Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])([O-:3])=[O:2].C(O)(=[O:19])C.C(O)(=O)C.[I:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[OH:19][I:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:14][S:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Reactant: Ic1ccccc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OI(O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 2,4-dinitrobenzenesulfonic acid (16.5 g, 62.0 mmol) in minimum quantity of CH3CN was added at once to a translucent solution of iodobenzene diacetate (10 g, 31.0 mmol) in CH3CN (100 mL). The reaction mixture was stirred for 1 hour at RT. The solution was chilled in ice and then the solution was kept in freezer. The solid was filtered and washed with Et2O to obtain [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) (13.9 g, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.91 (brs, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.56 (dd, J=2.0, and 8.4 Hz, 1H), 8.38 (m, 2H), 8.24 (d, J=8.4 Hz, 1H), 7.88 (m, 1H), 7.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Cl-:9].[Al+3].[Cl-:11].[Cl-].Cl[CH:14]([Si:17]([Cl:20])([Cl:19])[Cl:18])[CH2:15]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[Cl:11])[CH2:14][Si:17]([Cl:20])([Cl:19])[Cl:18]
Reactant: [Cl-]
Reactant: Clc1cccc(Cl)c1
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Agent: [Al+3]
Product: Clc1ccc(C(C[Si](Cl)(Cl)Cl)c2ccc(Cl)cc2Cl)c(Cl)c1
Reaction time: 1 h
Yield: 187.2 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1 above, 49.1 ml (430 mmol) of 1,3-dichlorobenzene and 2.30 g (17.2 mmol) of aluminum chloride were alkylated with 19.40 g (83.5 mmol) of (1,2-dichloroethyl)trichlorosilane for 30 min at 120° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane was distilled, the reaction products were vacuum distilled to give 14.6 g of [2,2-bis(2,4-dichlorophenyl)ethyl]trichlorosilane (bp; 175-180° C./0.5 torr, yield; 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[N+:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N+:16]#[C-:17])#[C-:9].[CH:18]1([CH:24]=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>Cl(O)(=O)(=O)=O>[CH:18]1([C:24]2[N:1]=[C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]3[C:9]=2[NH:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N+:16]#[C-:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCCC1
Reactant: [C-]#[N+]CCCCCC[N+]#[C-]
Reactant: Nc1cnccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: [C-]#[N+]CCCCCCNc1c(C2CCCCC2)nc2cnccn12

Procedure:
Compound (3) was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml 1,6-diisocyanohexane solution (0.2 M, MC), 0.500 ml cyclohexanecarbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:25]1[CH2:35]CN2C(=NCCC2)C[CH2:26]1.C(I)(C)C>C(#N)C>[CH:25]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[C@@H:13](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:14]([OH:16])[CH2:15][C@@H:2]1[OH:1])([CH3:35])[CH3:26]
Reactant: CCCCCC/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CC(C)I
Product: CCCCCC/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O

