Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:25])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][C:14](=[O:15])[N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:26])=[O:2])[C:11]2=[O:25])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc(N2C(=O)CN(c3ccc(C(C)C)cc3)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1ccc(N2CC(=O)N(c3cccc(C(=O)O)c3)C2=O)cc1

Procedure:
A solution of methyl-3-[3-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-1-yl]-benzoate (0.69 g, 1.96 mmol) and lithium iodide (2.62 g) in pyridine (10 mL) was heated to reflux for 40 h. The solution was cooled and evaporated, and the residue was partitioned between ethyl acetate and 1 N aqueous HCl. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and evaporated. The residual material was separated by column chromatography (silica gel, 50:50 ethyl acetate-hexane then ethyl acetate) to afford the product, 3-[3-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-1-yl]-benzoic acid, as a powder (0.33 g, 0.98 mmol, 50%). m.p. 224-226° C. TLC Rf (20:80 CH3OH—CH2Cl2) 0.3. 1H NMR (CDCl3, 300 MHz): δ 8.24 (1H, t, J=2 Hz), 8.14 (1H, dt, J=8, 2 Hz), 7.73 (1H, dt, J=8, 2, 1 Hz), 7.61 (1H, t, J=7 Hz), 7.51 (2H, d, J=8 Hz), 7.28 (2H, d, J=8 Hz), 4.50 (2H, s), 2.92 (1H, m, J=7 Hz), 1.25 (6H, d, J=7 Hz). Mass spectrum (ES+): m/z 340 (21), 339 (100). Elemental analysis: calculated for C19H18N2O4.0.149H2O C, 66.91, H, 5.41, N, 8.21; observed C, 66.82; H, 5.17; N, 8.10.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O-])=[O:10])=[C:7]([CH2:12][CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.B.O>O1CCCC1>[F:23][CH:2]([F:1])[C:3]1[N:4]=[C:5]([C:19]([F:22])([F:20])[F:21])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([CH2:12][CH3:13])[C:8]=1[CH2:9][OH:10]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)[O-])c1CC
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(CO)c1CC
Temperature: 10 °C
Reaction time: 160 h
Yield: 84.9 %

Procedure:
To a dry 500 ml four-necked flask is charged 30.6 g (0.09 mole) of the product of Example 28 and 40 ml of tetrahydrofuran under nitrogen. The reaction mixture is cooled to 10° C. with an ice-water bath. To the above solution is added via a syringe 180 ml (0.18 mole) of 1M borane in tetrahydrofuran. The reaction mixture is stirred for 160 hours and poured into water. The organics are extracted into 300 ml of ether and the ether extract washed with 200 ml of saturated sodium bicarbonate, dried (MgSO4), and concentrated. The residue is crystallized from petroleum ether to give 25 g (84.9%) of the desired product, m.p. 59.5°-60.5° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[O:34]1[C:39]([C:40](=[N:44][O:45][CH2:46][CH2:47][CH3:48])[C:41](O)=[O:42])=[CH:38][S:37][CH2:36][CH2:35]1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[O:34]1[C:39]([C:40](=[N:44][O:45][CH2:46][CH2:47][CH3:48])[C:41]([NH:2][CH:3]2[C:24](=[O:25])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]23)=[O:42])=[CH:38][S:37][CH2:36][CH2:35]1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CCCON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCO1
Yield: 98.9 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (5.0 g.) and trimethylsilylacetamide (11.3 g.) in dry ethyl acetate (100 ml.) and a solution of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 3.13 g.), dry N,N-dimethylformamide (1.13 ml.) and phosphoryl chloride (1.33 ml.) in ethyl acetate (54.4 ml.) were treated in a similar manner to that of Example 19-(1) to give 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 7.10 g).
Reaction SMILES: O[CH2:2][C:3]1([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]([CH3:17])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C=CC=C(C)C=1>[CH3:17][N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])=[CH:2][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]1=2
Reactant: CN(C)CCC1(CO)c2ccccc2N(C)c2ccccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(C)c1
Product: CN(C)CCC1=Cc2ccccc2N(C)c2ccccc21
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
A mixture of 24.5 gm of 9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane in a liter of m-xylene and 125 gm of phosphoric acid anhydride was heated at reflux for 3 hours and after cooling, the reaction mixture was poured over ice. The mixture was stirred for 15 minutes and was made alkaline by the addition of sodium hydroxide. The mixture was extracted with ethyl acetate and the ethyl acetate was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in ether and the solution was filtered and concentrated to a small volume and pentane was added while distilling off the ether. After filtering, the filtrate was concentrated to about 100 cc and crystallization was started with icing for one hour. After filtering, the precipitate was washed with water and dried in vacuo to obtain 16 gm (70% yield) of 5-methyl-10-(β-dimethylaminoethyl)-dibenzo (b,f) azepine melting at 78°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Br:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2ccc(Br)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-bromo-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as white solid. MS: 380.1 ([M−H]−).
Reaction SMILES: [C:1]([C:9]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:28]>>[C:1]([C:9]1[C:17]([S:18](=[O:20])(=[O:19])[NH2:28])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCCCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1C(=O)c1ccccc1
Agent: [OH-]
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1C(=O)c1ccccc1
Reaction time: 4.5 h

