Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23](N)=[O:24].Cl.O>CN1C(=O)CCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH:21][C:23]([NH2:22])=[O:24])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: NC[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)NC[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-methylamine hydrochloride salt (4.6 kg) and urea (3.4 kg) were suspended in fresh NMP (9.5 kg). Concentrated aqueous 37% HCl (0.15 kg) was added and the reaction mixture was heated to 100° C. for three hours. On completion of reaction (confirmed by HPLC), the reaction mixture was cooled to 60° C. and water (45 kg) was added. The resulting slurry was stirred vigorously while cooling down to 20° C., and the mixture was allowed to sit for 24 hours. The resulting solid was filtered and washed with water. The wet filter cake was taken into toluene (23.6-kg) and heated to 80° C., then washed with water (twice with 13.5 L) and the reaction mixture was cooled to 40° C. [(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea crystallized on addition of n-heptane (7.8 kg). The product was filtered and dried under reduced pressure at 50° C. to afford 3.78-kg of [(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea: MP=115.1-116.0° C.; MS (M+1)=288; H1 NMR (300 MHz): δ ppm (DMSO): 1.59-1.84 (3H, m), 2.59-2.78 (2H, m), 2.86 (1H, m), 3.10 (1H, ddd, J=6.03, 9.04 Hz), 3.28 (1H, ddd, J=5.65, 6.03), 3.34 (1H, s), 5.46 (2H, s, NH), 6.11 (1H, t, J=6.03 Hz) 6.96-7.09 (3H, m), 7.17-7.23 (2H, m), 7.26-7.31 (1H, m), 7.32-7.41 (1H, m): [α]D=25.5° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak AS-H (150×4.6 mm), mobile phase 80/20 hexane/ethanol(isocratic), flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.03/(S)-isomer 0.97.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2NS(C(C)C)(=O)=O)=[CH:4][CH:3]=1.[OH-:18].[Na+].C[CH2:21][OH:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:21]([OH:22])=[O:18])=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of racemic trans-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate 2) (4.97 g, 18.47 mmol) in 76.72 mL of EtOH was added dropwise 49.08 mL of 2N NaOH and the mixture was stirred at room temperature for 1 h. The solution was then concentrated in vacuo, 20 mL of water were added and the aqueous phase washed with 2×20 mL Et2O. The aqueous phase was then acidified with 2M HCl to pH 3 (approx.) and extracted with 3×100 mL Et2O. The collected organic phases were dried over Na2SO4, filtered and concentrated in vacuo to get 4.43 g of the title compound as a white solid, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][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)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][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)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 45 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
A mixture of 506.1 mg (1.2 mmol) of 7-chloro-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and 390.0 mg (6.0 mmol) of sodium azide in 10.0 mL of DMSO is heated at 40-50° C. for 5 hours, and then at room temperature for 15 hours. The mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. Removal of the solvent yields 493.4 mg (97.7%) of 7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as a yellow solid which is used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)[CH3:2].Cl.[NH2:15][OH:16]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1)[CH3:2]
Reactant: NO
Reactant: CCOCCCN1CCC(=O)CC1
Agent: Cl
Product: CCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Ethoxypropyl)-4piperidone oxime is prepared from 1-(3-ethoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:39])[CH3:40])[NH:37][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
Boc-Val-OH (2.86 g, 13.2 mmol) was coupled to valine benzyl ester p-toluenesulfonate (5.0 g, 13.2 mmol) using the procedure of Example 55 to give 5.41 g, (100%) of the desired product (RF 0.15; 20% ethyl acetate in hexane) as a colorless gum. Mass spectrum (M+H)+ =407.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17](=[N:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH2:32]([Mg]Br)[CH:33]=[CH2:34]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C@:17]([NH:25][S@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:34][CH:33]=[CH2:32])[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)N(CCC(=N[S@@](=O)C(C)(C)C)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@](CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)(N[S@@](=O)C(C)(C)C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
To a solution of methyl (1S)-1-(4-bromophenyl)ethyl(3-((S)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl)carbamate (200 mg, 0.4 mmol) in anhydrous THF (5 mL) was added 1M allylmagnesium bromide (1.2 mL, 1.2 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 4 h and allowed to warm to rt. After stirring for 2 h at rt, the reaction mixture was quenched with satd aq NH4Cl and extracted with EtOAc (2×). The combined organic phases were dried, filtered and concentrated to give a residue, which was purified by TLC to provide methyl (S)-1-(4-bromophenyl)ethyl((S)-3-((S)-1,1-dimethylethylsulfinamido)-3-(4-fluorophenyl)hex-5-enyl)carbamate (96 mg, 45%). 1H NMR (CD3OD): 1.28 (m, 9H), 1.48 (m, 3H), 2.10 (m, 1H), 2.30 (m, 1H), 2.72 (m, 4H), 3.66 (m, 3H), 5.08 (m, 2H), 5.40 (m, 2H), 7.10 (m, 4H), 7.32 (m, 2H), 7.50 (m, 2H).
