mg, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. The starting material was gone but no right mass was observed. The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give colorless oil (2.52 g, yield 89%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1[O:12]C(C)(C)O[C:8](=[O:9])[CH:7]=1>>[SH:1][CH2:2][CH2:3][O:4][C:8](=[O:9])[CH2:7][C:6]([CH3:5])=[O:12]
Reactant: OCCS
Reactant: CC1=CC(=O)OC(C)(C)O1
Product: CC(=O)CC(=O)OCCS
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a 300 ml. round bottom flask fitted with a thermometer, mechanical stirrer, Dean Stark trap and reflux condenser was placed 25.0g.(0.32 mole) of 2-mercaptoethanol. This was stirred and heated to 130° C.; 45.4g. (0.32 mole) of 2,2,6-trimethyl-1,3-dioxen-4-one (TKD) was added dropwise at a uniform rate over the period of one hour. Heating was continued for 1/2 hour; acetone distillate was collected in the Dean Stark trap. After distillate collection was completed, the mixture was distilled under vacuum and the portion boiling at 110°-115° C.(at 5 mm. Hg.) was collected to give a colorless liquid of mercaptoethylacetoacetate. The yield was about 90% based on starting material. The product was identified by NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:29])=[O:28]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Product: COc1cc(C(=O)/C=C/c2cn(S(C)(=O)=O)c3ccccc23)cc(OC)c1OC
Yield: 80.2 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and methanesulfonyl chloride (0.86 g) except that the reaction product was purified by silica gel column chromatography and that the obtained crude crystals were recrystallized from ethanol, to give Compound 9 (1.67 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[Br:15]Br>C(Cl)Cl.[Fe]>[Br:15][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1
Reactant: CC1Cc2cc(S(C)(=O)=O)ccc2O1
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CC1Cc2cc(S(C)(=O)=O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
To a mixture of the title compound from Step 1 (300 mg, 1.42 mmol) in DCM (10 mL) was added Fe (159 mg, 2.84 mmol) and Br2 (454 mg, 2.84 mmol) in one portion under N2. The mixture was stirred at room temperature for 6 h. The reaction mixture was washed with saturated aqueous Na2SO3 (200 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA=3/1) to give the title compound (300 mg, 73%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 5.20-5.14 (m, 1H), 3.53-3.47 (m, 1H), 3.01-2.95 (m, 1H), 3.04 (s, 3H), 1.56 (d, J=6.4 Hz, 3H). LCMS: 291.0 (M+1)+; 293.0.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:22])=[C:6]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[NH:7][C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[OH-].[Na+].S(OC)(O[CH3:29])(=O)=O>CC(C)=O>[C:1]([C:4]1[C:5]([I:22])=[C:6]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[N:7]([CH3:29])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: Nc1c(I)c(NC(=O)CCCC(=O)O)c(I)c(C(=O)O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C(=O)CCCC(=O)O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reaction time: 3 h

Procedure:
To a solution of 26.0 g. of 3'-carboxy-5'-amino-2',4',6'-triiodoglutaranilic acid (Example 21, part d) in 100 ml. of 10% aqueous sodium hydroxide cooled in an ice bath was added 8 ml. of dimethyl sulfate in acetone. After three hours of stirring an additional 15 ml. of 10% sodium hydroxide and 2 ml. of dimethyl sulfate were added and the mixture stirred three hours longer. The reaction mixture was acidified, and the product collected and recrystallized from acetic acid to give 3'-carboxy-5'-amino-2',4',6'-triiodo-N-methylglutaranilic acid, pale gray crystals, m.p. 218°-220° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][O:31]C3CCCCO3)[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][OH:31])[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(C(=O)N2CCC(CCCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 11.5 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidine (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO.[Pd]>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A solution of 4-benzyl 1-tert-butyl 2-methylpiperazine-1,4-dicarboxylate (4.8 g, 14.4 mmol) in methanol (25 mL) was added 480 mg of 10% Pd/C and stirred at room temperature under hydrogen overnight. Filtered and concentrated to give the title product (2.8 g, yield 97%) as colorless oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.21 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 2.64-2.70 (m, 1H), 2.74-2.78 (m, 1H), 2.88-3.01 (m, 3H), 3.78 (d, J=12.4 Hz, 1H), 4.16 (m, 1H); LC-MS (ESI) m/z: 201 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[O:19][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)CCc1c(O)cccc1OCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cccc(OCCCCCO)c1CCC(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.3 %

