Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]I)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][N:7]1[C:3](=[O:13])[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]1=[O:8])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
Sodium hydride (0.522 g,13.05 mmol) is added to a solution of phthalimide (2.33 g, 15.84 mmol) and 18-crown-6 (0.01 g) in 20 mL of N,N-dimethylformamide (DMF). After stirring at RT for 20 min, a solution of the title F compound, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (4.61 g,11.55 mmol) in 5 mL of DMF is added, and the solution is stirred at RT for 30 min, then at 60° C. for 8 h. The solvent is removed under reduced pressure, and the residue is partitioned between 300 mL of ethyl acetate and 225 mL of 0.05M aqueous HCl. The organic phase is washed with 100 mL water and 50 mL of brine, dried over anhydrous Na2SO4 and concentrated to give 4.83 g (100%) of (2R)-(t-butyloxycarbonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a tan solid: NMR(CDCl3) 1.43 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.71 (t, 2H, J=6.6), 4.18-4.26 (m, 1H), 5.06 (br d, 1H, J=7.9), 7.70-7.73 (m, 2H), 7.83-7.86 (m, 2H); IR 1712, 1500, 1155; ESI-MS 290 (M++1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([O:28][CH3:29])=[CH:7][C:8]2[C:17]3[CH2:16][CH2:15][N:14]([C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]=3[C:11](=O)[NH:10][C:9]=2[CH:27]=1.[CH3:30]I>CN(C)C=O>[CH3:3][O:4][C:5]1[C:6]([O:28][CH3:29])=[CH:7][C:8]2[C:17]3[CH2:16][CH2:15][N:14]([C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]=3[CH2:11][N:10]([CH3:30])[C:9]=2[CH:27]=1
Reactant: CI
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(C)CC1=C2CCN(C(=O)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A stirred suspension of 0.017 m of NaH (washed with petroleum ether) in 50 ml of dimethyl formamide was treated in portions with 5 g (0.0137 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-benzoyl-benzo[c][2,7]naphthyridin-5(6H)-one. After stirring for 10 min, the reaction was treated with 5 g (0.035 m) of CH3I and stirred an additional 45 min. Dilution with water to 250 ml and filtration gave 4.8 g (93%) of crude material. Crystallization from methanol/CH2Cl2 afforded pure material, mp 241°-243° C.
Reaction SMILES: [C:1]([N:8]([CH3:34])[C@H:9]([C:31](O)=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:35]1([CH:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][NH2:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:44]1([CH:41]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:42][NH:43][C:31](=[O:32])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:34])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(c1ccccc1)c1ccccc1

Procedure:
Using Procedure A, Nα-Boc-Nδ-Fmoc-Nα-methylornithine and 2,2-diphenylethylamine afforded a colorless solid: 1H NMR (400 MHz, CDCl3) δ1.39 (s, 10H), 1.57 (m, 2H), 1.77 (m, 1H), 1.98 (m, 1H), 2.50 (s, 3H), 3.19 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.19 (t, J=9.5 Hz, 1H), 4.22 (m, 1H), 4.40 (d, J=7.2 Hz, 2H), 4.46 (m, 1H), 7.20-7.34 (m, 12H), 7.41 (t, J=6.6 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), and 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=4Br)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH3:27][N:28]1[CH2:32][CH2:31][N:30]([C:19]2[CH:20]=[C:21]([N:30]3[CH2:31][CH2:32][N:28]([CH3:27])[C:29]3=[O:33])[CH:22]=[CH:23][C:18]=2[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:26])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])[C:29]1=[O:33]
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2Br)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2N2CCN(C)C2=O)CC1
Yield: 25.7 %

Procedure:
Using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](2,4-dibromophenyl)methanone (238 mg) described in Preparation Example 238 and 1-methylimidazolidin-2-one (149 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (66 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:40])[C:37]#[C:38][CH3:39]>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:40])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:39]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1ccc(F)cc1F
Product: C/C(=C/C(=O)c1ccc(F)cc1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg (0.33 mmol) of Intermediate 39 to yield 63 mg (35% yield) of Example 31: TLC (DCM/MeOH (4:1): Rf=0.72; 1H NMR (DMSO-d6, 400 MHz) δ11.37 (d, 1H, J=9.4), 7.87 (m, 2H), 7.72 (q, 1H, J=6.4), 7.43 (m, 3H), 7.14 (m, 4H), 6.79 (d, 2H, J=8.8), 5.25 (s, 1H), 4.13 (m, 3H), 3.18 (m, 1H), 2.85 (t, 2H, J=6.0), 2.77 (dd, 1H, J=14.0, 9.8), 2.29 (s, 3H), 1.62 (s, 3H) ; low resolution MS (ES−)m/e 545.1 (M-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([OH:27])=O)[CH:4]=1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([NH:29][CH3:28])=[O:27])[CH:4]=1
Reactant: COc1cc2c(c(C(=O)O)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (74) (0.13 g, 0.33 mmol) in anhydrous THF (10 mL) and anhydrous DMF (0.7 mL), was prepared under N2. To the solution, HATU (0.15 g, 0.40 mmol) and Hunig's base (0.08 mL, 0.4 mmol) were added. The mixture was stirred at room temperature for 1 h. MeNH2 (2 M in THF, 2.0 mL, 4.0 mmol) was added and the flask was sealed and stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with brine and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/EtOAc, 5:1) to yield (1R,10R,11S,16S)-5-methoxy-N,1,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (75) (0.08 g, 59%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([O:37][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: O=C(CCl)OC1CCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)OC2CCCC2)CCN(C)CC1
Temperature: 90 °C
Yield: 12.8 %

