Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:44][O:43][CH2:42][CH2:41][N:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[C:32]([NH:31][C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[CH:15]=2)[CH:25]=1)=[O:45])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(N)c2)c1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(OC4CCN(C(=O)OC(C)(C)C)C4)c3)c2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-[N-(2-methoxyethyl)-N-methylamino]benzamide to give N-(5-{3-[-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 2.08 (m, 2H), 2.18 (s, 3H), 2.96 (s, 3H), 3.22 (s, 3H),3.25 (m, 2H), 3.52 (m, 6H), 5.07 (s, 1H), 6.87 (d, 1H), 7.2 (m, 5H), 7.43 (t, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 9.86 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M-C3H7+ 547.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][C:14]4=[C:13](I)[C:12]=3[CH:11]=2)[CH2:8][CH2:7]1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>CCCCCC.O1CCCC1>[C:23]([O:27][C:28](=[O:29])[NH:30][C@@H:34]([CH3:33])[CH2:35][C:13]1[C:12]2[CH:11]=[C:10]([O:9][CH:6]3[CH2:8][CH2:7]3)[CH:18]=[CH:17][C:16]=2[N:15]2[CH2:19][CH2:20][CH2:21][C:14]=12)([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: Ic1c2n(c3ccc(OC4CC4)cc13)CCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](Cc1c2n(c3ccc(OC4CC4)cc13)CCC2)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
37.4 mL of a 1.6 M solution of n-butyllithium in n-hexane was added at −78° C. dropwise during 10 min to a solution of 18.65 g 6-cyclopropoxy-8-iodo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene in 250 mL tetrahydrofuran. The mixture was stirred at −78° C. for 30 min. 15.55 g (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added to the resulting suspension and the mixture stirred at −78° C. for 30 min and at 0° C. for 45 min. The reaction mixture was distributed between ice-cold 10% citric acid and ethyl acetate. The phases separated, the organic phase washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane: ethyl acetate=4: 1 to yield 11.91 g (S)-[2-(6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester as beige crystals melting at 83-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:14].C1N2CCN(CC2)C1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[S:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25](=[S:26])[O:14][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc([N+](=O)[O-])c2c(c1O)CCC2
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2c(c1OC(=S)N(C)C)CCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
5-Methyl-7-nitroindan-4-ol (5.0 g) was dissolved in N,N-dimethylformamide (50 mL). After adding triethylenediamine (5.8 g) and dimethylthiocarbamoyl chloride (4.8 g) with stirring at room temperature, the mixture was stirred at 75° C. for 5 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture. The insoluble material was collected by filtration, washed with diethyl ether and dried to give the title compound (5.80 g).
Reaction SMILES: ClC1C=C2C(C)(C)C(/C=C/C(/C3C=CC=C(CCC(O[N:58]4[C:62](=[O:63])[CH2:61][CH2:60][C:59]4=[O:64])=O)C=3)=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)=NC2=[N+](CCCS([O-])(=O)=O)C=1.[Na+:65].[Na+].[C:67]([CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][C:75](/[C:78](/[CH:103]=[CH:104]/[C:105]2[C:106]([CH3:123])([CH3:122])[C:107]3[C:108]([N:121]=2)=[N+:109]([CH2:114][CH2:115][CH2:116][S:117]([O-:120])(=[O:119])=[O:118])[CH:110]=[C:111]([Cl:113])[CH:112]=3)=[CH:79]\[CH:80]=[C:81]2\[N:82]([CH2:96][CH2:97][CH2:98][S:99]([O-:102])(=[O:101])=[O:100])[C:83]3[C:88]([C:89]\2([CH3:91])[CH3:90])=[CH:87][C:86]([S:92]([O-:95])(=[O:94])=[O:93])=[CH:85][CH:84]=3)=[CH:74][CH:73]=1)([OH:69])=[O:68].[Na+].