Procedure:
A mixture of the 2-hydroxy-6-[(5-hydroxypentyl)oxy]benzenepropanoic acid methyl ester from the preceding example (1.4 g; 4.96 mmol), 1.13 g (5.4 mmol) of ethyl 5-bromovalerate, 1.57 g (11.4 mmol) of anhydrous, granular potassium carbonate, and 12 mL of dimethyl sulfoxide was stirred at room temperature for 6 hr. The resulting slurry was filtered with suction and the solids were washed well with ethyl acetate. The filtrate and washed were combined and treated with water. Work-up with ether in the usual manner gave an oily product which was purified by chromatography on silica gel. Elution with 1:3 hexane-ether afforded 1.0 g (49.3%) of 6-[(5-hydroxypentyl)oxy]-2-(5-ethoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.[Li]C(CC)C.[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].IC.[NH4+].[Cl-]>C1COCC1>[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[C:35]([CH3:1])[CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1c(Br)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Br)c(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (699 mg, 4.9 mmol, 2.0 eq) in THF (7.5 mL) at −50° C. was added sec-BuLi (3.8 mL, 1.3 M, 4.9 mmol, 2.0 eq) dropwise. The reaction was stirred for 20 min at −15° C. to −10° C., then cooled to −65° C. and a solution of tert-butyl N-tert-butoxycarbonyl-N-(3-bromo-6-fluoro-2-methylphenyl)carbamate (See example 13) (1 g, 2.47 mmol, 1.0 eq) in THF (7.5 mL) added dropwise. The reaction was stirred a further 2 h at −65° C. Iodomethane (1.05 g, 7.41 mmol, 3.0 eq) was added in one portion and the reaction allowed to warm to −10° C. over 30 min. The reaction was then poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 30:1) to give the title compound as a white solid (880 mg, 85%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9].[N-:14]=[N+:15]=[N-:16].[Na+]>O>[N:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(O)c(CCl)c1
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCc1cc(CC(=O)O)ccc1O

Procedure:
A solution of 3-chloromethyl-4-hydroxybenzeneacetic acid (0.1 mole) and sodium azide (0.1 mole) in 250 ml of water is stirred at room temperature for about 16 hours. Removal of the solvent gives the title compound combined with sodium chloride.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10]1.[CH3:29][Sn:30](Cl)([CH3:32])[CH3:31]>C1COCC1>[CH3:29][Sn:30]([CH3:32])([CH3:31])[C:10]1[N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2
Reactant: C[Sn](C)(C)Cl
Reactant: COC(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc([Sn](C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Temperature: 0 °C

Procedure:
A solution of lithium diisopropylamide (0.50 M, 72.6 mL, 36.2 mmol, 1.6 equiv) was added via cannula to a solution of 1-tert-butyl 6-methyl 1H-indole-1,6-dicarboxylate (1-5, 6.23 g, 22.6 mmol) in THF (100 mL) at −78° C. The resulting mixture was stirred for 2 hours at −78° C. before a solution of trimethyltin chloride in THF (2.3 M, 19.7 ml, 45.3 mmol, 2.00 equiv) was added. The resulting solution was warmed to 0° C. for 15 minutes, then partitioned between EtOAc (2×150 mL) and aqueous half-saturated NH4Cl solution (200 mL). The combined organics layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 20% EtOAc in hexanes) to afford 1-tert-butyl 6-methyl 2-(trimethylstannyl)-1H-indole-1,6-dicarboxylate (1-6) as an orange oil. 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.88 (dd, 1H, J=8.2, 1.8 Hz), 7.53 (d, 1H, J=8.2 Hz), 6.77 (br s, 1H), 3.95 (s, 3H), 1.74 (s, 9H), 0.33 (s, 9H).
Reaction SMILES: [Li]C(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1.B([O-])([O-])OC(C)(C)C.[Li+].[Li+].CCCC[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].BrC1CCCCCC1.[Cl-].[NH4+]>[Fe](Cl)Cl.CCCCCC.C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCCCCCCCCC
Agent: Cl[Fe]Cl
Agent: BrC1CCCCCC1
Agent: CC(C)(C)OB([O-])[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(C2CCCCCC2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
1.80 M t-BuLi in pentane (0.78 mL, 1.40 mmol) was added at −40° C. to 5.0 mL of a THF solution of 4-methoxyphenylboronic acid pinacol ester (351.2 mg, 1.5 mmol). The reaction mixture was stirred at −40° C. for 30 minutes, and then stirred at 0° C. for 30 minutes. The solvent was removed at 0° C. under reduced pressure. White crystals of the residual lithium t-butyl borate were dissolved in 2.4 mL THF at 0° C. To the resulting solution of lithium t-butyl borate were added undecane (66.2 mg, 0.42 mmol), bromocycloheptane (178.2 mg, 1.01 mmol), a 0.10 M THF solution of magnesium bromide MgBr2 (2.00 mL, 0.20 mmol), and a THF solution (0.60 ml, 0.030 mmol, 3.00 mol %) of an iron chloride.1,2-bis(bis(3,5-trimethylsilylphenyl)phosphino)benzene complex (FeCl2.[3,5-(t-Bu)2]-DPPBz complex). The coupling reaction was performed at 40° C. for 3 hours. The resulting reaction mixture was cooled to 0° C., and 2.0 mL of a saturated aqueous solution of ammonium chloride was subsequently added thereto. The aqueous layer was extracted five times with diethylether. The combined organic extract was filtered using a Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). After thin-layer chromatography (hexane), (4-methoxyphenyl)cycloheptane was obtained as a colorless liquid (0.199 g, yield 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C(O)C>[CH3:21][N:22]([CH3:24])/[CH:23]=[N:11]\[C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:2]=2[CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(/N=C\N(C)C)c1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (2.05 g, 8.34 mmol) in ethanol (9 mL) was added dimethoxy-N,N-dimethylmethanamine (1.18 mL, 8.34 mmol). After heating to 80° C. for 1 hour, the mixture was concentrated under reduced pressure to provide the crude product as dark oil.
Reaction SMILES: [C:1]1([CH2:13][CH2:14][C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[OH2:17]>>[C:1]1([CH2:13][CH2:14][C:15]([NH2:16])=[O:17])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: N#CCCc1cn2c3c(cccc13)CCC2
Reactant: O
Product: NC(=O)CCc1cn2c3c(cccc13)CCC2