Procedure:
The title compound 8 was obtained as a colorless oil (36 mg, 95%), following a procedure similar to that disclosed in Example 5 except that the compound 6 obtained above (33 mg, 0.1 mmole) was dissolved in acetonitrile (1 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (40 μl, 0.3 mmole) and then isopropyl iodide (0.19 μl, 1 mmole) were added thereto.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1ncccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: Cc1ncccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 18 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-methyl-pyridin-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 50) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-pyridin-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (0.26 g, 18%); ES+-HRMS m/e calcd for C25H32N6O4 [M+H+] 481.2558 found 481.2556. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.74 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 2.38 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.74 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.39 (dd, Jo=8.1 Hz, Jo=4.7 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.73 (dd, Jo=8.1 Hz, Jm=1.3 Hz, 1H), 8.18 (d, J=2.9 Hz, 1H), 8.45 (dd, Jo=4.7 Hz, Jm=1.3 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13](Cl)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:32])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:32][C:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[O:2][CH3:1])=[O:14])[CH3:30]
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl
Reactant: CCN(N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(NC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The 3-methyloxy-2-phenyl-4-quinolinecarbonyl chloride obtained in Step 1 was dissolved in CH2Cl2 (2 mL) and added dropwise to a solution of Et3N (104 μL, 0.76 mmol) and 1-ethyl-1-phenylhydrazine (102 mg, 0.76 mmol) [Synthesis 1983, 157-158] in CH2Cl2 (3 mL) at 0° C. After stirring at 0° C. for 2 h the cooling bath was removed and the solution stirred at room temperature for 18 h. The solvent was evaporated and the residue taken up in ethyl acetate (20 mL). The organic phase was washed with H2O (2×10 mL), 1N NaOH (20 mL) and brine (20 mL). The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with isohexane:ethyl acetate (2:1). The fractions containing the desired product were combined, evaporated and triturated with diethyl ether. The title compound (159 mg, 53%) was isolated as a colourless solid. 1H NMR (CDCl3, 400 MHz), δ 8.09 (1H, d, J=7.6 Hz), 7.96-7.93 (2H, m), 7.70 (1H, d, J=7.6 Hz), 7.63 (1H, dt, J=7.0 and 1.4 Hz), 7.51-7.45 (6H, m), 7.42-7.28 (4H, m), 5.36-5.35 (1H, broad s), 4.21-4.19 (1H, m), 3.48 (3H, s). MS (ES+) C26H25N3O2 requires: 411, found: 412 (M+H+, 100%).
Reaction SMILES: O[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([OH:20])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:20])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1c(-c2ccccc2)c(O)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1c2ccccc2-c2c(Cl)nc3ccccc3c21
Temperature: 150 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2.65 g (10 mmol) of 2-hydroxy-3-phenylquinoline-4-carboxylic acid (3a) was added into POCl3 (30 mL) and heated at 150° C. for 48 hrs (TLC monitoring). After cooling, the mixture was poured into ice-water (150 mL) to result in precipitation, followed by filtration. The resultant filter cake was poured into 5% NaHCO3(aq) (200 mL) with vigorous stirring for 1 hr, washed with H2O, and dried to give a brown solid, which was recrystallized with EtOH to give the title compound 4a as a red solid (2.31 g, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.IC.I[CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]([CH2:30][CH3:31])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c[nH]c3ccnc(Nc4ccccc4)c3c2=O)cc1
Reactant: CCI
Solvent: CI
Product: CCn1cc(-c2ccc(OC)cc2)c(=O)c2c(Nc3ccccc3)nccc21

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-methoxyphenyl)-1,4-dihydro-4-oxo-5-phenylamino-1,6-naphthyridine and iodomethane was replaced with iodoethane. MS 372 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21]
Reactant: Brc1ccccc1Br
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 75 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with benzaldehyde (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=150 cm) was 6.93 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, (2-bromophenyl)phenylmethanol (GC retention time: 23.7 min) was obtained in 75% yield. 1H NMR (400 MHz, CDCl3) δ: 2.59-2.78 (m, 1H), 6.11 (s, 1H), 7.09 (dt, J=7.6, 2.0 Hz, 1H), 7.19-7.36 (m, 6H), 7.47-7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 74.7, 122.6, 126.9, 127.51, 127.53, 128.25, 128.29, 128.9, 132.6, 141.9, 142.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.N1([C:16]([N:18]2[CH:22]=[CH:21]N=C2)=[O:17])C=CN=C1.Cl.NCC([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:22][NH:18][C:16]3=[O:17])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: O=C1NCC(c2ccc(F)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.665 g, 5 mmol), di(1H-imidazol-1-yl)methanone (0.891 g, 5.5 mmol), TEA (2.09 mL, 15 mmol), aminomethyl-(4-fluorophenyl)ketone hydrochloride (0.948 g, 5 mmol), TEA (1.39 mL, 10 mmol), PdC (10%, 0.02 g) as described in method 1.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28]>O1CCCC1>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:19][C:27]([C:26]([NH:20][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:30])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(=O)NCCCCCCCCCCCCCCCCCC
Yield: 35 %

