Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][N:23]1[N:22]=[N:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[N:24]1
Reactant: Cn1nnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nnc(-c2ccc(N3CCNCC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4(b) from 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.1 (MH+, 100%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[OH-].[Na+].[C:11]1([CH:17]([N:24]=[C:25]=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>>[CH:17]([NH:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[O:26])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: NCCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCCS(=O)(=O)O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The 3-amino-1-propanesulfonic acid (1.0 g, 7.2 mmol) was dissolved in 3N NaOH (370 mg, 9.4 mmol in 3 mL of water). After the solution was cooled to 0° C., diphenylmethyl isocyanate (1.4 mL, 7.2 mmol) was added. The reaction mixture was allowed to warm up to room temperature, stirred for 8 h (r.t.), and followed by addition of 3N NaOH (3 mL). The reaction mixture was stirred for 18 h. The pH of the reaction mixture was brought to 3 with 5N HCl. The solvent was evaporated under reduced pressure. EtOH (15 mL) was added and the mixture was stirred at reflux for 30 sec. The hot mixture was filtered. The filtrate was evaporated to dryness. This process was repeated 2 more times. The final product was dried in vacuo, affording compound AF, 837 mg (34%).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)(=O)=O.[NH:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15]>CN(C=O)C>[CH3:1][O:15][C:14](=[O:16])[C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[NH:8]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
To methanol (30.0 mL), cooled to -10 to -15° C., was slowly added sulfuryl chloride (11.0 mL, 178 mmol), DMF (0.133 mL) and L-pyroglutamic acid (L=(S) configuration, 10.0 g, 77.5 mmol, Sigma Chemical Co.). The stirred mixture was allowed to warm slowly and then stirred at room temperature for 36 hours. The methanol was removed under vacuum, and the residue was dissolved in ethyl acetate (400 mL). Water (~10 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, the slurry was washed with ethyl acetate (4×15 mL), and the organics were then combined and dried over magnesium sulfate. Removal of the solvent gave crude pyroglutamic methyl ester (10.04 g, 91%). NMR and MS analysis indicated >95% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:34][C:35]([F:56])([F:55])[S:36]([O:39][C:40]1[C:45](OS(C(F)(F)F)(=O)=O)=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:54])(=[O:38])=[O:37]>O1CCOCC1.CO.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>[F:56][C:35]([F:34])([F:55])[S:36]([O:39][C:40]1[C:41]([Cl:54])=[CH:42][CH:43]=[CH:44][C:45]=1[C:4]1[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]2([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=1)(=[O:38])=[O:37]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B(O)O)cc1F
Reactant: O=S(=O)(Oc1cccc(Cl)c1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(Cl)c2OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 90 °C

Procedure:
3-Fluoro-4-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-phenylboronic acid (0.050 g, 0.138 mmol), tetrakis(triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol), and potassium phosphate (0.035 g, 0.166 mmol) were added to a flame-dried flask under argon. 2-Chloro-6-{[(trifluoromethyl)sulfonyl]oxy}phenyl trifluoromethanesulfonate (0.068 g, 1.66 mmol) as a solution in dioxane (0.33M) was added to the solids and heated to 90° C. After 3 hours the reaction was diluted with methanol, filtered and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. The product was lyophilized to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].[N:38]1([CH2:43][CH2:44][CH2:45][NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[NH2:53])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:46]([CH2:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:47]3[CH:48]=[N:49][CH:50]=[CH:51][C:52]=3[N:53]=2)[CH2:10][C:11]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1ccncc1NCCCN1CCCC1
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)c2nc3ccncc3n2CCCN2CCCC2)cc1C(F)(F)F
Yield: 11 %

Procedure:
The product was prepared analogously to Example 62 starting from 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) and N3-(3-pyrrolidin-1-yl-propyl)-pyridine-3,4-diamine (Intermediate product 41) at 100° C. and purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Lyophilisation of a 1 N aqueous solution of the product yielded the corresponding hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[C:19]([C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])#[N:20]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 7 %

Procedure:
Prepared as in Example 197c from tert-butyl 4-hydroxybutylcarbamate and 2,6-dinitrobenzonitrile in 7% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 9H), 1.52-1.55 (m, 2H), 1.72-1.76 (m, 2H), 2.94-2.99 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 6.86 (brs, 1H), 7.69-7.72 (m, 1H), 7.85-7.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][C@H:6]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:5][CH2:4][C@@H:3]1[OH:22].[NH2:24][CH2:25][C:26]1[C:27]([C:34]([F:37])([F:36])[F:35])=[CH:28][C:29]([CH3:33])=[N+:30]([O-:32])[CH:31]=1>O1CCOCC1>[OH:22][C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:24][CH2:25][C:26]3[C:27]([C:34]([F:37])([F:35])[F:36])=[CH:28][C:29]([CH3:33])=[N+:30]([O-:32])[CH:31]=3)[N:10]=2)[CH2:7][C:2]1([CH3:23])[CH3:1]
Reactant: CS(=O)c1ncc(C(F)(F)F)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Reactant: Cc1cc(C(F)(F)F)c(CN)c[n+]1[O-]
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c[n+]1[O-]
Yield: 30 %