Procedure:
4-Benzoyl-3-n-butoxy-5-chlorosulfonylbenzoic acid (1.5 g) is in portions added to conc. ammonium hydroxide (15 ml) while stirring at 10°-12° C. After additional stirring at room temperature for 16 hours, the mixture is left in a refrigerator for 4-5 hours. The separated ammonium salt is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in 1 N sodium hydroxide (15 ml) and the solution is dropwise added to icecold 1 N acetic acid (20 ml) while stirring. The separated material is collected by filtration, washed with water and dried in the air. The product is recrystallized from aqueous ethanol, and the thus purified material is dissolved in 1 N NaOH (15 ml). The solution is dropwise added to icecold 1 N acetic acid (18 ml) while stirring. The precipitated material is collected by filtration, washed with water and dried in vacuo in the presence of P2O5, to give 4-benzoyl-3-n-butoxy-5-sulfamylbenzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([O:22][CH3:23])[C:13]=1Br.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:13]2[C:14]([O:22][CH3:23])=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[O:11][CH3:10])[CH:2]=1
Reactant: COc1cc2ccccc2c(OC)c1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc2ccccc2c(OC)c1-c1cccnc1
Yield: 77.8 %

Procedure:
Pyridine-3-boronic acid (3.94 g 32 mmol, Frontier Scientific, Inc.), 1,3-dimethoxy -2-bromonaphthalene 8 (6.6 g, 24.7 mmol), glyme (200 ml), and tetrakis(triphenylphosphine) palladium (Ph3P)4Pd (3 g, 2.7 mmol) were stirred for 15 minutes followed by the addition of potassium carbonate (11.4 g in 50 mL of water). After refluxing over-night, the reaction mixture was poured into 800 ml of 1:1 water:ethyl acetate. The organic layer was washed with water (300 ml×2) and brine (200 ml), solvent was removed, and the crude product was purified by silica-gel chromatography eluting with dichloromethane and acetone (0% to 5% acetone) yielding 5.1 g (84%) of 9.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:17][CH2:18]1
Reactant: NCCN1CCOCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCN1CCOCC1

Procedure:
The product was made from D-glucose and N-(β-aminoethyl)-morpholine comparable as in Example A. A resin-like, colorless product was obtained.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>CO.[OH-].[Na+]>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCn1ccnc1
Temperature: 20 °C