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionitrile (300 mg, 1.4 mmol) in polyphosphoric acid (8 ml) was heated to 100° C. for 3 hours. The mixture was then added to water (150 ml) and triturated to give a precipitate. The precipitate was filtered off, washed with water and dried under reduced pressure to give 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionamide as a tan powder (249 mg). 400 MHz 1H NMR (DMSO-d6) δ: 7.31 (s, 2H), 7.06 (s, 1H), 6.9-6.7 (m, 3H), 4.08 (s, 2H), 2.89 (s, 4H), 2.4 (m, 2H), 2.1 (m, 2H); LCMS: 229 [M+H].
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:22][N:23]1[CH2:29][C:28]2[CH:30]=[C:31](/[CH:34]=[CH:35]/[C:36](O)=O)C=N[C:27]=2[NH:26][C:25](=O)[CH2:24]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:26]([CH3:27])[CH2:25][C:24]2[N:23]([CH3:22])[C:29]3[C:35]([CH:36]=2)=[CH:34][CH:31]=[CH:30][CH:28]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCCC1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CN2CCCCC2)c1
Yield: 54 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-(6-amino-5-piperidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (294 mg, 54%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.78-7.68 (m, 1H), 7.49-7.38 (m, 3H), 7.14-6.97 (m, 3H), 6.63 (s, 2H), 6.41-6.18 (m, 1H), 5.02-4.83 (m, 2H), 3.72-3.67 (m, 3H), 3.39-3.34 (m, 3H), 3.09-2.96 (m, 3H), 2.29 (br s, 3H), 1.49-1.40 (m, 6H); MS (ESI) m/e 418 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:26][CH2:25][CH2:24][C:6]3=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[N:3]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Br[C:36]1[C:37]([CH:42]2[O:46][CH2:45][CH2:44][O:43]2)=[N:38][O:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O.C(OCC)(=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>[O:46]1[CH2:45][CH2:44][O:43][CH:42]1[C:37]1[C:36]([C:7]2[CH:8]=[C:9]3[C:4](=[C:5]4[CH2:26][CH2:25][CH2:24][C:6]=24)[N:3]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:2]([CH3:1])([CH3:34])[C:11](=[O:12])[C:10]3([CH3:13])[CH3:14])=[C:40]([CH3:41])[O:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N1c2c(cc(B3OC(C)(C)C(C)(C)O3)c3c2CCC3)C(C)(C)C(=O)C1(C)C
Reactant: Cc1onc(C2OCCO2)c1Br
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: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1onc(C2OCCO2)c1-c1cc2c(c3c1CCC3)N(C(=O)OC(C)(C)C)C(C)(C)C(=O)C2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of tert-butyl 2,2,4,4-tetramethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (1.2 g) obtained in Example 1, 9) in isopropanol (11 ml) were added 4-bromo-3-[1,3]dioxolan-2-yl-5-methylisoxazole (500 mg), 2.0 M aqueous potassium carbonate solution (3.2 ml) and tetrakis(triphenylphosphine)palladium(0) (250 mg), and the mixture was stirred at 80° C. for 16 hr. The reaction solution was diluted with water and ethyl acetate, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane-ethyl acetate=6:1) to give tert-butyl 6-(3-[1,3]dioxolan-2-yl-5-methylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (410 mg, 32%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([C:26](=[O:31])N(OC)C)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([C:26]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=2)=[O:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cn2)C1
Temperature: -80 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
Add dropwise n-BuLi (3.2 mL, 5.1 mmol) to an suspension of 2,5-dibromopyridine (1.0 g, 4.2 mmol) in dry toluene (50 mL) at −80° C. under nitrogen. Allow the mixture to stir at −80° C. for 2 h. Slowly add a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.5 mmol) in dry toluene (10 mL). Allow the reaction mixture to stir for 1 h at −78° C., then warm to −10° C. Quench the mixture with saturated NH4Cl (1 mL) and warm to RT. Separate the organic layer and concentrate. Purify the crude material by flash chromatography, eluting with 10-20% ethylacetate/hexane to give 0.61 g (43%) of the title compound. LC-MS/ES m/z (79Br) 299 [M-tert-Bu+H]+.