Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O.CO>[O:27]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC([C@H](C)NC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 0.72 g of benzyl [(2S)-3-hydroxybutan-2-yl]carbamate (Example 133A, 3.3 mmol, 1 equivalent), 0.57 g of 1H-isoindole-1,3(2H)-dione (3.9 mmol, 1.2 equivalents) and 1.3 g of triphenylphosphine (4.9 mmol, 1.5 equivalents) were dissolved in 15 ml of THF, and 1.1 g of di-tert-butyl(E)-diazene-1,2-dicarboxylate (DIAD, 4.9 mmol, 1.5 equivalents) were added at RT. The mixture was stirred at RT overnight, 2 drops of water and Extrelut® were added and the mixture was concentrated. The residue was purified on a silica gel cartridge (Biotage SNAP Cartridge KP-Sil 25 g) (gradient cyclohexane/ethyl acetate from 5% to 100%). The crude product obtained was left in a mixture of 5 ml of methanol and 1 ml of water overnight. The solid obtained was filtered off, washed with a little methanol/water mixture and dried under reduced pressure. The filtrate was purified by preparative HPLC (Method 9). This gave a total of 692 mg (53% of theory, purity 87%) of the title compound (diastereomer mixture in a ratio of about 4:1).
Reaction SMILES: [C:1](C1C=CC=CC=1O)(C)(C)C.[Cl:12][C:13]1[CH:37]=[C:36]([CH:38]2[CH2:43]CCC[CH2:39]2)[CH:35]=[CH:34][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][C@:26]([CH3:33])([C:30]([OH:32])=[O:31])[O:27]2)=[CH:22][CH:21]=1>>[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([CH3:43])([CH3:1])[CH3:39])[CH:35]=[CH:34][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][C@:26]([CH3:33])([C:30]([OH:32])=[O:31])[O:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: C[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCCCC4)cc3Cl)cc2O1
Product: CC(C)(C)c1ccc(OCCCOc2ccc3c(c2)O[C@@](C)(C(=O)O)CC3)c(Cl)c1

Procedure:
The title compound was prepared following the procedures described in Example 5, Step B-E employing tert-butylphenol instead of 4-(2,2,2-trifluoroethoxy)phenol, and (2R)-methyl 2-methyl-7-hydroxychromane-2-carboxylate (Example 23, Step A) instead of ethyl 2-ethyl-7-hydroxychromane-2-carboxylate.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CO>C(OCC)C>[Br-:18].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCCCBr
Reactant: C=Cn1ccnc1
Solvent: CCOCC
Solvent: CO
Product: C=C[n+]1ccn(CCCCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-decyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The white precipitate was filtered off and dried at room temperature to yield a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[O:16]=[C:17]([Cl:23])OC(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:17]([Cl:23])(=[O:16])[NH2:5].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Clc1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Product: NC(=O)Cl
Temperature: 140 °C

Procedure:
To a suspension of 2-chlorophenothiazine (2 g) in xylene (20 ml)was added diphosgene (3.4 g). The mixture was heated to 140° C. for 18 hrs. The mixture was then cooled and the xylene removed under reduced pressure. The residue was purified by flash chromatography (2–5% ethyl acetate/hexane) to afford the sub-title compound as a brown solid (2.04 g): 1H NMR (400 MHz, CDCl3) δ 7.26–7.43 (4H, m), 7.45–7.51 (1H, m), 7.59–7.68 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][CH2:8]2.[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21]O)=[CH:16][N:15]=1>>[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21][C:5]2[CH:6]=[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:16][N:15]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1cccc2c1NCCC2
Product: COc1cc(Cc2cnc(N)nc2N)cc2c1NCCC2

