Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]([F:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][CH:10]1[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1CCNCC1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 1-tert-butoxycarbonyl-3-fluoro-4-piperidinylacetate (653 mg, 2.26 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL) at 0° C. After being stirred at room temperature for 4 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCO3 solution and extracted with THF-EtOAc (1:1, v/v). The extracts were dried over MgSO4 and concentrated to afford ethyl 3-fluoro-4-piperidinylacetate (420 mg, 98%) as a yellow oil. 1H-NMR (CDCL3) δ 1.26 (t, J=7.4 Hz, 3H), 1.68–1.80 (m, 2H), 2.18 (m, 1H), 2.32 (dd, J=16.6, 6.8 Hz, 1H), 2.54 (dd, J=16.6, 7.5 Hz, 1H), 2.82 (m, 1H), 2.90, 3.00 (each d, J=14.4 Hz, total 1H), 3.31 (m, 1H), 3.51 (m, 1H), 4.15 (q, J=7.4 Hz, 2H), 4.82, 4.71 (each broad s, total 1H).
Reaction SMILES: [CH2:1]([CH:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[NH:6]1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[C:28]3[NH:38][N:37]=[N:36][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Nc2ccc(C)cc2C(=O)N1Cc1ccc(-c2ccncc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2ccncc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 2-butyl-6-methyl-3-[[4-(3-cyanopyridin-4-yl)phenyl]methyl]quinazolin-4(1H)-one (1.0 eq.) and trimethylstannylazide (3 eq.) in toluene is heated to reflux for 4 days. The mixture is cooled to rt, concentrated, then purified by flash chromatography on SiO2 to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5](=[NH:6])[O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: N#CCc1ccccc1Cl
Agent: Cl
Product: CCOC(=N)Cc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 2-chlorobenzyl cyanide (32.4 g, 0.214 mol) in ethanol (70 ml) was cooled to 5 ° C., then HCl gas was passed through with stirring for 30 minutes and the resultant mixture was allowed to stand at room temperature for 18 hours. Evaporation of the solvent and trituration with ether gave the desired product, which was used immediately without further purification. Yield 49.0 g (98%).
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(OCC)(=O)C.CCCCCC>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:4])=[O:1])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.6 %

Procedure:
Using N-Boc-L-tHyp(Tosyloxy)-OMe (5g, 10.5 mmol), powdered KOH (1.75 g, 26.5 mmol) and 4-nitrophenol (3.66 g, 26.3 mmol) after 4 days at reflux, 2.52 g (65%) of the corresponding 4-nitrophenyl ether was obtained by column chromatography (silica ge, ethyl acetate/hexane mixtures) and crystallization of the appropriate fractions from ethyl acetate/hexane (1:1). An alternate method is to triturate the oily crude and pentane several times [hexane doesn't work] and then add a very, small amount of ethyl acetate to solidify the product. The filtered, solid product may than be crystallized as above. Elemental analysis for C17H22N2O7 (366.324 g/mmol): Calculated C, 55.74; H, 6.05; N, 7.65. Found C, 55.71; H, 6.05; N, 7.65.
Reaction SMILES: [CH2:1]([NH:15][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH:16]1([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation in analogy to Example 11 from N-tetradecylglucopyranosylamine and stearoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][C@@H:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:31][C@H:23]([CH3:22])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)Cc1ccccc1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1ccccc1)NC(=O)c1c(N)ccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-amino-2-(trifluoromethyl)nicotinic acid (15 g, 61.83 mmol) was suspended in a mixture of anhydrous DMF (300 mL) and anhydrous dichloromethane (500 mL). To this was added triethylamine (30.4 mL, 216 mmol), followed by L-amphetamine hydrochloride (12.7 g, 74.2 mmol). HBTU (30.5 g, 80.4 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo to remove dichloromethane. The resultant DMF solution was poured into water, extracted with ethyl acetate (1 L). The organic layer was washed successively with 1N NaOH, saturated sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography using 40-70% ethyl acetate/heptanes as eluant to provide the product as a colorless foam (18.3 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.2-7.4 (m, 5H), 6.6 (d, 1H), 5.8 (d, 1H), 4.7 (bs, 2H), 4.5 (m, 1H), 2.9 (m, 2H), 1.25 (d, 3H). MS m/z 324.3 (M+H)+.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C1(CN(CC2C=CC=CC=2)[C:17]2[C:26]3[N:27]=[C:28]([CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33]Cl)[NH:29][C:25]=3[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=2)C=CC=CC=1.[CH3:43][C:44]([CH3:46])=O>>[C:44]1([CH2:46][N:29]([CH2:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[N:18]=[CH:17][C:26]2[N:27]=[C:28]4[CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33][N:29]4[C:25]3=2)[CH:32]=[CH:31][CH:30]=[CH:28][CH:43]=1
Reactant: CC(CCl)CCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1CCc2nc3cnc4c(N(Cc5ccccc5)Cc5ccccc5)cccc4c3n2C1