Procedure:
A solution of (1S,4R)-2,2-dimethyl-4-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanol (1.0 equiv.) and 5-(aminomethyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (1.0 equiv.) in dioxane (0.15 M) was heated at 110° C. for 14 h. Standard work-up afforded 5-(((4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (30% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 (s, 1H) 7.81-7.99 (m, 3H) 5.94-6.14 (m, 1H) 4.53 (m, 2H) 4.24-4.42 (m, 1H) 3.91 (m, 1H) 2.98-3.24 (m, 1H) 2.23-2.39 (m, 3H) 1.28-1.75 (m, 4H) 0.83-1.24 (m, 3H) 0.74 (s, 3H) 0.57 (s, 3H); MS(ESI) m/z 494.3[M+1]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[N:22]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:20]=[C:19]([O:33][C@H:34]([CH3:40])[C:35](OCC)=[O:36])[CH:18]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[CH:18]=[C:19]([O:33][C@H:34]([CH3:40])[CH2:35][OH:36])[N:20]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:22]=2)(=[O:14])=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (2R)-2-({6-[({5-[(tert-butylamino)carbonyl]-2-furyl}sulfonyl)amino]-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)propanoate (the product of step (0.25 g) in THF (10 mL) was added a solution of lithium borohydride (0.6 mL, 2.0M in hexanes) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 18 h. After cooling to 0° C., 1N HCl (20 mL) was added slowly, and the mixture extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude oil was purified by reverse phase HPLC (75% to 5% gradient of 0.2% aqueous trifluoroacetic acid in acetonitrile as eluent) to give the title compound as a white solid. Yield: 90 mg.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][N:4]=[CH:3]1.[Br:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:28][C:20]1=2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([S:29]([NH:7][C:6]3[S:2][CH:3]=[N:4][CH:5]=3)(=[O:30])=[O:31])[CH:27]=[CH:28][C:20]1=2
Reactant: Nc1cncs1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.7 %

Procedure:
A flask containing thiazol-5-amine hydrochloride (0.093 g, 0.684 mmol), 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (INTERMEDIATE C, 0.284 g, 0.622 mmol), and THF (4.15 mL) was cooled to 0° C. LHMDS (1.0 M in THF) (1.866 mL, 1.866 mmol) was added dropwise and the reaction was stirred for 5 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (40 g, gradient elution 0 to 100% EtOAc:Heptane) to afford 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.083 g, 0.160 mmol) as an orange oily solid. 1H NMR (400 MHz, DMSO-d6) δ=10.66 (s, 1 H), 8.69 (d, J=0.9 Hz, 1 H), 8.21 (d, J=1.6 Hz, 1 H), 7.91 (dd, J=1.5, 8.3 Hz, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.35 (d, J=0.9 Hz, 1 H), 7.12 (d, J=2.2 Hz, 1 H), 7.05 (dd, J=2.2, 8.6 Hz, 1 H), 6.24 (d, J=8.6 Hz, 1 H), 4.37 (d, J=17.2 Hz, 2 H), 3.85-3.63 (m, 2 H). m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[CH2:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)OCC=C2N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a mixture of 7-vinylchroman-4-one (Preparation 2D, 0.370 g, 2.12 mmol) and morpholine (0.925 mL, 10.6 mmol) in toluene (8 mL) at 0° C. was added titanium(IV) chloride (1.0 M in toluene) (1.17 mL, 1.17 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered under reduced pressure through a pad of CELITE®, which was rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give 4-(7-vinyl-2H-chromen-4-yl)morpholine (0.448 g, 1.84 mmol, 87% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 2.85-2.90 (m, 4), 3.84-3.89 (m, 4), 4.71 (d, J=4.16 Hz, 2), 5.10 (t, J=4.16 Hz, 1), 5.27 (d, J=11.37 Hz, 1), 5.76 (d, J=17.48 Hz, 1), 6.67 (dd, J=17.62, 10.96 Hz, 1), 6.98-7.03 (m, 2H), and 7.29 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 78 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 78%). 1H NMR (300 MHz, CDCl3): δ 2.44-2.47 (m, 3H), 3.19-3.26 (m, 4H), 3.78 (s, 3H), 4.12 (s, 4H), 6.87 (d, J=8.9 Hz, 2H), 7.01-7.11 (m, 1H), 7.22-7.26 (m, 3H), 7.52-7.61 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:11])[CH2:7]1
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: C=CCN
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(C)c2)C1
Reaction time: 18 h