[Na+]>>[Cl:113][C:111]1[CH:112]=[C:107]2[C:106]([CH3:123])([CH3:122])[C:105](/[CH:104]=[CH:103]/[C:78](/[C:75]3[CH:74]=[CH:73][C:72]([CH2:71][CH2:70][C:67]([O:69][N:58]4[C:62](=[O:63])[CH2:61][CH2:60][C:59]4=[O:64])=[O:68])=[CH:77][CH:76]=3)=[CH:79]/[CH:80]=[C:81]3/[N:82]([CH2:96][CH2:97][CH2:98][S:99]([O-:102])(=[O:101])=[O:100])[C:83]4[C:88]([C:89]/3([CH3:90])[CH3:91])=[CH:87][C:86]([S:92]([O-:95])(=[O:93])=[O:94])=[CH:85][CH:84]=4)=[N:121][C:108]2=[N+:109]([CH2:114][CH2:115][CH2:116][S:117]([O-:120])(=[O:118])=[O:119])[CH:110]=1.[Na+:65].[Na+:65]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(CCC(=O)O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)ON3C(=O)CCC3=O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 13 is prepared analogously to compound 11 (Example 11), except that compound 12 is used as a starting material.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[CH2:23](OCC)C>C(OCC)(=O)C>[CH3:23][N:21]1[CH2:2][CH:1]([C:4]2[CH:13]=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: CCOCC
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1Cc2ccccc2C(c2ccc3c(c2)CCCC3)C1

Procedure:
2-Methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline was prepared from 6-acetyltetralin and benzylamine as described in Example 58 (Steps A to D). It was dissolved in ethyl acetate and treated with 2 M hydrogen chloride in diethyl ether (2 equiv) to give the corresponding hydrochloride salt (0.43 g, 98.6% AUC HPLC): 1H NMR (300 MHz, MeOD) δ 7.22-7.34 (m, 3H), 7.08 (d, J=7.8 Hz, 1H), 6.94 (br s, 3H), 4.49-4.62 (m, 3H), 3.81 (dd, J=12.0, 6.0 Hz, 1H), 3.53 (t, J=11.7 Hz, 1H), 3.08 (s, 3H), 2.76 (br s, 4H), 1.82 (br s, 4H), EI MS m/z=278 [C20H23N+H]+. Anal. Calcd. for C20H24ClN: C, 75.60; H, 7.59; N, 4.41 with 1.1 equiv HCl. Found: C, 75.44; H, 8.11; N, 4.26.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[CH:10]/[C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH3:26])[C:13]=3[N:12]=2)=[C:7]([O:29][CH3:30])[CH:6]=1)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH2:22]([N:16]1[C:17](=[O:21])[C:18]2[N:19]([CH3:20])[C:11](/[CH:10]=[CH:9]/[C:8]3[CH:27]=[CH:28][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[O:29][CH3:30])=[N:12][C:13]=2[N:14]([CH2:25][CH3:26])[C:15]1=[O:24])[CH3:23]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)OC)cc3OC)n2C)n(CC)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)O)cc3OC)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Compound 20 (108 mg, 0.262 mmol) obtained in Example 19 was suspended in a solvent mixture of 2 ml of tetrahydrofuran, 2 ml of ethanol, and 1 ml of water. To the suspension was added 55 mg (1.311 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was acidified with 2N HCl, and the precipitated crystals were collected by filtration. The obtained crude crystals were purified by column chromatography (eluent: chloroform/methanol/acetic acid=40/1/1) to give 25 mg (yield 24%) of Compound 22, which was further recrystallized from isopropanol to give a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].CN1CCOCC1>CN(C)C=O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][NH:17][C:12]([CH2:13][N:8]([CH2:9][C:10]([OH:11])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:26][CH:25]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Yield: 80.2 %

Procedure:
2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 11.6 mmol) was added to a solution of 2-amino-1-(4-bromo-phenyl)-ethanone hydrochloride (3.05 g, 12.2 mmol) and 4-methylmorpholine (1.92 mL, 17.4 mmol) in dimethylformamide (15 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), and saturated sodium bicarbonate (2×50 mL). The basic extracts were neutralized and extracted with ethyl acetate (2×75 mL). The combined organic phases from the second extraction were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to provide ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol, 80%). C17H21BrN2O6 calculated 428.0 observed [M+1]+ 431.1; rt=2.36 min.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C@@H:19]([NH2:21])[CH2:20][C@H:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)C.O>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:27])=[C:13]3[CH2:18][C@@H:19]([NH2:21])[CH2:20][C@H:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1Cc2cccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 88.7 %