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:3]1.[NH:35]([C:52]([CH3:54])=[O:53])[C@H:36]([C:49]([OH:51])=[O:50])[CH2:37][S:38]SC1N=CC=CC=1[N+]([O-])=O>>[C:52]([NH:35][CH:36]([CH2:37][S:38][S:1][CH:2]1[CH2:3][CH:4]([C:20](=[O:21])[N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[CH2:6]1)[C:49]([OH:51])=[O:50])(=[O:53])[CH3:54]
Reactant: CC(=O)N[C@@H](CSSc1ncccc1[N+](=O)[O-])C(=O)O
Reactant: O=C(O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Product: CC(=O)NC(CSSC1CC(C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1)C(=O)O
Reaction time: 2 h

Procedure:
(2S,4R)-{[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid (32.6 mg, 0.07 mmol) and Ac-Cys(Npys)—OH (20.6 mg, 0.07 mmol) were dissolved in argon-degassed DMF (abs. 2 ml) and degassed 0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The reaction mixture was magnetically stirred for 2 h under argon. Ethyl acetate (30 ml), water (20 ml) were added and the organic phase was washed with water (3×20 ml) and concentrated under reduced pressure to give a yellow oil: 37 mg. Prep. RP-HPLC purification followed by pooling and freeze-drying of desired fractions yielded 2-acetylamino-3-[5-(carboxymethyl-phenethyl-carbamoyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yldisulfanyl]-propionic acid as a white lyophilisate (20 mg) MS: 657.9 (M-H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)[CH3:14]>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]2[CH2:13][CH3:14])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CCC1CCCCN1
Reactant: CC#CCOc1cc(Cl)ncn1
Product: CC#CCOc1cc(N2CCCCC2CC)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.56 g of 2-ethylpiperidine were mixed and left for 18 hours at 80° C. The reaction mixture was cooled to near room temperature and subjected to silica gel column chromatography to obtain 0.14 g of 4-(2-butynyloxy)-6-(2-ethylpiperidino)pyrimidine (hereinafter, referred to as Compound (22)).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[N:9][CH:8]=[CH:7][N:6]2[C:21]=1[C:22](O)([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[N:6]([C:21](/[C:22](/[CH2:26][CH2:27][CH3:28])=[CH:23]\[CH2:24][CH3:25])=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCCC(O)(CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C=C(/CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
4-[2-Ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-4-heptanol (115 mg, 0.29 mmol) and triethylamine (0.48 mL, 3.5 mmol) were dissolved in methylene chloride (3 mL), then methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (111 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:22]([CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH2:15][CH2:16]1)([OH:24])=[O:23]
Reactant: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 82.1 %

Procedure:
2.9 g of the compound from Example 9 are dissolved in a mixture of 14 ml of acetic acid and 9.5 ml of water, and 1.4 ml of concentrated sulphuric acid are added. The mixture is heated at 150° to 160° C. for 1.5 hours and poured into 90 ml of water. The precipitate is filtered off with suction, washed with water and methanol and dried. 2.3 g (72% of theory) of 7-[4-(2-carboxyethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid semisulphate semihydrate of decomposition point 258° to 261° C. are isolated.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:43][CH2:42]1>C(#N)C.C(N(CC)CC)C>[C:47]1([CH:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:46][CH2:45]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCC(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCC(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 1.60 g (6.89 mM) of 1-(4-aminobutan-1-yl)-4-phenylpiperidine and 1.3 ml (9.33 mM) of triethylamine in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol/ethyl acetate 20-50-80%) to provide the title compound as red-purple solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].CN[N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1)[NH2:16].[C:24](O)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:8]([CH3:24])[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[N:14]=1)[CH3:11]