Procedure:
A stirred solution of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 2.25 g (0.03 mole) of 2-propenylamine. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and a reddish oil separated. A sample of this oil crystallized at -70° C. and was used to seed the oil residue. The resulting solid was collected by filtration to yield 3.6 g which was recrystallized from benzene-ligroin yielding, after charcoal treatment, 1.53 g (62.2%) of pale beige crystals, m.p. 95°-96° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](C(O)=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:14].[NH2:15]O>>[ClH:14].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: NO
Agent: Cl
Product: Nc1cccc2c1OCCO2
Temperature: 120 °C

Procedure:
1,4-Benzodioxan-5-carboxylic acid (120 g) was added in portions at 40° C. to a stirred mixture of hydroxylamine hydrochloride (52 g) and polyphosphoric acid (380 g), then the mixture was heated to an internal temperature of 120° C. The source of heat was removed, and the mixture was stirred vigorously until frothing subsided, then it was stirred at 165° C. for 90 minutes, cooled to 80° C., added to an excess of ice-water, and basified by the addition of 5M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (6×500 ml), the extracts were dried (MgSO4), and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (800 ml), and the cloudy solution was filtered then saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at ambient temperature to give 1,4-benzodioxan-5-amine monohydrochloride as a buff solid (65.9 g).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19]>O1CCOCC1>[CH2:16]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:26])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCCCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)C2CCCCNC2=O)cc1
Reaction time: 3 h
Yield: 561.5 %

Procedure:
To a 1 liter flask equipped with drying tube, condenser and overhead stirrer is charged 0.13 moles of caprolactam, 0.16 moles of triethylamine and 150 ml of dioxane. The resultant solution is heated to reflux, and a solution of 0.13 moles of 4-butoxybenzoyl chloride in 50 ml of dioxane is added over 15 minutes. The mixture is refluxed with stirring for 3 hours followed by stirring at room temperature for a further 18 hours. The mixture is filtered, and the solvent removed by rotary evaporation leaving a brown oil which is recrystallized from 25 ml of carbon tetrachloride to yield 0.73 moles of 4-butoxybenzoyl caprolactam which NMR shows to be 90% pure. The 4-butoxybenzoyl caprolactam has a melting point of approximately 87-92° C. 1H NMR reveals 0.9 ppm (t, 3H); 1.2-1.8 ppm (m, 12H); 2.7 ppm (m, 2H); 3.8 ppm (m, 2H); 4 ppm (t, 2H); 6.9 ppm (d, 2H); 7.5 ppm (d, 2H). 13C NMR provides 14 ppm (s); 20 ppm (s); 24 ppm (s); 29 ppm (d); 31 ppm (s); 39 ppm (s); 46 ppm (s); 68 ppm (s); 114 ppm (s); 128 ppm (s); 131 ppm (s); 162 ppm (s); 174 ppm (s); 178 ppm (s). IR (cm−1) at 2933, 1677, 1604, 1254.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.N[C@H:32](C1C=CC(C(OC)=O)=CC=1)C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[CH3:32])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3): 1H-NMR (CDCl3) the data of the title compound were identical with that of the racemate (step 2 of Example 2); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([N:24](CC(O)=O)[CH3:25])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:83])[CH3:82])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:44](=[O:71])[C@H:45](C)NC(=O)CNC(=O)[C@H](CC1C=CC(O)=CC=1)NC(OC(C)(C)C)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:82])[CH3:83])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:44](=[O:71])[CH2:45][N:24]([C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN(C)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-L-tyrosylglycylsarcosine is substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylsarcosyl-L-phenylalanyl-L-leucine benzyl ester.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11].O>C1COCC1>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)cn1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at 0° C. was treated with a solution of 4-iodopyrazole (8.97 g, 46.2 mmol) in THF (20 mL), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 14.4 g of the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:28])[CH:24]=4)[C:19]3=[O:29])[CH:15]=[N:16][CH:17]=2)[CH2:8]1)(C)(C)C.Cl>O1CCOCC1>[Cl:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:29])[N:18]([C:14]1[CH:15]=[N:16][CH:17]=[C:12]([N:9]3[CH2:10][CH2:11][C@@H:7]([OH:6])[CH2:8]3)[CH:13]=1)[CH2:27][CH2:26]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2cncc(N3CCc4cc(Cl)ccc4C3=O)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(N2CC[C@@H](O)C2)c1

Procedure:
In analogy to the procedure described in example 135 [D], 2-{5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridin-3-yl}-6-chloro-3,4-dihydro-2H-isoquinolin-1-one was deprotected with 4M HCl in dioxane to give the title compound as a white foam. MS: 344.0 (M+H+).