Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[CH:4]=[C:3]1[Si:19]([CH3:22])([CH3:21])Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCCCCC.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[CH:4]=[C:3]1[Si:19]([CH3:22])([CH3:21])[NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC(C)(C)N
Reactant: CC1C([Si](C)(C)Cl)=Cc2c1c1ccccc1c1ccccc21
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1C([Si](C)(C)NC(C)(C)C)=Cc2c1c1ccccc1c1ccccc21

Procedure:
To a 500 ml round bottom flask containing 1.699 g (0.00526 mole) of (1-methyl-1H-cyclopenta[l]phenanthrene-2-yl)dimethylchlorosilane and 100 ml of hexane and 150 ml toluene was added 0.975 g (0.0132 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.785 g (94.6 percent). 1H NMR analysis indicated the predominant isomer was substituted at the 2 position.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][C:14]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:13][CH:12]=1>>[CH2:18]([N:15]([CH2:16][CH3:17])[C:14]1[CH:20]=[CH:21][C:11]([NH:10][C:2]2[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CNc1cc(Cl)ncn1
Product: CCN(CC)c1ccc(Nc2cc(NC)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl)-methyl-amine and 4-amino-N,N-diethylaniline. The ethyl acetate layer is dried over Na2SO4 and evaporated in vacuo. The residue is suspended in CH2Cl2, filtered off and dried to afford the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-phenoxyphenol (50 g, 0.27 mol) and pyridine (22 mL, 0.27 mol) in 500 mL of methylene chloride was added under nitrogen dropwise over 1.5 hours to a solution of 4-nitrophenyl chloroformate (54 g, 0.27 mol) at room temperature. After the addition the reaction was stirred overnight at room temperature. The reaction was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 94.86 g of a light yellow crystalline solid. Recrystallization from methylene chloride-diisopropyl ether gave 69.13 g (73%) of the title compound as a light tan crystalline solid, mp 113°-115° C.
Reaction SMILES: [N:1]#CBr.[CH2:4]([N:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:7]C)[CH3:5]>CCOCC>[CH2:4]([N:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:7]#[N:1])[CH3:5]
Reactant: N#CBr
Reactant: CCN(CC)c1cccc2ccccc12
Solvent: CCOCC
Product: CCN(C#N)c1cccc2ccccc12
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A mixture of cyanogen bromide (3.32 g, 31.3 mmol) and N,N-diethyl-1-naphthylamine (5 g, 25 mmol) was heated at 100° C. for 4 hours under nitrogen. It was then allowed to cool to room temperature, ether was added, and the insoluble N,N-diethyl-1-naphthylamine hydrobromide was filtered off. The ether layer was washed with 15% aqueous HCl solution (2×50 ml), water (2×50 ml), and dried over MgSO4. It was filtered, concentrated and the residue was flash chromatographed on silica gel to give N-ethyl-N-(1-naphthyl)-cyanamide (2.34 g, 48%) as a yellow thick liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccc(O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCCCCBr)cc21
Temperature: 65 °C
Yield: 65.4 %

Procedure:
A mixture of 6-hydroxyindan-1-one (100 gm, 0.675 mol), potassium carbonate (96 gm, 0.695 mol), 1,4-dibromo butane (365 gm, 1.69 mol) and tetrabutyl ammonium bromide in acetone was introduced in to a three necked round bottomed flask filtered with a water condenser and a mechanical stirrer. The mixture was brought to a temperature 65° C. and maintained at 65° C. for nine hours and then distilled off solvent, diluted with water (400 ml). The aqueous layer was extracted with ethyl acetate, and the extract was washed with water, dried and evaporated in the rotavapour under reduced pressure to get a residue which on crystallization from isopropyl ether gave 125 gm of 6-(4-bromo butoxy)-indan-1-one of the formula 3
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)=O>ClCCl.CC(C)=O>[C:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:21]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 77 %