Procedure:
n-Pentylbromide (30 ml; 0.24 mole) was added dropwise to a stirred solution of imidazole (13.6 g; 0.2 mole) in a mixture of methanol (30 ml) and sodium hydroxide solution (30 ml, 10M) maintained at 20° C. When the addition was complete the reaction mixture was stirred and refluxed for 24 hours. The solvent was evaporated, the residue extracted with chloroform (2×50 ml) and the solid remaining removed by filtration. The chloroform solution (filtrate) was dried over magnesium sulphate and concentrated to give a yellow oil which on purification gave 1-n-pentylimidazole as a colourless oil, b.p. 66°-68° C./0.15 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[N:24]([CH2:27][C@H:28]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)[NH2:29])=[N+:25]=[N-:26].CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:29][C@@H:28]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([Cl:37])[CH:31]=3)[CH2:27][N:24]=[N+:25]=[N-:26])=[O:19])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: [N-]=[N+]=NC[C@@H](N)c1cc(F)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Cl)c1
Reaction time: 15 h
Yield: 57.7 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (126 mg, 0.398 mmol) in DMF (1328 μl) was added (S)-2-azido-1-(3-chloro-5-fluorophenyl)ethanamine (100.0 mg, 0.398 mmol), DIEA (348 μl, 1.991 mmol), EDC (153 mg, 0.797 mmol), and aza-HOBt (81 mg, 0.597 mmol). The reaction mixture was stirred for 15 h. After water was added, the reaction mixture was worked up with EtOAc. The organic layer was dried over Na2SO4, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography (gradient EtOAc in heptane) to provide (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)-2-fluorobenzamide (118 mg, 58%). LCMS (m/z): 514.2 (MH+), 0.91 min.
Reaction SMILES: [C:1]1(C)[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O(Cl)Cl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:17])([Cl:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccccc1C#N
Agent: ClOCl
Product: N#Cc1ccccc1C(Cl)(Cl)Cl
Yield: 100 %

Procedure:
o-Tolunitrile (1.83 g, 0.0156 mole) and dichlorine monoxide (6.79 g, 0.078 mole) in carbon tetrachloride were heated at 75° for 18.5 hrs in a Carrius tube following the procedure described in Example 6. The reaction mixture was dried (MgSO4) and the solvent removed on a rotary evaporator to give a white crystalline solid (4.09 g, purity by HPLC 85.45%, yield 100%). The product was combined with that of a similar run and recrystallized from cyclohexane to give substantially pure 2-trichloromethylbenzonitrile mp 98.9°-100° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=1>C(#N)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([NH:10][C:38]([NH:39][C:40]3[N:41]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:42]=[C:43]([C:45]([CH3:49])([CH3:48])[CH2:46][F:47])[CH:44]=3)=[O:37])=[CH:12][C:13]=2[CH3:33])[CH2:22][CH2:21]1)=[O:24]
Reactant: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1
Temperature: 80 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Add DIEA (2 equiv.) to a solution of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (400 mg, 1.205 mmol) and [5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (1 equiv) in acetonitrile (12 mL). Stir the mixture at 80° C. in a sealed tube. After 4 days, remove solvent. Dilute crude with DCM, extract with water, and dry over Na2SO4. Filter and remove solvent under reduced pressure. Subject solid to silica gel chromatography, eluting with hexane/acetone 3:1 to obtain 352 mg of 1-{6-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-5-methyl-pyridin-3-yl}-3-[5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid (48% yield). ES+(m/z): 606 [M+1]
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:8]=2[C:4]2[CH:3]=[C:2]([O:1][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:22]=1
Reactant: ClCCCN1CCCCC1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cccc(OCCCN3CCCCC3)c2)cc1
Yield: 92.4 %