Procedure:
(2aR,4S)-1-Benzoyl-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole (29.4 g, 0.106 mole) was placed into a 500 ml three neck round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a constant addition funnel. The substrate was dissolved in glacial acetic acid (250 ml), and sodium acetate (34.7 g, 0.423 mole, 4 mol equiv) was then added. A solution of bromine (21.8 ml, 0.424 mole) in acetic acid was then added dropwise over a period of one hour with vigorous stirring and then stirred at room temperature overnight. The resulting thick slurry was diluted with ethyl ether, filtered and washed with ethyl ether. The material thus obtained was slurried in H2O and the pH adjusted to 11-12 with 5N NaOH. The solid was filtered, washed well with H2O and dried in vacuo to provide 33.6 g (88.8%) of the title compound. An analytical sample was prepared by recrystallization from isopropyl alcohol. m.p.: 169°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:20]([CH3:19])(=[O:22])=[O:21])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(Br)ccc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)ccc1CNS(C)(=O)=O
Reaction time: 1 h

Procedure:
To 4-bromo-2-ethyl-benzylamine (650 mg, 3 mmol) and triethylamine (500 μL, 3.6 mmol) in dichloromethane (5 mL) at room temperature was added methanesulfonyl chloride (283 μL, 3.6 mmol). The solution was stirred 1 h, diluted in water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid (880 mg, 100%). 1H NMR (300 MHz, CDCl3): δ ppm 1.25 (t, J=7.54 Hz, 3 H) 2.69 (q, J=7.54 Hz, 2 H) 2.90 (s, 3 H) 4.27-4.31 (m, 2H) 4.40-4.50 (m, 1 H) 7.21 (d, J=8.10 Hz, 1 H) 7.32-7.40 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13](=[O:14])[CH2:12][C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: N#CCC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
According to the Scheme 1 Step 1: A mixture of 4-chlorobenzylamine (10.0 g, 71 mmol), cyanoacetic acid (6.13 g, 72 mmol), HOBt (11 g, 72 mmol), EDCI.HCl (20 g, 106 mmol) in 100 mL of dioxane was stirred for 3 h at room temperature. The solvent was removed under vacuum and 300 mL of DCM was added. The organic layer was successively washed with 2×100 mL of water, 2×50 mL of a solution 1N of NaOH, 4×100 mL of water until neutral pH. The organic layer was dried over Na2SO4, filtered and concentrated to afford N-(4-chlorobenzyl)-2-cyanoacetamide 1(A) (13.12 g, 89%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15]O)[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@H]2C[C@H]21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CN2C(=O)c3ccccc3C2=O)CC[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of D7 (10 g, 44 mmol), phtalimide (10.29 g, 70 mmol) and triphenylphosphine (18.34 g, 70 mmol) in THF (150 mL) was cooled at 0° C., then a 40% solution of DEAD in toluene (31.94 mL, 70 mmol) was added. The mixture was stirred at room temperature for 3 hours, then water was added and the mixture was concentrated under vacuum; the residue was dissolved in DCM, washed with water and organics were evaporated. Cyclohexane (300 mL) and DCM (10 mL) were added, the precipitate was discarded and the filtrate was concentrated. The crude mixture was purified by silica gel column chromatography (cyclohexane/ethyl acetate=95:5 to 70/30) to give the title compound as a white solid. Yield (11 g, 71%).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3][C:2]1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].COC(OC)OC>C1COCC1>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([N:17]2[C:4](=[O:3])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: Cc1c(Br)cccc1-n1cnc2ccccc2c1=O