Procedure:
To a solution of 53.5 g of stearylamine and 15.7 g of pyridine in 599.2 g of tetrahydrofuran was added under room temperature a solution of 12.0 g of oxalyl chloride in 120.0 g of tetrahydrofuran dropwise. After stirring, the mixture was stirred at room temperature for 5 hours. The deposited crystal was filtrated, washed with water and re-crystallized from toluene, to obtain 19.6 g of the intended compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1.[CH2:19]([O:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:30][N:29]([C:31]3[CH:36]=[CH:35][C:34]([C@@H:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=3)[CH2:28]2)=[CH:24][CH:23]=1)[CH3:20].[O:42]1CCOC[CH2:43]1>>[CH2:19]([O:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([C@@H:37]([NH:39][C:43]([NH:12][C:13]4[CH:18]=[CH:17][N:16]=[CH:15][N:14]=4)=[O:42])[CH3:38])=[CH:33][CH:32]=3)[CH2:30]2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: C1COCCO1
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Reactant: Nc1ccncn1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)Nc4ccncn4)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.03 mL (0.20 mmol) DBU and 0.033 g (0.20 mmol) CDT are added to 0.010 g (0.10 mmol) 4-aminopyrimidine in 1.0 mL 1,4-dioxane. The mixture is stirred for 5 min at rt followed by addition of 0.048 g (0.092 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 1.0 mL 1,4-dioxane. The mixture is stirred for 12 h at rt and subsequently concentrated in vacuo. The residue is purified by HPLC (XBridge, ACN/water (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:31])=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH:20]2[O:24][C:23](=[O:25])[NH:22][CH2:21]2)[CH:9]=1)([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br>>[F:28][C:29]([F:42])([F:43])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:33][N:22]1[CH2:21][CH:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:26][CH3:27])[O:24][C:23]1=[O:25]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1

Procedure:
Following the procedure described in EXAMPLE 50, 43 mg of 5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one, enantiomer A, and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the title compound. Analytical HPLC on Chiralpak AS 4.6×250 mm, eluting with 5% isopropanol in heptane at 0.5 mL/min: tR=9.9 min
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[F-].[K+]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: [F-]
Agent: [K+]
Product: O=C(O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 170 °C
Reaction time: 16 h

Procedure:
A mixture of 2-nitrofluorobenzene (1.5 mL, 14.2 mmol, 1.5 equiv) (Aldrich), 4-aminophenyl acetic acid (1.44 g, 9.5 mmol), and KF (0.550 g, 9.5 mmol) is stirred at 170° C. for 16 h in a sealed tube. The reaction mixture is then allowed to cool to rt, triturated in CH2Cl2/MeOH (95:5) and filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (CH2Cl2/MeOH, 97:3→95:5) to provide the title compound as a red solid: ES-MS: 273.0 [M+H]+; single peak at tR=4.44 min (System 1); Rf=0.20 (CH2Cl2/MeOH, 95:5).
Reaction SMILES: [CH:1]12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C(O[C:24]([N:26]1CCC2C(NC2)[CH2:27]1)=O)(C)(C)C.ClC1C=C(C)N=C(N(C)C)[N:36]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C@@H:1]12[N:8]([C:9]3[N:10]=[C:11]([N:26]([CH3:27])[CH3:24])[CH:16]=[C:15]([CH3:14])[N:36]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1cc(Cl)nc(N(C)C)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(N(C)C)nc(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 4-chloro-2-dimethylamino-6-methylpyrimidine for 2-chloro-quinoxaline in Step A. The residue was purified (FCC, SiO2, MeOH (2M NH3)/DCM, 0-10%). MS (ESI) mass calcd. for C13H21N5, 247.34; m/z found 248.1 [M+H]+. 1H NMR (CDCl3): 5.40 (s, 1H), 4.21-4.10 (m, 1H), 3.85 (t, J=7.4, 1H), 3.63-3.49 (m, 2H), 3.33 (s, 1H), 3.09 (d, J=9.3, 7H), 2.97 (dd, J=14.3, 3.8, 1H), 2.71-2.52 (m, 2H), 2.19 (s, 3H), 2.09-1.97 (m, 1H), 1.77-1.59 (m, 1H).
Reaction SMILES: C([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4]1)C.CI.[CH:12]1(C(O)=O)[CH2:15][CH2:14][CH2:13]1.ICCCC>>[CH2:15]([C:5]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C1CCC1
Reactant: CCC1CC(C(=O)O)C1
Solvent: CI
Solvent: CCCCI
Product: CCCCC1(C(=O)O)CCC1