Procedure:
8-Methoxy-1,2,3,4-tetrahydroquinoline (J. L. Neumeyer and J. G. Cannon, J. Pharm. Sci., 51, 804 (1962)) (2.88 g) was treated by the method of Example 1 with 2,4-diamino-5-hydroxymethylpyrimidine. The product crystallized from the reaction mixture as an off-white solid, which was washed with water and treated with ammonia, followed by recrystallization from absolute ethanol (5.0 g). A slight impurity was removed on a silica gel column, which was eluted with 19:1 methylene chloride:methanol, taken to dryness, and recrystallized once more from absolute ethanol; m.p., 201°-203° C. Anal. Calcd. for C15H19N5O: C, 63.14; H, 6.71; N, 24.54. Found: C, 63.23; H, 6.75; N, 24.47.
Reaction SMILES: [CH2:1]([CH2:6][NH2:7])[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(Cl)([Cl:17])=O>>[ClH:17].[CH:8]1([O:4][C:3](=[O:5])[CH2:2][CH2:1][CH2:6][NH2:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCCCC1
Reactant: O=S(Cl)Cl
Reactant: NCCCC(=O)O
Product: Cl
Product: NCCCC(=O)OC1CCCCC1

Procedure:
GABA (8 g, 77.6 mmol) was suspended in 100 ml (0.96 mol) of cyclohexanol. Thionyl chloride (40 ml) was added dropwise to the mixture at 0° C. The mixture was then refluxed for 4 hours, cooled and crystallized from ethyl ether. The white crystals obtained in this manner were filtered and dried. NMR analysis confirmed the identity of the product.
Reaction SMILES: [N+:1](/[CH:4]=[C:5](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH3:6])([O-:3])=[O:2].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])([O-:3])=[O:2]
Reactant: C/C(=C\[N+](=O)[O-])c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C[N+](=O)[O-])c1ccccc1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
In a 10 mL Schlenk-flask, 6.8 mg of cuprous tert-butoxide and 37.3 mg of (S)-p-tol-BINAP were dissolved in 5 ml of toluene. After stirring for 30 minutes at room temperature to give an asymmetric copper complex. One hundred microliters (100 μL) of this solution (containing 1 μmol of the asymmetric copper complex) were mixed with 4.9 ml of toluene, and 90 μL (1.5 mmol) of poly(methylhydrosiloxane) (15-40 mPas (20° C.), d=1.004 g/mL, nD20=1.398, produced by Fluka) and 221 mg (1.2 mmol) of diphenylsilane were added thereto. After stirring for 5 minutes, 1 mmol of (E)-1-nitro-2-phenyl-1-propene was added, and the mixture was further stirred for 24 hours at room temperature. Four milliliters (4 mL) of a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L) were added to the reaction mixture and stirring was continued for 3 hours. Water was added and the mixture was extracted with diethyl ether (30 mL×2). After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide optically active 1-nitro-2-phenylpropane.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N+:16]([O-:39])=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)n1
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine (250 mg, 0.56 mmol) and 3-chloroperoxy-benzoic acid (77%, 150 mg, 0.67 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 2 hours. The mixture is diluted with CH2Cl2 (20 mL) and washed with saturated Na2CO3, brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified on PTLC (1:1 hexane:EtOAc) to give 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine 1-oxide. 1H NMR (CDCl3) 7.90 (m, 1H), 7.50-7.04 (m, 3H), 6.90-6.71 (m, 3H), 5.18 (m, 2H), 4.55 (m, 1H), 3.95 (m, 1H), 2.78 (s, 3H), 2.52-2.20 (m, 4H), 2.20 (s, 3H), 1.35 (d, 6H), 1.25 (d, 6H), 1.08 (t, 6H).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](I)=[CH:12]2.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]([C:13]2[CH:14]=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:6])[OH:23])[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Clc1cccc2cc(I)cnc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
iso-Propyl magnesium chloride (2M solution in tetrahydrofuran)(3.76 ml, 7.5 mmol) was added dropwise over 0.25 h to a stirred solution of 8-chloro-3-iodoquinoline (D1)(2.0 g, 6.9 mmol) in tetrahydrofuran (16 ml) at −40° C. under argon. After stirring the solution at this temperature for 0.5 h, 3-chlorobenzaldehyde (0.77 ml, 6.8 mmol) was added dropwise over 10 mins. The solution was allowed to warm to ambient temperature over 1 h and then quenched by the addition of a saturated solution of sodium chloride (100 ml). The mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (D2) as a crude solid (1.84 g, 6.0 mmol, 88%) which was used directly in the next stage (see D3).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)=[CH:8][CH:7]=1)[CH3:2].BrC1C=CC(CCN2CCCC2)=CC=1>>[N:3]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]5[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=3[C:19]=45)=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:27][CH2:26]1
Reactant: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Agent: Brc1ccc(CCN2CCCC2)cc1
Product: O=C1NCCc2c(-c3ccc(CCN4CCCC4)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example YY), the tricyclic bromide (198 mg, 0.75 mmol) and 1-[2-(4-bromo-phenyl)-ethyl]-pyrrolidine were coupled to yield 2-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 160 mg (59%) as a beige solid: m.p. 228-229° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ1.69 (m, 4H), 2.51 (m, 4H), 2.67 (m, 2H), 2.81 (m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.56 (m, 3H), 7.68 (d, J=7.5 Hz, 1H), 8.08 (br t, 1H), 11.31 (br s, 1H). MS (FAB, MH+): 360. Anal. (C23H25N3O) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](N)[CH3:8])[CH:2]=1.[N:10]1[C:19]2[C:14](=CC=[CH:17][C:18]=2C(=O)C)C=CC=1.N.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:17][C:18]=2[CH:19]([NH2:10])[CH3:14])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1cccnc1
Reactant: CC(=O)c1cccc2cccnc12
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cccc2cccnc12
Yield: 98 %