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (200 mg, 1.226 mmol), 3-bromo-2-methylaniline (228 mg, 1.226 mmol), and trimethoxymethane (390 mg, 3.68 mmol) in THF (2 mL) was heated overnight in a sealed tube at 100° C. The mixture was cooled to room temperature and concentrated, and the residue was purified by column chromatography, eluting with EtOAc-hexane (gradient from 10:90 to 50:50) to provide the desired product (140 mg, 36% yield). LCMS (M+H)+ m/z 315, 317.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:38][CH2:39][CH2:40][CH2-].ICCC>C1COCC1>[Si:1]([C:8]1[S:9][C:10]([CH2:38][CH2:39][CH3:40])=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCc1sc([Si](C)(C)C(C)(C)C)nc1C[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g, 0.269 mmol) in THF (3 mL) was cooled to −78° C. when N-BUTYLLITHIUM (2.5 M in hexanes) (0.119 ml, 0.296 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. 1-Iodopropane (0.0549 g, 0.323 mmol) was added dropwise and the solution was allowed to slowly warm to −50° C. and stirred for 1 hr. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification for the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[O:26][CH3:27])[C:4]1=[O:28].[C:29]([O:33][C:34]([N:36]([CH3:43])[C@@H:37]([CH2:41][CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[C:15]([CH2:14][N:5]1[C:4](=[O:28])[C@@H:3]([NH:2][C:38](=[O:39])[C@@H:37]([N:36]([CH3:43])[C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:41][CH3:42])[CH2:9][O:8][C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=3)=[C:16]([O:26][CH3:27])[CH:17]=[CH:18]2
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture of (S)-3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (54 mg, 116 μmol), (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (27.8 mg, 128 μmol), DIEA (80.6 μl, 466 iumol), and HBTU (48.6 mg, 128 μmol) in DMF (388 μL) was stirred at RT for 30 min. The mixture was diluted with EtOAc, washed with sat. NaHCO3, H2O and brine, then dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to provide tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (67.5 mg, 93%) as a white solid. MS m/z 648/650 (MNa)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Reactant: CC(=O)N1CCNC1=O
Product: COc1cc(N2CCN(C(C)=O)C2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 58.5 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.01 g) described in Preparation Example 252 and 1-acetylimidazolidin-2-one (0.38 g) and by the reaction and treatment in the same manner as in Example 1, the title compound (0.66 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](Br)[CH2:21][CH3:22].[CH2:24](I)C>>[CH2:17]([C:4]([CH2:20][CH2:21][CH3:22])([N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)[C:3]([N:2]([CH3:1])[CH3:19])=[O:18])[CH3:24]
Reactant: CCCBr
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Product: CCCC(CC)(C(=O)N(C)C)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 95, but substituting α-ethyl-N,N,4-trimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and propyl bromide for ethyl iodide, there was obtained α-ethyl-N,N,4-trimethyl-3-phenyl-α-propylpyrazole-1-acetamide having a melting point of 147°-148° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]=1[F:34])[O:6][CH2:7][CH3:8])C.O.O[Li].O>C1COCC1.CO>[F:34][C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (62.5 g) in THF (250 ml) and MeOH (250 ml) was added H2O (200 ml) and LiOH.H2O (10.5 g) and it was stirred 2 h at 65° C. MeOH and THF were evaporated and the aqueous residue was washed with Hept/Et2O 9:1 (2×150 ml). The organic layers were extracted with two portions of H2O (200 ml). The combined aqueous layers were cooled in an ice bath and acidified with 35 ml 25% aq. HCl. Extraction with AcOEt (3×200 ml) followed by washing with brine, drying (Na2SO4) and evaporation of the solvent afforded 28.7 g (99%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid. Yellow viscous oil. MS 231.2 ([M−H]−).