Procedure:
Dissolve 2-(3-hydroxypropyl)isoindole-1,3-dione (2 g, 9.74 mmol, 1 eq) in 40 mL of dichloromethane under N2. Add sulfuric acid (780 μL) and cool reaction mixture to −5° C. Condense isobutylene gas to a liquid using a −78° C. cold finger charged with dry ice and acetone. Add approximately 20 mL of the condensed liquid to the reaction mixture and slowly warm the solution to room temperature overnight while stirring. Add saturated, aqueous sodium hydrogencarbonate to the reaction mixture and extract product into the organics. Wash separated organic layer with water and dry over magnesium sulfate to give 1.969 g (77% yield) of 2-(3-tert-butoxypropyl)isoindole-1,3-dione as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[C:26]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: CC(=O)Cl
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Reactant: Nc1ccccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3ccccn3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 46.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.077 mL, 0.58 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 30) (200 mg, 0.49 mmol) in DCM (5 mL) and stirred at ambient temperature for 50 minutes. 2-Amino-pyridine (93 mg, 0.98 mmol) and pyridine (0.080 mL, 0.98 mmol) were added and the reaction stirred for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (40 mL), washed with water (10 mL), and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 0-100% methanol in DCM to afford the product (112 mg, 47%). 1H NMR δ (300 MHz, CDCl3) 2.12-2.26 (m, 1H), 2.35 (quintet, 2H), 2.53-2.66 (m, 1H), 2.93 (s, 3H), 3.34-3.57 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.93 (t, 1H), 6.97 (s, 1H), 7.08 (t, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 7.75 (t, 1H), 8.11 (d, 1H), 8.29 (d, 1H), 8.33 (q, 2H), 8.68 (s, 1H); m/z 488 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([N:72]1[CH2:73][CH2:74][N:69]([CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:70][CH2:71]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-phenyl-propionic acid (3 g, 11.3 mmol) was dissolved in DMF (100 mL), and PyBOP (5.9 g, 11.3 mmol) and Hünig's base (3.36 g, 25.99 mmol) were added, followed by 1-benzyl-piperazine (2 g, 11.3 mmol). Stirring at rt was continued for 8 h, followed by the addition of EtOAc (400 mL). The mixture was washed with 1 N aq. HCl (300 mL), sat. aq. sodium hydrogencarbonate solution (300 mL) and brine (300 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4.375 g (91%) of [(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester. LC-MS: tR=0.80 min; [M+H]+=424.34.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]S(C)(=O)=O)[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)nn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)nn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
(5R)-3-[3-Fluoro-4-(4-methyl-1,2,3-triazol-1-yl)phenyl]-5-[(methanesulfonyl)methyl]-oxazolidin 2-one (Intermediate 18) (5.0 g, 13.5 mmol) was dissolved in DMF (45 ml). Sodium azide (1.75 g, 27.0 mmol) was added and the reaction mixture was stirred at 70° C. for one hour. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give the product as a white solid (4.1 g), which was used without further purification.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:22]1([C:7]2[S:6](=[O:29])(=[O:28])[N:5]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccncc1

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) and 4-(chloromethyl)pyridine in a similar manner as described for e.g. Example 2 and 3 1H NMR (500 MHz, CDCl3): δ 8.66-8.60 (m, 2H), 7.54-7.38 (m, 7H), 7.31-7.24 (m, 2H), 7.23-7.16 (m, 1H), 7.10-7.04 (m, 2H), 5.34-5.27 (m, 1H), 4.82 (s, 2H), 2.92-2.84 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.35 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.3, 150.3, 143.4, 141.5, 135.4, 131.7, 130.0, 128.8, 128.5, 128.4, 126.1, 124.7, 123.1, 107.2, 44.1, 42.3, 35.3, 31.5, 29.0, 28.2; Mass Spectrum: M−H+ 448.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21](SC)=[N:22][S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[N:13]=1>O1CCCC1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][C:21]([NH:22][S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[O:7])[N:13]=1
Reactant: COc1cc(OC)nc(NC(=NS(=O)(=O)c2cccnc2)SC)n1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2)n1
Reaction time: 0.33 h

Procedure:
To 8 ml of 15% aqueous tetrahydrofuran was added with stirring 0.8 g of mercuric acid oxide and 0.56 ml of borontrifluoride etherate. The mixture was stirred for 20 minutes, and then 0.8 g of N-(4,6-dimethoxypyrimidin-2-yl)-N'-(3-pyridinylsulfonyl)carbamimidothioic acid, methyl ester was added. The slurry was stirred at room temperature for 1 hour, filtered, and the solid was rinsed with 50 ml of water, followed by 40 ml of dichloromethane, and dried to give 0.3 g of the desired product, m.p. 176° C. dec.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[F-].[Cs+]>[C:1]1([NH:7][C:8](=[O:9])[O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Oc1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: O=C(Nc1ccccc1)Oc1ccccc1
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
1.28 g (8.4 mmol) of cesium fluoride was weighed into a flask and dried under a reduced pressure at 130° C. for 30 minutes. 50 g (0.42 mol) of phenyl isocyanate and 39.5 g (0.42 mol) of phenol were added thereto with stirring at 105° C. for 10 minutes, followed by the removal of an unreacted raw material at a reduced pressure. Thus, 88.3 g of phenyl N-phenylcarbamate having a melting point of 123° to 124° C. was obtained at a yield of 93.1%.
Reaction SMILES: [O:1]=O.[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[OH-].[Na+]>[Br-].[NH4+].[NH4+].[NH4+].[NH4+].[Br-].[Br-].[Br-].C1(C)C=CC=CC=1>[Br:3][C:4]1[C:5](=[O:1])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=1)[CH:7]=2
Reactant: O=O
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [Br-]
Agent: [NH4+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Yield: 85.8 %