Procedure:
In a manner similar to that used in Example 2, 1.04 g (2.9 mmol) of 1-(3-hydroxyphenyl)-2-(4-methoxyphenyl)-6-methoxynaphthalene, 0.86 g (4.35 mmol) of 1-(3-chloropropyl)piperidine hydrochloride, and 2 g (14.4 mmol) of K2CO3 were converted to 1.29 g of the title compound, isolated as a brown oil.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].Br[C:13]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:20]2[C:19](=[O:30])[N:18]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[C:17](=[O:43])[N:16]([CH3:44])[C:15]=2[N:14]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:21]2[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[C:17](=[O:43])[N:16]([CH3:44])[C:15]=3[N:14]=[C:13]2[O:8][CH2:7][C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:9])[CH:2]=2)=[CH:24][CH:25]=1
Reactant: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Cc1cccc(CO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cccc(COc2nc3c(c(=O)n(CCOCCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of m-tolylmethanol (37 mg, 0.3 mmol) in DMF (2 mL) was added sodium hydride (18 mg, 0.45 mmol) at 0° C. After stirring at 0° C. for 30 min, 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (80 mg, 0.15 mmol, intermediate 11) was added. The mixture was stirred at 0° C. for 15 min, then aqueous ammonium chloride solution (2 mL) was added at 0° C. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.967 min; LCMS MH+-THP 499.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:12]2)C1C=CC=CC=1.B(Br)(Br)Br.O>ClCCl>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:12]2
Reactant: FC(F)(F)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(ccn2CC(F)(F)F)c1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A solution of 5-benzyloxy-1-(2,2,2-trifluoroethyl)indole (1.56 g, 4.09 mmol) in dichloromethane (10 mL) at 0° C. was treated dropwise with 1M BBr3 in dichloromethane(5.73 mL, 5.73 mmol), stirred for 2 hours, transferred to 2:1:1 water/10% NaHCO3/brine (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed with brine (40 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 9:1 hexane/ethyl acetate to provide 118 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]#[N:51])[N:41]2[C:40]1=[O:52]>>[C:50]([C@H:49]1[N:41]2[C@@H:42]([S:43][CH2:44][CH2:45][C@H:39]([NH:38][C:8](=[O:9])[C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=3)[CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH3:16])[C:17]([NH:18][C@H:19]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[C:20]3=[O:34])=[O:35])[C:40]2=[O:52])[CH2:46][CH2:47][CH2:48]1)#[N:51]
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(2R,5S)—N1-((4S,7S,10aS)-7-Cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-2-(4-fluorobenzyl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-5-propylhexanediamide was synthesized as described in General Procedure H using Intermediate 76 (8.5 mg, 0.017 mmol) and Intermediate 36 (5.0 mg, 0.019 mmol) to give a white solid (5.9 mg, 49% yield). Anal. Calcd. for C39H50FN5O5S m/z 719.7. found: 720.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (1H, d, J=6.6 Hz), 7.33-7.25 (1H, m), 7.09-7.02 (3H, m), 7.01-6.94 (3H, m), 6.86 (2H, t, J=8.8 Hz), 5.54-5.32 (3H, m), 5.29 (1H, d, J=4.9 Hz), 5.06-4.86 (2H, m), 4.04-3.89 (1H, m), 3.83 (3H, s), 3.54-3.35 (1H, m), 3.10-2.88 (1H, m), 2.80-2.54 (3H, m), 2.41-2.29 (1H, m), 2.21-1.18 (21H, m), 0.93-0.82 (3H, m).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][CH3:25])=[CH:22][CH:23]=3)=[C:14]([CH2:26][CH3:27])[N:13]=[C:12]([NH2:28])[N:11]=2)=[CH:6][C:5]=1[F:29]>C1COCC1>[NH2:28][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH3:25])=[CH:22][CH:23]=2)=[C:14]([CH2:26][CH3:27])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(NC)nc1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 238 mg (0.59 mmol) 4-[2-amino-6-ethyl-5-(6-methylamino-pyridin-3-ylethynyl)-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 0.88 mL (0.88 mmol) 1 N NaOH in 3 mL THF.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:30][CH:31]=1
Reactant: CCC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: CCC(NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 69.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.1 g, 3.7 mmol) was reacted with tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propylcarbamate (2.0 g, 5.5 mmol) to afford the desired product (1.2 g, 68%) as a white solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C>[CH:10](=[C:2]1/[N:1]2[CH2:8][CH2:7][CH:4]([C:3]/1=[O:9])[CH2:5][CH2:6]2)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1/C(=C/c2ccccc2)N2CCC1CC2
Yield: 91.2 %

Procedure:
A mixture of 3-quinuclidinone (20.9 g, 167 mmol), benzaldehyde (17.7 g, 167 mmol), and one pellet of sodium hydroxide in 75 mL of ethanol was refluxed for 1.5 h. After the solution was cooled, the yellow precipitates were collected, washed with ethanol, and dried to give (Z)-2-benzylidenequinuclidin-3-one (32.5 g, yield: 91.2%, mp 130-132° C.).