Procedure:
A large excess (about 10 fold) of both sodium iodide and potassium carbonate were added to a solution of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine (about 0.5 g) in acetone (about 75 mL). The reaction mixture was heated at reflux overnight, diluted with additional acetone, filtered and then concentrated under vacuum. The residue was washed with methylene chloride to recover the product from salts then purified by column chromatography (silica gel eluting with 3% ethyl acetate in methylene chloride v/v) to provide 0.35 g of N,N-bis(phenylmethyl)-8,9,10,11 tetrahydro-10-methylpyrido[1',2':1,2]imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH:21]([CH2:22][C:23]([O:25]C)=[O:24])[C:20]2[N:19]=[CH:18][CH:17]=[C:16]([Cl:27])[C:15]=2[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:29]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH:21]([CH2:22][C:23]([O-:25])=[O:24])[C:20]2[N:19]=[CH:18][CH:17]=[C:16]([Cl:27])[C:15]=2[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3].[Na+:29]
Reactant: COC(=O)CC1c2nccc(Cl)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(Cl)ccnc2C1CC(=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.8 %

Procedure:
94-7. To a stirred solution of methyl 2-(7-(2-((tert-butoxycarbonyl)amino)acetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate (540 mg, 1.36 mmol) in MeOH (10 mL), 4N aqueous NaOH (0.39 mL, 1.56 mmol) was added and the solution was stirred at RT for 5 days. The solvent was evaporated under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as a beige powder (540 mg) which was used without further purification in the next step. UPLC-MS: MS 384.1 (M+H+); UPLC rt 0.81 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=3)[NH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CCCCO)cc23)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1cc(-c2c[nH]c3ncc(CCCCO)cc23)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To crude azaindole 66 (76 mg, 0.19 mmol) in EtOH (6 mL) was added 10% NaOH (1 mL) and the mixture was stirred in an oil bath (90° C.) for 2 h. The mixture was then cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was purified by means of PTLC employing AcOEt as eluent to afford the azaindole 67 (16 mg, 31%); 1H NMR (400 MHz; CDCl3) δ 1.61-1.80 (m, 8H), 2.77 (t, J=7.6 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 7.34 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 7.73 (d, J=0.6 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 9.29 (br s, 1H).
Reaction SMILES: [C:1]([N:4]([C:10]1[N:15]=[CH:14][CH:13]=CN=1)[CH2:5][CH2:6][CH2:7][C:8]#[CH:9])(=[O:3])[CH3:2]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([N:4]1[C:10]2[C:7](=[C:8]([CH3:9])[CH:13]=[CH:14][N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C#CCCCN(C(C)=O)c1ncccn1
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N1CCc2c(C)ccnc21

Procedure:
A solution of 2-(N-acetyl-N-pent-4-ynylamino)pyrimidine (3.49 g, 17.2 mmol) in nitrobenzene (35 mL) was heated under argon at 180° C. for 2 days. The reaction mixture was cooled and loaded directly onto a dry silica get column. The column was first eluted with methylene chloride to wash off the nitrobenzene and then was eluted with ether to give after evaporation in vacuo to give the title compound as a pale yellow solid:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25]>C(#N)C.CN(C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25])=[O:8])([O-:3])=[O:2]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
22.4 g of 3-nitro-4-fluorobenzoyl chloride (0.12 mols) were added dropwise at 0° C. to a suspension of 19.1 g of 5-amino-1-naphthol (0.12 mols) in 120 ml of acetonitrile and 14.2 g of N,N-dimethylaniline. The mixture was further stirred until it reached room temperature, and then heated for 30 minutes at 50° C. The yellow deposit was suction filtered and washed with acetonitrile. The deposit was dissolved in tetrahydrofurane and stirred with charcoal, filtered and the product was precipitated from the filtrate with petrol 50/75. Yield: 25.8 g=66% of the theoretical yield; mp. 235°-238° C.
Reaction SMILES: [C:1]([C:5]1[NH:9][CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[C:1]([C:5]1[N:9]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cncn1COCC[Si](C)(C)C
Yield: 57.6 %

Procedure:
Reaction of 5-tert-butyl-1H-imidazole (423 mg, 3.41 mmol), NaH (60%, 132 mg, 3.31 mmol), and SEMCl (639 uL, 3.61 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (500 mg, 57%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ major isomer: 0.00 (s, 9H), 0.89 (t, 2H, J=7.5 Hz), 1.29 (s, 9H), 3.47 (t, 2H, J=7.5 Hz), 5.19 (s, 2H), 6.73 (s, 1H), 7.50 (s, 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]([CH3:17])[CH3:16])[C:29](=[O:30])[CH2:28][Cl:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)CCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19]S(C)(=O)=O)=[C:14]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[C:14]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Temperature: 50 °C
Yield: 80.3 %