Reactant: CNN=C(N)c1cccc(C)n1
Reactant: CCOC(OCC)C(=N)OC
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(OCC)c1nc(-c2cccc(C)n2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
Methyl 2,2-diethoxyethanimidoate (42 g, 0.26 mol) was dissolved in methanol (200 mL), and a solution of compound N′,6-dimethylpyridine-2-carbohydrazonamide (43 g, 0.25 mol) in methanol (200 mL) while cooling with a water bath, followed by the addition of acetic acid (22 mL, 0.37 mol). The mixture was stirred at room temperature for 3 h, and then K2CO3 (10 g, 0.071 mol) was added. The mixture was stirred for 10 min, and then the methanol was evaporated. The residue was stirred with a solution of K2CO3 (20 g) in water (200 mL), and extracted with ether (2×150 mL). The organic layer was washed with water and then saturated NaCl solution, dried over Na2SO4 and evaporated. The residue (62 g) was purified by chromatography on a silica gel column to afford 39.5 g (57%) of the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17](=O)[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17]([Cl:48])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(=O)[nH]cnc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Cl)ncnc2c1

Procedure:
Using an analogous procedure to that described in the portion of Example 31 that is concerned with the preparation of starting materials, 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-methoxy-3,4-dihydroquinazolin-4-one (1 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazoline (0.8 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.1 (m, 4H), 3.5–3.7 (m, 4H), 3.96 (s, 3H), 4.72 (m, 2H), 6.6 (d, 1H), 6.98 (d, 1H), 8.82 (s, 1H); Mass Spectrum: M+H+ 394 and 396.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH3:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:13]N1C(=O)C2=CC=CC=C2C1=O.[C:25]([OH:28])(=O)[CH3:26]>>[CH3:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([CH3:1])([CH2:9]3)[CH2:3]1)[CH2:5]2.[OH:28][C:25]12[CH2:26][C:4]3([CH3:5])[CH2:10][CH:8]([CH2:9][C:2]([CH3:11])([CH2:3]3)[CH2:1]1)[CH2:7]2.[OH:28][C:25]12[CH2:26][C:6]3([CH3:7])[CH2:5][C:4]([CH3:12])([CH2:3][C:2]([OH:13])([CH2:11]3)[CH2:1]1)[CH2:10]2
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC12CC3CC(C1)CC(C)(C3)C2
Product: CC12CC3(C)CC(O)(C1)CC(O)(C2)C3
Product: CC12CC3CC(C)(C1)CC(O)(C3)C2
Temperature: 70 °C
Reaction time: 6 h
Yield: 39 %
Yield: 58 %

Procedure:
A mixture of 1.64 grams (10 millimoles) of 1,3-dimethyladamantane, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide, 0.015 gram (0.06 millimole) of Co(AA)2 and 10 milliliters of acetic acid was stirred under oxygen atmosphere at a temperature of 70° C. for six hours. As a result, with a transformation rate for 1,3-dimethyladamantane of 99%, 1-hydroxy-3,5-dimethyladamantane (yield 39%), and 1,3-dihydroxy-5,7-dimethyladamantane (yield 58%) were obtained. The selectivity for the alcohols was 97%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[CH:12]=[CH2:11]
Reactant: OCCc1ccc(O)cc1
Reactant: C=CCBr
Product: C=CCOc1ccc(CCO)cc1
Yield: 77 %

Procedure:
The two-step synthetic procedure of Example 1 was repeated starting with 2-(4-hydroxyphenyl)ethyl alcohol. In this case 1.2 equivalents of allyl bromide was employed in the alkylation step and the intermediate 4-allyloxyphenethyl alcohol was obtained in 77% yield following vacuum distillation (104-112° C. at 0.2 torr). Esterification of the alcohol with methacrylic acid afforded 4-allyloxyphenethyl methacrylate (AOPMA) in 88% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH:14]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][CH2:16][N:17]2[C@H:22]3[CH2:23][CH2:24][C@@H:18]2[CH2:19][CH:20]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[CH2:21]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].OO.NC(N)=[O:45].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:34][C:26]1[N:25]([CH:20]2[CH2:19][C@H:18]3[N:17]([CH2:16][CH2:15][CH:14]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:13][NH:12][S:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]([NH2:2])=[O:45])(=[O:10])=[O:11])[C@H:22]([CH2:23][CH2:24]3)[CH2:21]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1
Reactant: NC(N)=O
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1cccc(C#N)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1cccc(C(N)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
The title compound from example 3 (65 mg, 0.12 mmol) was dissolved in acetone (1 mL) and water (0.5 mL). To the solution was added urea hydrogen peroxide (110 mg, 1.2 mmol) followed by K2CO3 (5 mg, 0.036 mmol) and the reaction stirred at room temperature for 2 h, whereupon the reaction was found to be mostly complete by LC-MS. The reaction was poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse-phase HPLC eluting with 10-90% water/acetonitrile/0.1% TFA. The title compound (37 mg, 54% yield) was obtained as a white solid (free-based with K2CO3).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[K].[NH2:18][NH2:19]>CO>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([NH:18][NH2:19])=[O:5]
Reactant: COC(=O)c1cc(S(=O)(=O)O)cc(O)c1O
Reactant: NN
Agent: [K]
Solvent: CO
Product: NNC(=O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester, monopotassium salt (2.7 g, 9.4 mmole) and neat hydrazine (0.88 ml, 28 mmoles) in 100 ml of methanol were refluxed for 48 hours. The resulting white precipitate was filtered, dried, and dissolved in water (10 ml). Acidification to pH =2.5 with 2N hydrochloric acid, filtering and drying gave 940 mg of the title compound as a solid.
Reaction SMILES: N1(C(C2CCCCC2C(O)=O)=O)CCOCC1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)=[N:25][C:21]=2[CH:20]=1.C[O:36][C:37](=[O:50])[C@H:38]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:39][C:40](O)=[O:41]>>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:40](=[O:41])[CH2:39][CH:38]([CH2:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:37]([OH:50])=[O:36])=[CH:30][CH:31]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Agent: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Product: O=C(CC(CC1CCCCC1)C(=O)O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Yield: 51 %

Procedure:
This compound was prepared by the procedure described in Example 1 part (a) from 4-(5-Chloro-1H-benzoimidazol-2-yl) phenylamine and (R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester to give the crude product (2.0 g, 51%), which was used in the next step without further purification.
Reaction SMILES: [ClH:1].Cl.Cl.[OH:4][CH2:5][CH2:6][N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.Cl.[C:34](=[NH:39])(OCC)[CH3:35].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:34]([N:18]1[CH2:17][CH2:16][CH:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[NH:28])[CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=2)[CH2:20][CH2:19]1)(=[NH:39])[CH3:35]
Reactant: N=C(N)c1cccc(/C=C/CN(CCO)c2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)CCO)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
To a solution of 3-[3-[N-(2-hydroxyethyl)-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (295 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (362 mg) and triethylamine (0.41 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 16% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (175 mg, yield 55%) as a pale yellow amorphous solid.