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-quinolin-8-yl-ethanone (1.71 g, 10 mmol), 2 M ammonia solution in methyl alcohol, acetic acid (25 mL, 50 mmol, Aldrich) and sodium cyanoborohydride (2.5 g, 40 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as light yellow solid in 98% yield (1.68 g, 9.8 mmol). MS (ESI, pos. ion) m/z: 173.2 (M+1); MS (ESI, neg. ion) m/z: 171.0 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and 2-acetoxyisobutyryl chloride. m.p.: 222-223° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:39]=[N:40]2)=[CH:35][C:34]=1[O:51][CH3:52])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:37]4[C:36]5[C:41](=[CH:42][C:33]([O:32][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[C:34]([O:51][CH3:52])[CH:35]=5)[N:40]=[CH:39][CH:38]=4)=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)c(F)c2)CC1
Reactant: COc1cc2c(OS(=O)(=O)C(F)(F)F)ccnc2cc1OCc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 143 °C
Yield: 48 %

Procedure:
To a flask containing cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide(4-fluoro-phenyl)-amide (2.25 g, 6.7 mmol) and trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester (1.87 g, 4.5 mmol) was added dry 2,6-lutidine (9 mL). The reaction mixture was heated to reflux (143° C.) with vigorous stirring. The reaction progress was monitored by LC-MS. 2,6-Lutidine was removed under reduced pressure when the reaction was complete (about 6 h). The residue was treated with charcoal (1.5 g) in refluxing EtOAc (50 mL) for 15 min, and filtered through celite. The volume of the filtrate was reduced to about 20 mL and was added 20 mL of 1N HCl. The crude product precipitated as the HCl salt, which was filtered and washed with EtOAc and H2O (88% purity by analytical HPLC). The HCl salt was free-based with saturated aqueous NaHCO3 solution. Further purification by column chromatography (hexans:EtOAc=1:4) gave cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide as an off-white solid (1.3 g, 48% yield. 1H NMR (400 MHz, DMSO, d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1H), 7.92 (dd, 1H), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+596.2. found 596.3.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:46][C:47]([F:61])([F:60])[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:60])([F:61])[F:46])=[CH:53][CH:52]=2)[CH2:59][CH2:58]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Iodo-5-methanesulfonyl-benzoic acid (Example C, 3.0 g, 9.2 mmol) in dimethylformamide (20 ml) were successively added TBTU (3.8 g, 11.5 mmol), N-ethyldiisopropylamine (8.0 ml, 46.0 mmol) and 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7], 2.5 g, 11.0 mmol). The reaction was then stirred at room temperature for two hours, then concentrated in vacuo and purified by column chromatography (SiO2, 50 g, CH2Cl2/MeOH/NH3=100/0/0 to 95/4.5/0.5), to give the title compound as a pale brown foam; MS (m/e): 539.1 (M+H+). TBTU=2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN([CH:24]=[N:25][C:26](=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C>CO.C(O)(=O)C>[N:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:18][CH:17]=3)[N:20]=[CH:24][N:25]=2)=[CH:28][CH:29]=1
Reactant: CN(C)C=NC(=O)c1ccncc1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Yield: 21.8 %