Procedure:
The title compound was prepared as in Example 2A by replacing 3-ethylcyclobutanecarboxylic acid and methyl iodide respectively with cyclobutanecarboxylic acid and 1-iodobutane (Aldrich Chemical Company; Beilstein 1: 123). The resultant product had the following physical characterisics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC[C:16](OCC)=[S:17].[C:21]([O:25]Cl)(C)(C)[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:17][CH:22]1[C:7]2[C:2](=[C:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][CH:6]=2)[NH:1][C:21]1=[O:25]
Reactant: CCOC(=S)CC
Reactant: CC(C)(C)OCl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(-c3ccccc3)cccc21
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
A solution of 25.5 g. (0.15 mole) of 2-aminobiphenyl in 450 ml. of methylene chloride was cooled to -65° C. and treated with 20.1 g. (0.15 mole) of ethyl 2-methylthioacetate. Immediately 16.7 g. (0.155 mole) of t-butylhypochlorite was added dropwise over a 15 min. period while the temperature was maintained at -65° C. The reaction mixture was stirred at -65° C. for 1.5 hr., 15.5 g. (0.155 mole) of triethylamine was added, and the mixture was allowed to warm to ambient temperature. The solution was washed with two 100 ml. portions of water and then concentrated. The residue was mixed with 200 ml. of methanol, the mixture heated to reflux, 40 ml. of 3 N hydrochloric acid was added and the mixture refluxed overnight. The solution was cooled and the resulting solid was collected by filtration, washed with methanol and recrystallized from benzene to yield 25.3 g. (66%) of product as tan needles, m.p. 164°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2F)cc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
As shown in Scheme 1, a well stirred mixture of 4-chloro-2-fluorophenol (1) (14.62 g, 99.8 mmol), 1-fluoro-4-nitrobenzene (2) (12.80 g, 90.72 mmol) and sodium carbonate (19.23 g, 181.43 mmol) in DMF (100 mL) was heated at 100° C. for 12 h. LC/MS showed that the reaction was complete. The cooled reaction mixture was poured into 350 mL of water with stirring and extracted with 2×100 mL of dichloromethane. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by chromatography yielded 24.2 g (99%) of 4-chloro-2-fluoro-1-(4-nitrophenoxy)benzene (3) as a pale yellow solid. 1H NMR CDCl3: 8.25-8.18 (m, 2H); 7.28-7.15 (m, 3H); 7.08-6.97 (m, 2H). Unless otherwise indicated all NMR chemical shifts reported herein are denoted by the delta (δ) scale.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After dissolving 4-aminomethylpiperidine (5.754 ml, 50 mmol) in acetonitrile (200 ml), potassium carbonate (13.82 g, 100 mmol) and benzyl chloride (17.13 g, 150 mmol) were added and the mixture was stirred at 60° C. overnight. Upon completion of the reaction, the reaction mixture was filtered and the solvent was distilled off. A developing solvent (CH2Cl2/MeOH/NEt3 90/5/5) was used for purification by silica gel column chromatography to obtain (1-benzyl-4-piperidyl)methylamine. The compound was identified by LC-MS.