Procedure:
The title compound was prepared by following general procedure 9. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) was added to the solution and stirred for 10 min. at RT cyclopentyl 2-chloroacetate (90 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. To obtain 20 mg of cyclopentyl 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate. Then purified compound was taken into ethanol in HCl to gives HCl salt of desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:9])[CH3:8])[CH:2]=1.[CH3:10][O:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:16][C:15]([CH:26]=O)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:10][O:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:16][C:15]([CH2:26][NH:9][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(N)c1cccnc1
Reactant: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2cc(CNC(C)c3cccnc3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
1-Pyridin-3-yl-ethylamine (245 mg, 2 mmol) and 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (121 mg, 0.5 mmol) were dissolved in dichloroethane (10 mL). After stirring for 6 h at room temperature, the sodium triacetoxyborohydride (212 mg, 1.0 mmol, Aldrich) was added to the solution at 0 C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with saturated aqueous sodium bicarbonate (10 mL). The organic phase was separated and the aqueous phase was extracted with dichloroethane (10 mL×3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated via vacuo. The crude was purified by column chromatography (silica gel, ethyl acetate) to give the title compound as white solid in 50% yield (87 mg, 0.25 mmol).
Reaction SMILES: C([O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][O:18]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[ClH:27].C(ONCCCCCCNOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+].Cl>C(O)C.O>[ClH:27].[OH:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][OH:18]
Reactant: O=C(ONCCCCCCNOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ONCCCCCCNO
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The specific laboratory procedure for carrying out the above reaction scheme is as follows. Benzoyloxy peroxide (24.2 g, 0.1 mol) is dissolved in 300 ml of absolute benzene. Then, 1,6-diaminohexane (1) (11.6 g, 0.1 mol) dissolved to 100 ml of absolute ether is added to the benzoyloxy peroxide-benzene solution dropwise. The reaction mixture is kept while stirring at 40°-50° C. for two hours. 100 ml of absolute ether is added and the resultant precipitate is separated. Then, dry HCl gas is passed through the solution to form 1,6-dibenzoyloxy amino hexane hydrochloride (3), (M.W. 429, M.P. 137°-138° C.), which is recrystallized in absolute ethanol (yield 45%). 1,6-dibenzoyloxy amino hexane (2) is formed by treating (3) with 10% NaHCO3 solution. (M.W. 356, M.P. 70° C.). Then the purified product (3) (6.45 g, 0.015 mol) is dissolved in 200 ml of absolute ethanol. 150 ml of concentrated HCl solution is added slowly and the mixture refluxed for one and a half hour at 85° to 95° C. The refluxing is stopped and the reaction mixture cooled to about 30° C. using an ice bath. Then 150 ml of distilled water is added and stirred for another half hour at 30° C. The entire solvent is evaporated with a rotary evaporator. The residue is then dissolved into an isopropanol-ethylacetate mixture for crystallization. Further, recrystallization is carried out in the same solvent system. The resulting white powder-like crystal is 1,6-dihydroxylamino hexane hydrochloride (4) (M.W. 221, M.P. 135° C.). The yield is 56%. The free base form of (4), 1,6-dihydroxylamine hexane (5) can be obtained by treating (4) with mild base, such as NaHCO3 solution.
Reaction SMILES: [Cl-].[Li+].CON(C)[C:6]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH3:13])=[O:7].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(OCC)C.[Cu]I.O>[CH3:13][C:9]1[N:10]=[CH:11][O:12][C:8]=1[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1ocnc1C
Agent: [Cu]I
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: Cc1ncoc1C(=O)c1ccccc1
Yield: 38.1 %