Procedure:
Dissolve methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl ester (5.2 g, 12.3 mmol) in 5M sodium hydroxide (12 mL, 60 mmol), THF (86 mL) and MeOH (86 mL). Heat to 50° C. for 1 hour. Cool and add ethyl acetate (100 mL). Wash the organic layer with 1N HCl, saturated sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo to obtain 3.4 g (89%) of 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-ol.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[S-2:15].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=O)[C:24]2[CH:30]=[CH:31][C:32]3[C:37]([C:23]=2[O:22]1)=[CH:36][CH:35]=[CH:34][CH:33]=3>C1(C)C=CC=CC=1>[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=[S:15])[C:24]2[CH:30]=[CH:31][C:32]3[C:37]([C:23]=2[O:22]1)=[CH:36][CH:35]=[CH:34][CH:33]=3
Reactant: [S-2]
Reactant: CN1CC(CCCl)Oc2c(ccc3ccccc23)C1=O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2c(ccc3ccccc23)C1=S
Yield: 84.1 %

Procedure:
A mixture of 9.55 g of phosphorus pentasulfide and 9.5 g of potassium sulfide were ground together and added to a solution of 20.2 g (0.07 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-one in 200 ml of dry toluene. The mixture was stirred and heated at reflux for 7 hr. The hot reaction mixture was filtered and the product crystallized from the cooled filtrate. Recrystallization from chloroform gave 18 g (84%) of yellow crystals, m.p. 167°-170° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:4]=2[N:3]=1.[CH:21]1[CH:22]=[CH:23]C2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([N:27]3[CH2:23][CH2:22][CH2:21][CH2:26][CH2:25]3)=[O:20])=[CH:17][C:4]=2[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(-n2c(C)nc3cc(C(=O)O)ccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cccc(-n2c(C)nc3cc(C(=O)N4CCCCC4)ccc32)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
The compound obtained in Step 3 (80.0 mg, 0.300 mmol) was dissolved in DMF, and then HOBT (81 mg, 0.6 mmol), TEA (126 uL, 1.2 mmol), and piperidine 28.1 mg (0.330 mmol) were added thereto. EDC hydrochloride (25 mg, 0.13 mmol) was put thereinto at 0° C., and then stirred at room temperature for 12 hours. The reacted mixture was diluted with ethyl acetate (32 mL), and then washed with water (32 mL). The organic layer was dried over anhydrous magnesium sulfate, followed by filtering and concentrating under reduced pressure, and then subjected to column chromatography (MC:MeOH=30:1), to obtain a target compound (79.4 mg, 79%).
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]#[CH:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]1([N:6]([CH2:22][C:21]#[CH:20])[C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC2CCCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN(C1CCCC1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
A mixture of (R)-tert-butyl 3-(cyclopentylamino)pyrrolidine-1-carboxylate (200 mg, 0.78 mmol), 3-bromo-1-propyne (140 mg, 1.18 mmol) and K2CO3 (217 mg, 1.57 mmol) in acetonitrile (3 mL) was stirred at reflux for overnight. The volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel (PE/EtOAc=4:1) to give the title compound. MS (m/z): 293 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:17]2[C:16](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CCOC(C)=O>[CH3:26][CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH:14]([NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:17]=1[C:16](=[O:15])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=Nc2ccccc2)o1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)C(Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Reaction time: 19.5 h

Procedure:
Piperidine (1 mL) was added to compound 178 (0.161 g, 0.5 mmol) and the reaction mixture was stirred for 19.5 h. The reaction mixture was then concentrated under reduced pressure to give a yellow gum. Trituration with 1:4 EtOAc:hexanes gave a small amount of compound 179 (0.041 g). Flash chromatography (1:4 EtOAc:hexanes) of the filtrate gave only a partially separable mixture of the expected products, the acetoxyquinazolinone compound 179 and the hydroxyquinazolinone (total mass 0.122 g). ESI-MS m/z=408 (MH+). The reaction described above and compound 179 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22](OC)[O:23]C)[CH:6]=1.Cl.CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH:22]=[O:23])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C(OC)OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
[3-(2-Dimethoxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.479 g, 1.42 mmol) and hydrogen chloride (4N in 1,4-dioxane; 1.5 mL, 6.0 mmol) were combined in THF (4 mL) and stirred at 70° C. for 1 hour. Some starting material was still seen by analytical LCMS, so additional hydrogen chloride (4N in 1,4-dioxane; 0.5 mL) was added, and the reaction was stirred for another hour at 70° C. After cooling to room temperature, the mixture was worked up with EtOAc and H2O, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH2:13]2)(=O)=O)=CC=1.[C:29]([O-])(=[O:31])[CH3:30].[K+]>CN(C=O)C.C(Cl)Cl>[C:29]([O:11][C@H:12]1[CH2:13][C@H:14]([C:16]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)=[O:17])[CH2:15]1)(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H](C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 110 °C

Procedure:
To a stirred solution cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutyl 4-methylbenzenesulfonate (73 mg, 0.18 mmol) in DMF (3 ml) at RT was added potassium acetate (108 mg, 1.1 mmol). The mixture was heated at 110° C. overnight and then cooled to RT and diluted with DCM. The resulting mixture was washed with 1:1 H2O/brine and the organic phase dried (Na2SO4), filtered and concentrated at reduced pressure to yield the title compound (50 mg, 94%), which was used without further purification.