Procedure:
Into a three-necked, 300-mL flask equipped with a stirrer, a molecular-oxygen-containing gas (air) inlet tube and a gas outlet tube (fitted with a condenser), 2,7-dibromofluorene (9.30 g, 0.029 mol) was charged, followed by its dissolution with toluene (100 g). Subsequent to addition of tetraammonium bromide (0.08 g) and a 48% aqueous solution of sodium hydroxide (2.66 g), the resulting mixture was vigorously stirred at 60° C. for 6 hours while introducing air at a flow rate of 0.2 L/min. After completion of the stirring, the reaction mixture was allowed to stand, and the resulting toluene layer was collected. The toluene layer was then subjected to acid washing, followed by water washing until its pH arose to 7. Toluene was then distilled off to recover crude crystals of 2,7-dibromofluorenone. The content of 2,7-dibromofluorene in the crude crystals at that time was 0%. Those crude crystals were recrystallized from N,N′-dimethylformamide (15 g) to afford 2,7-dibromofluorenone as yellow crystals (7.91 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:36][CH:35]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (32 mg, 0.81 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (6 ml). After stirring at room temperature for 30 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (142 g, 0.74 mmol) was added to the obtained suspension. They were stirred at room temperature for 40 minutes and then at 50° C. for 40 minutes. A solution of (S)-3-methanesulfonyloxy-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (254 mg, 1.81 mmol) in dimethyl sulfoxide (3 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 5 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl)propyl]pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (78 mg, 25%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]1=[O:18].[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.C(N(CC)CC)C>ClCCl>[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH:29][S:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:18])[C:4](=[O:17])[N:5]4[CH3:16])(=[O:14])=[O:13])[CH:27]=[CH:28][C:20]1=2
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Nc3ccc4c(c3)OCCO4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (example 6-3a, 450 mg, 1.6 mmol) was added to a stirred solution of the 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (215 mg, 1.4 mmol) and triethylamine (170 mg, 1.7 mmol) in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then concentrated. The crude product was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to provide N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. MS (M+H, 404.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.47 (s, 3H), 3.49 (s, 3H), 4.12 (m, 4H), 6.55 (m, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 7.59 (d, J=2 Hz, 1H), 10.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[Br:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:18](=[O:19])[CH2:17][CH2:16][Br:15]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=O)CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,6-dimethylaniline (2 g, 16.5 mmol), diethyl ether, and aqueous saturated sodium bicarbonate (50:50 v/v) was added dropwise 3-bromopropionoyl chloride (2 g, 19.8 mm) in ether (5 mL). The mixture was allowed to stir at 0° C. for 2 hours, and at room temperature for an additional 1 hour. The organic layer was washed with 10% citric acid, dried over MgSO4, then filtered. The solvent was evaporated to afford N-(2,6-dimethylphenyl)-3-bromopropanamide, a compound of formula (1), as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)(=O)C.[CH2:24]1[CH:29]([CH:30]=O)[CH2:28][CH2:27][O:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[CH2:30][CH:29]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:12])[S:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)sn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2CC2CCOCC2)sn1
Reaction time: 4 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (3-tert-butyl-isothiazol-5-yl)-amide; hydrochloride (40.4 mg; 0.11 mmol) in DMF (1 mL) is added acetic acid (0.05 mL; 0.87 mmol) and a solution of tetrahydropyranyl-4-carboxaldehyde (37.7 mg; 0.33 mmol) in DMF (1 mL). The reaction is shaken for 4 hours. To the mixture is added a solution of sodium triacetoxyborohydride (93.2 mg; 0.44 mmol) in DMF (0.4 mL). The reaction mixture is shaken for 16 hours at room temperature. After this time, the reaction is quenched with water (0.1 mL) and the mixture is concentrated in vacuo. Purification by preparative HPLC provides the title compound, m/z 366 [M+H+].