Procedure:
To a mixture of lithium chloride (0.77 g, 18.2 mmol) and copper(I) iodide (0.087 g, 0.45 mmol) was added diethylether (30 ml). After stirring for 5 minutes a solution of N-methoxy-N,4-dimethyl-1,3-oxazole-5-carboxamide (2.58 g, 15.16 mmol) in diethylether (30 ml) was added followed by the slow addition of phenylmagnesium bromide (4.12 g, 22.74 mmol). After stirring for 20 hours at room temperature 1N HCl (20 mL) and water (30 mL) were added. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material on silica gel afforded (4-methyl-1,3-oxazol-5-yl)(phenyl)methanone (1.08 g, 30%)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:14].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([Br:1])=[C:3]([F:13])[CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:14]
Reactant: O=C1Nc2c(ccc(F)c2Br)C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(C(=O)O)ccc(F)c1Br
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, addition funnel, and temperature probe. The flask was charged with 7-bromo-6-fluoroindoline-2,3-dione (719b; 11.53 g, 47.3 mmol) and 1 N NaOH (104 mL, 104 mmol) at RT; 30% hydrogen peroxide (10.62 mL, 104 mmol) was added via addition funnel over 15 min when the temperature of the brown solution raised to 45° C. The reaction mixture was stirred for 1.5 h when mostly product was observed via LCMS. The slurry was acidified to pH 7 with 2 N HCl when a solid was still present; the reaction mixture was diluted with water (100 mL) to effect stirring when it began to bubble. The slurry was then acidified to pH 1.8 with 2 N HCl (no exotherm was observed). After stirring at RT for 30 min, the slurry was filtered, washed with water, and dried in a vacuum oven to give 2-amino-3-bromo-4-fluorobenzoic acid (9.90 g, 42.3 mmol, 90% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.59 (t, J=8.61 Hz, 1H) 7.08 (br. s., 2H) 7.86 (dd, J=8.90, 6.75 Hz, 1H) 13.04 (br. s., 1H). 19F NMR (377 MHz, DMSO-d6) δ ppm −97.39 (s, 1F). MS (ESI, pos. ion) m/z: 233.9/235.9 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:22][S:23](NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:25])=[O:24].CS(Cl)(=O)=O.N1C=CC=CC=1>>[CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1C1CC2CC1CC2Cc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1C1CC2CC1CC2Cc1cnccn1

Procedure:
{2-[2,5-Diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenyl}-(methylsulfonyl)amine was prepared from 2-[2,5-diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenylamine (Step 2) (690 mg, 2.5 mmol) according to the procedure for Preparation III using methanesulfonyl chloride (190 μl, 2.46 mmol) and pyridine (220 μl, 2.72 mmol). The crude mix was purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford the desired sulfonamide (533 mg). MS (ESI, pos. ion) m/z: 358 (M+H), (ESI, neg. ion) m/z: 356 (M−H). Calc'd for C19H23N3O2S: 357.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:20][CH2:21]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: c1ccc(N2CCNCC2)nc1
Product: Brc1ccc2nccc(N3CCN(c4ccccn4)CC3)c2c1

Procedure:
291 mg 6-bromo-4-chloroquinoline and 0.91 mL 4-(2-pyridyl)piperazine were reacted by the same method as in Production Example 74 to give 373 mg of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][C:4]([CH3:10])([CH2:3][CH2:2][O:1][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCOS(C)(=O)=O
Temperature: -20 °C

Procedure:
To a solution of methyl 4-hydroxy-2,2-dimethylbutanoate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added methanesulfonyl chloride (1.5 eq.) and triethylamine (3.0 eq.). The reaction was warmed to −20° C. over 30 min and then quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]([CH2:15][C:16]1[C:25]2[C:20](=[C:21]([NH:26][C:27](=[O:36])[C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[CH:37]=[CH2:38])([OH:14])=O.NCC1C=CC=CN=1>ClCCl>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C:27]([NH:26][C:21]1[C:20]2[C:25](=[C:16]3[C:17](=[CH:18][N:19]=2)[CH:37]=[CH:38][C:12]([OH:14])=[CH:15]3)[CH:24]=[CH:23][CH:22]=1)=[O:36]
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Agent: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc2c1ncc1ccc(O)cc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a mixture of dimethylformamide (80.5 mg) and dichloromethane (2 ml) was added oxalyl chloride (140 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (340 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added a solution of 2-aminomethylpyridine (458 mg) in dichloromethane (2 ml) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane-methanol) to give 4-(2,6-dichlorobenzoylamino)-9-hydroxyphenanthridine (75.7 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:7]=[C:6]([N:20]3[CH:24]=[C:23](I)[N:22]=[CH:21]3)[N:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:1]1([C:4]2[N:5]=[C:6]([N:20]3[CH:24]=[C:23]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[N:22]=[CH:21]3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)nc(-n3cnc(I)c3)c2)cc1
Product: Nc1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-cyclopropyl-6-(4-iodo-imidazol-1-yl)-4-(4-trifluoromethyl-phenyl)-pyridine (example E.17) (1.0 g, 2.2 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.628 g, 2.85 mmol) according to the general procedure VI. Obtained as an off-white solid (0.180 g, 46%). MS (ISP) 422.2 [(M+H)+]; mp 233-235° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=1)(=O)OCC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(F)cc2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 78.2 %

Procedure:
Following the procedure in Example 1, Step 4, using [3-(4-fluoro-phenoxy)-benzyl]-phosphonic acid diethyl ester (1.2 g, 3.5 mmol) (Step 1) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (707 mg, 3.55 mmol) yielded the title compound (1.05 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:16])[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:16])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:22]([C:21]4[CH:25]=[CH:26][C:18]([I:17])=[CH:19][CH:20]=4)=[O:23])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Yield: 90 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 65 and using 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.42 g) described in Preparation Example 96, 4-iodobenzoyl chloride (1.83 g), the title compound (2.63 g) was obtained.