Procedure:
Isonicatinamide (4.15 g) was heated in 35 ml of N,N-Dimethylformamide diethyl acetal at reflux for 3 h. The reaction mixture was cooled to ambient temperature and concentrated to give 5.02 g of N-Dimethylaminomethylene-isonicotinamide. To a solution of [4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine (3.16 g) in methanol (30 mL) and acetic acid (2.5 mL) was added N-Dimethylaminomethylene-isonicotinamide (1.10 g) and the reaction mixture heated at reflux for 72 h. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to provided the title compound (514 mg). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=5.8 Hz, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.76 (m, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.56 (m, 1H), 7.56 (m, 1H), 7.38 (d, J=6.2 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.11 (d, J=9.1 Hz, 2H), 5.42 (s, 2H); MS: (M+H m/z=380.3).
Reaction SMILES: Cl.[C:2]([C:4]1[S:5][C:6]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)#N.[OH2:14].[CH3:15][OH:16]>>[F:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]=[C:4]([C:2]([O:16][CH3:15])=[O:14])[S:5][C:6]=2[CH:12]=1
Reactant: O
Reactant: CO
Reactant: N#Cc1nc2ccc(F)cc2s1
Agent: Cl
Product: COC(=O)c1nc2ccc(F)cc2s1
Yield: 68 %

Procedure:
Hydrogen chloride gas was introduced over 3 minutes into a flask containing a solution of 137.2 mg of 2-cyano-6-fluorobenzothiazole in 2.7 ml of methanol with stirring, the reaction mixture being cooled in an ice-water bath. The reaction mixture was stirred at the same temperature for 2 minutes, and then water was added thereto. The resulting mixture was extracted with ethyl acetate to give an extract which was washed first with water and then an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 106.8 mg (yield 68%) of the title compound as a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2N=N1.[ClH:18].CN(C)CCCN=C=NCC.CN([CH:33]=[O:34])C>>[ClH:18].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:33]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:9])[CH:12]=2)=[O:34])[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(N)c2)CC1
Reaction time: 18 h

Procedure:
Dissolve 3.0 g of the product of Preparation 3, 1.3 g of N-methylpiperazine, 1.9 g of 1-hydroxybenzotriazole and 2.7 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of DMF. Stir for 18 hrs. and then concentrate in vacuo. Dissolve the resultant residue in 100 ml of ethyl acetate, wash with 20 ml of 1N NaHCO3 solution, and 20 ml of saturated sodium chloride solution. Dry the organic layer over MgSO4, filter and concentrate in vacuo. Dissolve 1.68 g of this residue in 10 ml of HCl:dioxane and stir for 2 hrs. Concentrate in vacuo to obtain the title compound as a white solid, mass spec M+=219.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[NH:5]2.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCC1Nc2cc(Br)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(Br)cc2N1C(=O)c1ccc(OC)cc1

Procedure:
7-Bromo-4-ethyl-5-(4-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 42) and p-anisoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 411/413 ([M+H]+); HRMS: calcd for C21H19BrN2O2, 410.0630; found (ESI+), 411.06959.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][CH:23]([O:32][CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:13][C:14]1[C:19]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([O:22][CH2:20][CH3:21])[O:32][CH2:33][CH3:34])[OH:31])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(OCC)c1ccccc1C=O
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)c1ccccc1C(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.5 ml of diisopropylamine in 20 ml of dry tetrahydrofuran at -78° C. was added 11 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred for 20 min. then a solution of 1.15 g of 2-fluoropyridine in 3 ml of tetrahydrofuran was added. The solution was stirred at -78° C. for 30 min then a solution of 2-formylbenzaldehyde diethylacetal in 3 ml of tetrahydrofuran was added dropwise. This solution was stirred for 1 h then warmed to room temperature overnight. The reaction was poured into a 5% solution of sodium carbonate and extracted with two 300 ml portions of ether. The combined organic layers were washed with 300 ml of water then the same volume of brine and dried over sodium sulfate. Evaporation of the solvent afforded (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenyl methanol as a viscous oil; 1H-NMR (200 MHz, CDCl3) d 5.60 (CHOEt).